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<script type="text/javascript" src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.boots.min.js"> </script><title>Discovery of Novel General Anesthetics Using Apoferritin as a Surrogate System - Probe Reports from the NIH Molecular Libraries Program - NCBI Bookshelf</title>
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<meta name="citation_inbook_title" content="Probe Reports from the NIH Molecular Libraries Program [Internet]">
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<meta name="citation_title" content="Discovery of Novel General Anesthetics Using Apoferritin as a Surrogate System">
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<meta name="citation_publisher" content="National Center for Biotechnology Information (US)">
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<meta name="citation_date" content="2013/05/08">
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<meta name="citation_author" content="Ganesha Rai">
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<meta name="citation_author" content="Weiming Bu">
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<meta name="citation_author" content="Wendy A. Lea">
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<meta name="citation_author" content="David Liang">
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<meta name="citation_author" content="Brian Weiser">
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<meta name="citation_author" content="Vince Setola">
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<meta name="citation_author" content="Christopher P. Austin">
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<meta name="citation_author" content="Anton Simeonov">
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<meta name="citation_author" content="Ajit Jadhav">
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<meta name="citation_author" content="Roderic Eckenhoff">
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<meta name="citation_author" content="David J. Maloney">
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<meta name="citation_pmid" content="23905204">
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<meta name="DC.Title" content="Discovery of Novel General Anesthetics Using Apoferritin as a Surrogate System">
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<meta name="DC.Type" content="Text">
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<meta name="DC.Publisher" content="National Center for Biotechnology Information (US)">
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<meta name="DC.Contributor" content="Ganesha Rai">
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<meta name="DC.Contributor" content="Weiming Bu">
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<meta name="DC.Contributor" content="Wendy A. Lea">
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<meta name="DC.Contributor" content="David Liang">
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<meta name="DC.Contributor" content="Brian Weiser">
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<meta name="DC.Contributor" content="Vince Setola">
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<meta name="DC.Contributor" content="Christopher P. Austin">
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<meta name="DC.Contributor" content="Anton Simeonov">
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<meta name="DC.Contributor" content="Ajit Jadhav">
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<meta name="DC.Contributor" content="Roderic Eckenhoff">
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<meta name="DC.Contributor" content="David J. Maloney">
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<meta name="DC.Date" content="2013/05/08">
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<meta name="DC.Identifier" content="https://www.ncbi.nlm.nih.gov/books/NBK153223/">
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<meta name="description" content="General anesthetics are administered to more than 40 million patients in the U.S. each year. Their considerable side effects, including toxicity, subtle durable effects, and potential for interaction with the neurodegenerative diseases have prompted the search for novel general anesthetics that may act in a more specific manner and with fewer undesirable features. Evidence has shown that general anesthetics exert their functions by directly interacting with specific proteins, such as the GABAA receptor, a ligand-gated ion channel (LGIC). Photolabeling studies have suggested that general anesthetics bind to LGIC transmembrane regions and allosterically regulating activity. Due to the limited availability of membrane proteins, especially hetero-oligomers like most GABAA receptors, detailed biochemical characterization has been difficult to perform. A surrogate approach was recently developed, where the iron-binding protein apoferritin, was demonstrated to possess not only strong binding capacity for many general anesthetics, but also to have a structural architecture highly resembling that of the GABAA receptor transmembrane region. Thus, identification of small molecules that bind to apoferritin, as detected by the use of a fluorescent reporter, can serve as a first step towards the identification of potent leads for novel general anesthetics. We adopted this apoferritin surrogate system to screen a ~351,000 member library using a highly miniaturized 1536-well based fluorescence assay in concentration-response mode. Using this approach, a novel general anesthetic class of 6-phenylpyridazin-3(2H)-ones was identified and developed, exemplified by ML306 which validated in two in vivo proof-of-concept models which utilized distinct probe delivery routes. The probe compound ML306 exhibits excellent pharmacokinetic properties and represents a useful tool molecule for the exploration of general anesthetic mechanisms and further pre-clinical development of safe anesthetics. ML306 is thus the first example of a candidate general anesthetic discovered through a rational high-throughput approach.">
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<meta name="og:title" content="Discovery of Novel General Anesthetics Using Apoferritin as a Surrogate System">
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<meta name="og:description" content="General anesthetics are administered to more than 40 million patients in the U.S. each year. Their considerable side effects, including toxicity, subtle durable effects, and potential for interaction with the neurodegenerative diseases have prompted the search for novel general anesthetics that may act in a more specific manner and with fewer undesirable features. Evidence has shown that general anesthetics exert their functions by directly interacting with specific proteins, such as the GABAA receptor, a ligand-gated ion channel (LGIC). Photolabeling studies have suggested that general anesthetics bind to LGIC transmembrane regions and allosterically regulating activity. Due to the limited availability of membrane proteins, especially hetero-oligomers like most GABAA receptors, detailed biochemical characterization has been difficult to perform. A surrogate approach was recently developed, where the iron-binding protein apoferritin, was demonstrated to possess not only strong binding capacity for many general anesthetics, but also to have a structural architecture highly resembling that of the GABAA receptor transmembrane region. Thus, identification of small molecules that bind to apoferritin, as detected by the use of a fluorescent reporter, can serve as a first step towards the identification of potent leads for novel general anesthetics. We adopted this apoferritin surrogate system to screen a ~351,000 member library using a highly miniaturized 1536-well based fluorescence assay in concentration-response mode. Using this approach, a novel general anesthetic class of 6-phenylpyridazin-3(2H)-ones was identified and developed, exemplified by ML306 which validated in two in vivo proof-of-concept models which utilized distinct probe delivery routes. The probe compound ML306 exhibits excellent pharmacokinetic properties and represents a useful tool molecule for the exploration of general anesthetic mechanisms and further pre-clinical development of safe anesthetics. ML306 is thus the first example of a candidate general anesthetic discovered through a rational high-throughput approach.">
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id="jr-fip-info-p"><a id="jr-fip-prev" class="wsprkl btn" title="Jump to previuos match">◀</a><button id="jr-fip-matches">no matches yet</button><a id="jr-fip-next" class="wsprkl btn" title="Jump to next match">▶</a></nav></nav></div><div id="jr-epub-interstitial" class="hidden"></div><div id="jr-content"><article data-type="main"><div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><div class="fm-sec"><h1 id="_NBK153223_"><span class="title" itemprop="name">Discovery of Novel General Anesthetics Using Apoferritin as a Surrogate System</span></h1><p class="contribs">Rai G, Bu W, Lea WA, et al.</p><p class="fm-aai"><a href="#_NBK153223_pubdet_">Publication Details</a></p></div></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="_abs_rndgid_" itemprop="description"><p>General anesthetics are administered to more than 40 million patients in the U.S. each year. Their considerable side effects, including toxicity, subtle durable effects, and potential for interaction with the neurodegenerative diseases have prompted the search for novel general anesthetics that may act in a more specific manner and with fewer undesirable features. Evidence has shown that general anesthetics exert their functions by directly interacting with specific proteins, such as the GABA<sub>A</sub> receptor, a ligand-gated ion channel (LGIC). Photolabeling studies have suggested that general anesthetics bind to LGIC transmembrane regions and allosterically regulating activity. Due to the limited availability of membrane proteins, especially hetero-oligomers like most GABA<sub>A</sub> receptors, detailed biochemical characterization has been difficult to perform. A surrogate approach was recently developed, where the iron-binding protein apoferritin, was demonstrated to possess not only strong binding capacity for many general anesthetics, but also to have a structural architecture highly resembling that of the GABA<sub>A</sub> receptor transmembrane region. Thus, identification of small molecules that bind to apoferritin, as detected by the use of a fluorescent reporter, can serve as a first step towards the identification of potent leads for novel general anesthetics. We adopted this apoferritin surrogate system to screen a ~351,000 member library using a highly miniaturized 1536-well based fluorescence assay in concentration-response mode. Using this approach, a novel general anesthetic class of 6-phenylpyridazin-3(2H)-ones was identified and developed, exemplified by <a href="/pcsubstance/?term=ML306[synonym]" ref="pagearea=abstract&targetsite=entrez&targetcat=term&targettype=pubchem">ML306</a> which validated in two <i>in vivo</i> proof-of-concept models which utilized distinct probe delivery routes. The probe compound <a href="/pcsubstance/?term=ML306[synonym]" ref="pagearea=abstract&targetsite=entrez&targetcat=term&targettype=pubchem">ML306</a> exhibits excellent pharmacokinetic properties and represents a useful tool molecule for the exploration of general anesthetic mechanisms and further pre-clinical development of safe anesthetics. <a href="/pcsubstance/?term=ML306[synonym]" ref="pagearea=abstract&targetsite=entrez&targetcat=term&targettype=pubchem">ML306</a> is thus the first example of a candidate general anesthetic discovered through a rational high-throughput approach.</p></div><div class="h2"></div><p><b>Assigned Assay Grant #:</b> <a href="/nuccore/1366655337" class="bk_tag" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=nuccore">MH084836</a></p><p><b>Screening Center Name & PI:</b> NIH Chemical Genomics Center, Christopher P. Austin</p><p><b>Chemistry Center Name & PI:</b> NIH Chemical Genomics Center, Christopher P. Austin</p><p><b>Assay Submitter & Institution:</b> Roderic G. Eckenhoff, Department of Anesthesiology and Critical Care, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA</p><p><b>PubChem Summary Bioassay Identifier (AID):</b>
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<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2385" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2385</a></p><div id="ml306.s1"><h2 id="_ml306_s1_">Probe Structure & Characteristics</h2><div id="ml306.fu1" class="figure"><div class="graphic"><img src="/books/NBK153223/bin/ml306fu1.jpg" alt="Image ml306fu1" /></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml306tu1"><a href="/books/NBK153223/table/ml306.tu1/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figml306tu1" rid-ob="figobml306tu1"><img class="small-thumb" src="/books/NBK153223/table/ml306.tu1/?report=thumb" src-large="/books/NBK153223/table/ml306.tu1/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ml306.tu1"><a href="/books/NBK153223/table/ml306.tu1/?report=objectonly" target="object" rid-ob="figobml306tu1">Table</a></h4></div></div></div><div id="ml306.s2"><h2 id="_ml306_s2_">Recommendations for Scientific Use of the Probe</h2><p><a href="/pcsubstance/?term=ML306[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML306</a> represents a novel probe series which was identified in an HTS campaign using apoferrtin as a surrogate protein for GABA<sub>A</sub> and was subsequently optimized through extensive medicinal chemistry optimization. Importantly, <a href="/pcsubstance/?term=ML306[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML306</a> possesses optimal pharmacokinetic properties for a potential general anesthetic and has demonstrated <i>in vivo</i> efficacy in two models (mouse and tadpole, which utilized distinct probe delivery routes) without exhibiting significant toxicity at the administered doses. The probe is useful to further evaluate the surrogate approach through the use of high-throughput assays for the discovery of novel compounds which exhibit anesthetic activity. Given <a href="/pcsubstance/?term=ML306[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML306</a>’s <i>in vivo</i> profile, it can be used to validate new anesthesia models such as those utilized in medium throughput zebrafish screening (studies in progress). The initial profiling of <a href="/pcsubstance/?term=ML306[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML306</a> presented in this report presents negative data that helps eliminate candidate targets, thus informing future mechanism of action studies, and its deviation from the Meyer-Overton rule make it an interesting candidate for studies in the field of general anesthetics. Finally, given its medicinal chemistry optimization potential, <a href="/pcsubstance/?term=ML306[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML306</a> serves as a starting point for the pre-clinical development of a novel class of general anesthetics.</p></div><div id="ml306.s3"><h2 id="_ml306_s3_">1. Introduction</h2><p>Anesthesia is defined as a state consisting of hypnosis, amnesia and analgesia, operationally measured as a lack of movement in response to what should be a painful stimulus. General anesthetics, drugs that bring about loss of consciousness, are distinct from local anesthetics which block sensation to only a region of the body. Since the first introduction of inhaled anesthetics to American medicine and its first public demonstration in surgery in 1846,[<a class="bibr" href="#ml306.r1" rid="ml306.r1">1</a>] detailed understanding of the molecular basis for their action has remained elusive. It is widely recognized that general anesthetics have significant and potentially lethal side effects. More recently, evidence has emerged that they induce neuronal apoptosis and enhance the generation and aggregation of amyloid β-protein (Aβ),[<a class="bibr" href="#ml306.r2" rid="ml306.r2">2</a>] which could in turn accelerate the onset of neurodegenerative diseases, such as Alzheimer and Parkinson disease.[<a class="bibr" href="#ml306.r3" rid="ml306.r3">3</a>] Although the detailed mechanism of action is not yet clear, in the last few decades, mounting evidence has suggested that anesthetics directly interact with specific protein targets to exert their function.[<a class="bibr" href="#ml306.r4" rid="ml306.r4">4</a>, <a class="bibr" href="#ml306.r5" rid="ml306.r5">5</a>] The identification of several such protein targets, such as GABA<sub>A</sub> receptors, two-pore-domain K<sup>+</sup> channels, and NMDA receptors, along with other plausible targets,[<a class="bibr" href="#ml306.r4" rid="ml306.r4">4</a>] now provides an opportunity for researchers to further characterize host-guest interactions in a more focused manner and by a variety of techniques, with the ultimate goal of developing more specific and safer drugs. Among these molecular targets, the potential importance of ligand-gated ion channels (LGIC), especially the GABA<sub>A</sub> receptors, has been widely suspected and highlighted.[<a class="bibr" href="#ml306.r4" rid="ml306.r4">4</a>]</p><p>GABA<sub>A</sub> receptors are ligand-gated ion channels that belong to the cys-loop receptor neurotransmitter-gated ion channel superfamily. Structurally, this transmembrane receptor/ion channel has five subunits, and each subunit transmembrane domain is characterized as a four-helix-bundle. In addition to the GABA active binding site at an extracellular subunit interface (the receptor’s endogenous ligand), a number of other allosteric sites are known to exist on the receptor. Many drugs are known to modulate the receptor’s activity through these allosteric sites, such as benzodiazepines,[<a class="bibr" href="#ml306.r6" rid="ml306.r6">6</a>] ethanol,[<a class="bibr" href="#ml306.r7" rid="ml306.r7">7</a>] injectable and inhaled anesthetics. Through photolabeling and microsequencing, a potential general anesthetic site at a subunit interface within the transmembrane region (cavities within transmembrane 4-α-helix bundles) was revealed.[<a class="bibr" href="#ml306.r8" rid="ml306.r8">8</a>–<a class="bibr" href="#ml306.r10" rid="ml306.r10">10</a>] Despite continued efforts in characterizing the GABA<sub>A</sub> receptor anesthetic binding site, little development has been made in the past few decades in the discovery of novel and specific general anesthetics. This is mainly because of a lack of overexpression strategies associated with this target and the inability to produce high-resolution structures of putative targets. Consequently, the insolubility and insufficient amount of membrane receptor proteins renders large-scale screens against diverse chemical space impractical, making development of general anesthetics largely an empirical process, as it was 150 years ago.</p><p>Anesthetics have been shown to interact specifically with pure soluble proteins, such as firefly luciferase,[<a class="bibr" href="#ml306.r11" rid="ml306.r11">11</a>] bovine,[<a class="bibr" href="#ml306.r12" rid="ml306.r12">12</a>] or human serum albumin[<a class="bibr" href="#ml306.r13" rid="ml306.r13">13</a>] and porcine odorant binding protein.[<a class="bibr" href="#ml306.r14" rid="ml306.r14">14</a>] Furthermore, apoferritin, a protein that emerged from a recent screen among soluble proteins that possess the signature 4-α-helix bundle motif, displayed not only a strong anesthetic binding ability but also an architectural resemblance to the LGIC transmembrane region to the quaternary level.[<a class="bibr" href="#ml306.r15" rid="ml306.r15">15</a>, <a class="bibr" href="#ml306.r16" rid="ml306.r16">16</a>] Crystal structures of apoferritin complexed with known anesthetics were obtained at high resolution.[<a class="bibr" href="#ml306.r15" rid="ml306.r15">15</a>, <a class="bibr" href="#ml306.r16" rid="ml306.r16">16</a>] Using a number of known general anesthetics, the binding affinities of these compounds with apoferritin have been shown to not only correlate well with their potentiation of GABA responses,[<a class="bibr" href="#ml306.r16" rid="ml306.r16">16</a>, <a class="bibr" href="#ml306.r17" rid="ml306.r17">17</a>] but also their anesthetic potency as measured by mammalian immobility in tadpoles.[<a class="bibr" href="#ml306.r18" rid="ml306.r18">18</a>] This evidence establishes apoferritin as a reasonable model protein to further study the structural and energetic bases of anesthetics recognition. Additionally, apoferritin can be readily procured from commercial sources (such as Sigma-Aldrich, St Louis, MO), making large scale high-throughput screen (HTS) to search for novel general anesthetics more feasible.</p><p>In order to construct an assay to report compound binding to the apoferritin anesthetic binding site, a change in protein activity or other reporter properties can be utilized. As little effect was observed on the intrinsic properties of the protein itself upon binding, a small molecule fluorophore, 1-aminoanthracene (1-AMA), was later identified to not only bind to the apoferritin anesthetic binding site but also exhibit anesthetic properties.[<a class="bibr" href="#ml306.r18" rid="ml306.r18">18</a>] Among several environmentally sensitive fluorophores that were tested, 1-AMA showed enhanced fluorescence emission at 515 nm (excitation max = 380 nm) upon binding to apoferritin[<a class="bibr" href="#ml306.r18" rid="ml306.r18">18</a>] (whereas, for example, 8-anilinonaphthalene sulfonic acid did not show fluorescence enhancement, suggesting a lack of interaction with apoferritin). This finding enabled us to set up a competition binding platform where potential general anesthetics could be identified through a decrease in 1-AMA fluorescence upon its displacement. This approach was subsequently validated using known general anesthetics, with their EC<sub>50</sub>s derived closely approximating their K<sub>D</sub> values obtained in another technique (isothermal titration calorimetry) [<a class="bibr" href="#ml306.r18" rid="ml306.r18">18</a>].</p><p>Current commonly applied general anesthetics include those that are injectable and those that are inhaled. Propofol (CID 4943) is an example of the former category, and its anesthetic properties were discovered more than 30 years ago in a screen of 97 alkylphenols.[<a class="bibr" href="#ml306.r19" rid="ml306.r19">19</a>] Examples of inhaled drugs are halothane (CID 3562), isoflurane (CID 3763) and sevoflurane (CID 5206). These general anesthetics have been shown to bind to apoferritin with affinities in the range of 50 – 300 μM. Herein, we report on the adoption and further execution of the apoferritin/1-AMA fluorescence assay for the interrogation of a 351,367-member library using a quantitative high-throughput screening approach.[<a class="bibr" href="#ml306.r20" rid="ml306.r20">20</a>]</p><div id="ml306.s4"><h3>Prior Art Analysis</h3><p>The inhalational anesthetics are recognized as being exceedingly promiscuous and are associated with undesirable off-pathway effects, and having the lowest therapeutic ratio. Injectable anesthetics such as propofol and etomidate (<a class="figpopup" href="/books/NBK153223/figure/ml306.f1/?report=objectonly" target="object" rid-figpopup="figml306f1" rid-ob="figobml306f1">Figure 1</a>), are more specific but are still associated with significant side effects, as the recent death of pop-star Michael Jackson so tragically emphasizes. All of the currently used injectable anesthetics were discovered empirically, but have been useful in implicating a specific molecular target, the GABA<sub>A</sub> receptor. This screening effort builds on this knowledge by continuing the search for the inherently more specific injectable agents and exploiting the GABA<sub>A</sub>R mimicry of the apoferritin system. It is to be emphasized that this is the first rational, unbiased approach to discovering novel classes of general anesthetics, as current efforts in the field almost exclusively involve structural modifications of known anesthetics to modulate their pharmacokinetic profile and/or physiochemical properties.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml306f1" co-legend-rid="figlgndml306f1"><a href="/books/NBK153223/figure/ml306.f1/?report=objectonly" target="object" title="Figure 1" class="img_link icnblk_img figpopup" rid-figpopup="figml306f1" rid-ob="figobml306f1"><img class="small-thumb" src="/books/NBK153223/bin/ml306f1.gif" src-large="/books/NBK153223/bin/ml306f1.jpg" alt="Figure 1. Example general anesthetics propofol and etomidate." /></a><div class="icnblk_cntnt" id="figlgndml306f1"><h4 id="ml306.f1"><a href="/books/NBK153223/figure/ml306.f1/?report=objectonly" target="object" rid-ob="figobml306f1">Figure 1</a></h4><p class="float-caption no_bottom_margin">Example general anesthetics propofol and etomidate. </p></div></div></div></div><div id="ml306.s5"><h2 id="_ml306_s5_">2. Materials and Methods</h2><p><b>General Methods for Chemistry.</b> All air or moisture sensitive reactions were performed under positive pressure of nitrogen with oven-dried glassware. Anhydrous solvents such as dichloromethane, <i>N,N</i>-dimethylforamide (DMF), acetonitrile, methanol and triethylamine were purchased from Sigma-Aldrich. Preparative purification was performed on a Waters semi-preparative HPLC system. The column used was a Phenomenex Luna C18 (5 micron, 30 × 75 mm) at a flow rate of 45 mL/min. The mobile phase consisted of acetonitrile and water (each containing 0.1% trifluoroacetic acid). A gradient of 10% to 50% acetonitrile over 8 minutes was used during the purification. Fraction collection was triggered by UV detection (220 nm). Analytical analysis was performed on an Agilent LC/MS (Agilent Technologies, Santa Clara, CA). Method 1: A 7 minute gradient of 4% to 100% Acetonitrile (containing 0.025% trifluoroacetic acid) in water (containing 0.05% trifluoroacetic acid) was used with an 8 minute run time at a flow rate of 1 mL/min. A Phenomenex Luna C18 column (3 micron, 3 × 75 mm) was used at a temperature of 50 °C. Method 2: A 3 minute gradient of 4% to 100% Acetonitrile (containing 0.025% trifluoroacetic acid) in water (containing 0.05% trifluoroacetic acid) was used with a 4.5 minute run time at a flow rate of 1 mL/min. A Phenomenex Gemini Phenyl column (3 micron, 3 × 100 mm) was used at a temperature of 50 °C. Purity determination was performed using an Agilent Diode Array Detector for both Method 1 and Method 2. Mass determination was performed using an Agilent 6130 mass spectrometer with electrospray ionization in the positive mode. <sup>1</sup>H NMR spectra were recorded on Varian 400 MHz spectrometers. Chemical shifts are reported in ppm with undeuterated solvent (DMSO-d<sub>6</sub> at 2.49 ppm) as internal standard for DMSO-d<sub>6</sub> solutions. All of the analogs tested in the biological assays have purity greater than 95%, based on both analytical methods. High resolution mass spectrometry was recorded on Agilent 6210 Time-of-Flight LC/MS system. Confirmation of molecular formula was accomplished using electrospray ionization in the positive mode with the Agilent Masshunter software (version B.02).</p><div id="ml306.s6"><h3>2.1. Assays</h3><div id="ml306.s7"><h4>qHTS assay using apoferritin and 1-AMA</h4><p>The primary qHTS assay was performed in PBS, pH 7.2, supplemented with 0.1% PEG 400. Three μL of reagents (free 1-AMA; 50% saturated solution of 1-aminoanthracene in the assay buffer) in columns 3, 4 as negative control and 1-AMA/apoferritin mixture (10 μM apoferritin, final concentration; 50% 1-AMA, final concentration) in columns 1, 2, 5–48 was dispensed into 1536-well Greiner black assay plates. Compounds (23 nL) was transferred via Kalypsys pintool equipped with 1,536-pin array (10 nL slotted pins, V&P Scientific, San Diego, CA). Titration of the positive control, propofol, was delivered via pin transfer from separate control plates to the 2<sup>nd</sup> column of each assay plate. The starting concentration of the control, dissolved in DMSO, was 160 mM, followed by two-fold dilution points in duplicate, for a total of 16 concentrations. The plates were incubated at room temperature for 10 min before being read on an EnVision HTS multilabel reader (Perkin-Elmer, Waltham, MA) (end point read, 3min/plate) using a Fura2 BFP excitation filter (380 nm, bandwidth 10 nm) and fluorescein emission filter (535 nm, bandwidth 25 nm) set (see <a class="figpopup" href="/books/NBK153223/table/ml306.t1/?report=objectonly" target="object" rid-figpopup="figml306t1" rid-ob="figobml306t1">Table 1</a> for protocol steps) coupled with a LANCE/DELFIA dichroic mirror with a cutoff wavelength at 400 nm. Two dispensers and two EnVisions were applied to facilitate the screen. Throughout the screen, reagent bottles and all liquid lines were made light-tight to minimize reagent degradation. All screening operations were performed on a fully integrated robotic system (Kalypsys, San Diego, CA) containing one RX-130 and two RX-90 anthropomorphic robotic arms (Staubli, Duncan, SC).</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml306t1"><a href="/books/NBK153223/table/ml306.t1/?report=objectonly" target="object" title="Table 1" class="img_link icnblk_img figpopup" rid-figpopup="figml306t1" rid-ob="figobml306t1"><img class="small-thumb" src="/books/NBK153223/table/ml306.t1/?report=thumb" src-large="/books/NBK153223/table/ml306.t1/?report=previmg" alt="Table 1. Apoferritin qHTS assay protocol." /></a><div class="icnblk_cntnt"><h4 id="ml306.t1"><a href="/books/NBK153223/table/ml306.t1/?report=objectonly" target="object" rid-ob="figobml306t1">Table 1</a></h4><p class="float-caption no_bottom_margin">Apoferritin qHTS assay protocol. </p></div></div><p>Library plates were screened starting from 6.9 to 153 μM, with the top concentration achieved through a “double-dipping” step of the highest concentration. This was done to achieve a higher compound concentration, and a total concentration series of 5 was performed against 1-AMA/apoferritin. Vehicle-only plates, with DMSO being pin-transferred to the entire 5–48 compound area, was inserted uniformly at the beginning and the end of each library in order to monitor for and record any shifts in the background. Activity was computed as the normalized fluorescence response relative to free 1-AMA and 1-AMA/apoferritin complex values. Concentration-effect relationships were derived by using publicly-available curve fitting algorithms developed in-house. A four parameter Hill equation was used to fit the concentration-response data by minimizing the residual error between the modeled and observed responses. (BioAssay <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2323" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2323</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/485281" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 485281</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/489008" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 489008</a>).</p></div><div id="ml306.s8"><h4>Isothermal titration calorimetry (ITC)</h4><p>In order to further triage primary hits identified from the qHTS screen, ITC was utilized to evaluate direct binding signatures between filtered compounds and apoferritin and provide a complete thermodynamic characterization of selected compounds. ITC was performed on a MicroCal VP-ITC instrument (<a href="http://microcal.com/" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">http://microcal.com/</a>, Northampton, MA). Compound powders were obtained directly from commercial sources, and ~1 mM solution was prepared in the qHTS assay buffer without DMSO. This was achieved by vigorous shaking and repetitive sonication of the solution, followed by filtration through 0.2 μm PTFE syringe filters to remove compound aggregates. Concentrations were then determined using absorption spectroscopy based on standards prepared in organic solvents. The ITC sample cell (1.43 mL) was loaded with apoferritin (also in the qHTS assay buffer; the reference cell contained water) while the syringe was loaded with compounds. Each ligand was titrated into the sample cell from the syringe containing 286 μL of ligand solution. Additional titrations were performed for correction of heat of dilution, including buffer into buffer, buffer into protein and compound into buffer. At least duplicate experiments were performed at room temperature, and data were corrected and fitted to single class binding models using Origin Software.</p></div><div id="ml306.s9"><h4>GABAa [<sup>3</sup>H] flunitrazepam Binding Assay</h4><p>[<sup>3</sup>H] flunitrazepam (specific activity 84.5Ci/mmol) was purchased from Perkin-Elmer (Life sciences Inc., Boston, MA) and dissolved in 50 mM Tris-HCl buffer, pH7.4. The piglet brain homogenate was used for the assay. 0.5 mg of membrane protein was incubated in Tris–HCl buffer (50 mM, pH 7.4) in a final volume of 500 μl with or without the 10μM compound in the presence of 1 nM of [<sup>3</sup>H]flunitrazepam at 4 °C for 60 min. Nonspecific binding was determined by carrying out incubations in the presence of 10μM lorazepam. Binding studies were terminated by separating the membrane material from the incubation solution using vacuum filtration. The samples were washed three times with ice-cold Tris–HCl buffer (50 mM, pH 7.4). Then the filters were transferred to scintillation vials and subjected to the scintillation counting (Tri-Carb 2800 TR, Perkin Elmer Inc, Shelto, CT) after additional of 10 mL scintillation fluid. The scintillation counting of compounds was compared with that of [<sup>3</sup>H]flunitrazepam.</p></div><div id="ml306.s10"><h4>Assay for general anesthetic phenotype in <i>Xenopus</i> Tadpoles</h4><p>Pre-limb bud Xenopus tadpoles were obtained in large batches from Nasco, Inc. Batches of 10 tadpoles were placed in 20 mm Petri dishes with approximately 20 ml of pond water (“pond water” is approximately a 20-fold dilution of Ringers saline solution). Compounds were added to the pond water from DMSO stock to obtain 100, 10 and 1 μM concentrations. Tadpoles were then incubated with these solutions for 1 hour, and then scored for “anesthesia”. Anesthesia in this case is lack of movement in response to a sharp tap on the Petri dish lid, i.e., a lack of startle response. This correlates well to the loss of righting reflex in rodents and the loss of consciousness in humans. The pond water is then changed, and the return of a startle response is monitored for 24 hours. Immobility at 24 hours is considered death (designated as “toxicity” in <a class="figpopup" href="/books/NBK153223/table/ml306.t2/?report=objectonly" target="object" rid-figpopup="figml306t2" rid-ob="figobml306t2">Tables 2</a>–<a class="figpopup" href="/books/NBK153223/table/ml306.t5/?report=objectonly" target="object" rid-figpopup="figml306t5" rid-ob="figobml306t5">5</a>).</p><p>All top active compounds were screened at 100 μM, and those producing 100% immobility at 1 hour were screened again at 10 μM, and then 1 μM respectively. Compounds producing delayed death without immobility, and those producing death at 1 and 10 μM concentrations were eliminated.</p></div><div id="ml306.s11"><h4><i>In Vivo</i> Anesthesia Model (Mouse species)</h4><p>Compounds showing activity at 1 μM were produced in larger quantity for mouse experiments. Solvating these compounds in DMSO for intravenous injections was not possible because the volumes necessary for reliable injection (50–100 μL) borders on the LD<sub>50</sub> for mice. Therefore, a β cyclodextrin formulation was used. A 60% (w/v) solution of (2-hydroxypropyl)-β-cyclodextrin (HP-β-CD) in 0.9% sterile sodium chloride (pH 7.4) was used as the vehicle. <a href="/pcsubstance/?term=ML306[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML306</a> was dissolved to achieve 28.5 mg/mL (54.2 mM). Injection volumes were calculated and rounded to the nearest 2.5 μL. Female C57BL/6 mice (18.6–25.3 g) were restrained and injections were made intravenously into the tail vein using a 30 gauge needle. With onset of sedation, mice were placed on their backs, and the time until righting reflex (3 of 4 paws on the ground) was regained was recorded.</p></div></div><div id="ml306.s12"><h3>2.2. Probe Chemical Characterization</h3><div id="ml306.fu2" class="figure bk_fig"><div class="graphic"><img src="/books/NBK153223/bin/ml306fu2.jpg" alt="Probe Characterization of ML306." /></div><h3><span class="title">Probe Characterization of ML306</span></h3><div class="caption"><p>*Purity >95% as determined by LC/MS and <sup>1</sup>H NMR analyses.</p></div></div><p><b>2-(6-Oxo-3-p-tolylpyridazin-1(6H)-yl)-N-phenethylacetamide:</b> LC-MS Retention Time: t<sub>1</sub> (Method 1) = 5.440 min and t<sub>2</sub> (Method 2) = 3.466 min; <sup>1</sup>H NMR (400 MHz, DMSO-<i>d</i><sub>6</sub>) δ; 2.36 (s, 3 H), 2.73 (t, <i>J</i> = 7.4 Hz, 2 H), 3.27 – 3.35 (m, 2 H), 4.72 (s, 2 H), 7.05 (d, <i>J</i> = 9.8 Hz, 1 H), 7.17 – 7.25 (m, 3 H), 7.29 (m, 4 H), 7.77 (d, <i>J</i> = 8.2 Hz, 2 H), 8.05 (d, <i>J</i> = 9.8 Hz, 1 H) and 8.24 (m, 1 H); <sup>13</sup>C NMR (400 MHz, DMSO-<i>d</i><sub>6</sub>) δ; 20.8, 35.0, 54.3, 125.7, 126.1, 128.3, 128.6, 129.5, 129.6, 131.0, 131.5, 139.0, 139.3, 143.5, 158.9, 166.2; HRMS (ESI) <i>m/z</i> (M+H)<sup>+</sup> calcd. for C<sub>21</sub>H<sub>22</sub>N<sub>3</sub>O<sub>3</sub>, 348.1707; found 348.1708.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml306tu2"><a href="/books/NBK153223/table/ml306.tu2/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figml306tu2" rid-ob="figobml306tu2"><img class="small-thumb" src="/books/NBK153223/table/ml306.tu2/?report=thumb" src-large="/books/NBK153223/table/ml306.tu2/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ml306.tu2"><a href="/books/NBK153223/table/ml306.tu2/?report=objectonly" target="object" rid-ob="figobml306tu2">Table</a></h4></div></div><div id="ml306.f2" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%202.%20List%20and%20structures%20of%20probe%20and%20related%20analogs%20that%20have%20been%20submitted%20to%20the%20MLSMR.&p=BOOKS&id=153223_ml306f2.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK153223/bin/ml306f2.jpg" alt="Figure 2. List and structures of probe and related analogs that have been submitted to the MLSMR." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 2</span><span class="title">List and structures of probe and related analogs that have been submitted to the MLSMR</span></h3></div></div><div id="ml306.s13"><h3>2.3. Probe Preparation</h3><div id="ml306.s14"><h4>Preparation of
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2-(3-oxo-6-<i>p</i>-tolylpyridazin-1(3H)-yl)-<i>N</i>-phenethylacetamide.TFA (ML306) as depicted in Scheme 1</h4><div id="ml306.f11" class="figure bk_fig"><div class="graphic"><img src="/books/NBK153223/bin/ml306f11.jpg" alt="Scheme 1. Synthetic route to probe ML306." /></div><h3><span class="label">Scheme 1</span><span class="title">Synthetic route to probe <b>ML306</b></span></h3></div><div id="ml306.f12" class="figure bk_fig"><div class="graphic"><img src="/books/NBK153223/bin/ml306f12.jpg" alt="Scheme 2. General synthetic routes to intermediates and analogs." /></div><h3><span class="label">Scheme 2</span><span class="title">General synthetic routes to intermediates and analogs</span></h3></div><p>A mixture of 2-(3-oxo-6-(<i>p</i>-tolyl)pyridazin-1(3H)-yl)acetic acid (1.2 g, 4.9 mmol, 1 eq.), EDC (1.88 g, 9.8 mmol, 1.5 eq.) and HOBT (0.75 g, 4.9 mmol, 1 eq.) in DMF (10 mL) was stirred at room temperature for 5 min. Diisopropylethylamine (0.86 mL, 4.9 mmol, 1 eq.) and 2-phenylethanamine (0.75 mL, 5.9 mmol, 1.2 eq.) were then added and stirred at room temperature for 1 hr. The reaction mixture was filtered and the filtrate containing the product was purified via reverse phase chromatography to give 2-(3-oxo-6-(<i>p</i>-tolyl)pyridazin-1(3H)-yl)-<i>N</i>-phenethyl-acetamide TFA (<a href="/pcsubstance/?term=ML306[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML306</a>) as a white solid.</p></div><div id="ml306.s15"><h4>General procedures for the alkylation of 6-Chloro/tolyl pyridazin-3-one</h4><p>6-Chloropyridazin-3(2H)-one or 6-(<i>p</i>-tolyl)pyridazin-3(2H)-one (33.2 mmol, 1 eq.), <i>tert</i>-butyl 2-bromoacetate (6.4 mL, 43 mmol, 1.3 eq.) and potassium carbonate (5.96 g, 43 mmol, 1.3 eq.) in acetonitrile (50 mL) was refluxed for 4 hr. The reaction mixture was filtered through a pad of celite and washed with ethyl acetate The filtrate was concentrated and the crude product was purified on via biotage<i>®</i> flash chromatography eluting with 40 % ethyl acetate in hexanes.</p></div><div id="ml306.s16"><h4>General procedure for the removal of <i>t</i>-butyl group</h4><p>A solution of containing <i>t</i>-butyl 2-(6-substituted-6-oxopyridazin-1(3H)-yl)acetate (16 mmol) in dichloromethane (30 mL) was added TFA (20 mL) and the reaction mixture was stirred at room temperature for 1 hr. Excess solvent was removed under diminished pressure and the oily product was triturated with water. The white precipitate formed was collected by filtration and dried under vacuum to get the pure product.</p></div><div id="ml306.s17"><h4>General procedure the for amide coupling</h4><p>A mixture of 2-(3-oxo-6-(p-tolylpyridazin-1(3H)-yl)acetic acid (0.41 mmol, 1 eq.), EDC (0.16 g, 0.82 mmol, 2 eq.) and HOBT (0.063 g, 0.41 mmol, 1 eq.) in DMF (2 mL was stirred at room temperature for 5 min. The amine (0.49 mmol, 1.2 eq.) were then added and stirred at room temperature for 1 hr. The reaction mixture was filtered and the filtrate containing the product was purified via reversed phase chromatography.</p></div><div id="ml306.s18"><h4>General procedure the Suzuki coupling</h4><p>A mixture of 2-(6-chloro-3-oxopyridazin-1(3H)-yl)-<i>N</i>-phenethylacetamide (0.1 g, 0.34 mmol, 1 eq.), representative boronic acid (0.41 mmol, 1.2 eq), K<sub>2</sub>CO<sub>3</sub> (0.14 g, 1.03 mmol, 3 eq.) and PEPPSI-IPr catalyst (2.4 mg, 3.43 μmol, 1 mol %) in dioxane (2 mL) was degassed with argon for 2–3 minutes and heated 110 °C in microwave for 30 min. The solvent was evaporated using a continuous stream of N<sub>2</sub> and the crude product was re-dissolved in DMF. The solution was then stirred with silica bound metal scavenger and filtered through the thiol cartridge to remove any metal impurities. The crude product was purified via reversed phase chromatography to give pure compound.</p></div></div></div><div id="ml306.s19"><h2 id="_ml306_s19_">3. Results</h2><div id="ml306.s20"><h3>3.1. Summary of Screening Results</h3><p>Initially, the assay was validated in an offline pilot screen using the library of pharmacologically active compound (LOPAC<sup>1280</sup>) collection[<a class="bibr" href="#ml306.r21" rid="ml306.r21">21</a>] where fluorescence was monitored on a ViewLux CCD camera-based microplate imager (PerkinElmer, Waltham, MA). Samples were excited at 340 nm and emission was collected at 530 nm. The excitation filter that comes with the ViewLux imager (340 nm) does not match the maximum excitation wavelength of 1-AMA (380 nm) very well. The lower excitation wavelength provided by the ViewLux imager resulted in an enhanced compound interference.[<a class="bibr" href="#ml306.r22" rid="ml306.r22">22</a>, <a class="bibr" href="#ml306.r23" rid="ml306.r23">23</a>] In order to further alleviate compound interference, the assay was further optimized by using an Envision multilabel reader, which was equipped with an excitation filter centered at 380 nm and an emission filter centered at 535 nm, better matching the spectral property of our assay reporter, 1-AMA. To further validate this approach, the top concentration of the LOPAC<sup>1280</sup> collection was tested using both instruments. It was found that red shifting the excitation wavelength by as little as 40 nm was accompanied by a significant reduction in the number of interfering compounds, identified as those whose response was above the positive controls (see <a class="figpopup" href="/books/NBK153223/figure/ml306.f4/?report=objectonly" target="object" rid-figpopup="figml306f4" rid-ob="figobml306f4">Figure 4A</a> for Envision data and B for Viewlux data).</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml306f4" co-legend-rid="figlgndml306f4"><a href="/books/NBK153223/figure/ml306.f4/?report=objectonly" target="object" title="Figure 4" class="img_link icnblk_img figpopup" rid-figpopup="figml306f4" rid-ob="figobml306f4"><img class="small-thumb" src="/books/NBK153223/bin/ml306f4.gif" src-large="/books/NBK153223/bin/ml306f4.jpg" alt="Figure 4. Optimization of the apoferritin/1-AMA fluorescence assay." /></a><div class="icnblk_cntnt" id="figlgndml306f4"><h4 id="ml306.f4"><a href="/books/NBK153223/figure/ml306.f4/?report=objectonly" target="object" rid-ob="figobml306f4">Figure 4</a></h4><p class="float-caption no_bottom_margin">Optimization of the apoferritin/1-AMA fluorescence assay. A) and B) are scatter plots of the top LOPAC concentration plate run on Envision (ex: 380 nm/em: 535 nm) and on ViewLux (ex: 340 nm/em: 530 nm), respectively; C) Effect of 0.1% PEG 400 in an AmpC <a href="/books/NBK153223/figure/ml306.f4/?report=objectonly" target="object" rid-ob="figobml306f4">(more...)</a></p></div></div><p>One downside of using the EnVision reader for end point fluorescence assays is that it takes longer per plate (3 min on Envision vs. <1 min on ViewLux). For the large collection qHTS screen, this was partially compensated through the utilization of two identical EnVision readers, whose performance will be addressed in <a href="#ml306.s21">section (3.2)</a>.</p><p>Another aspect that we investigated during assay optimization was the need to minimize the effect of compound aggregation and to reduce assay false positives caused by such mechanism. Tween-20, a common detergent used for this purpose, was tested, but it showed interference with our assay readout. Therefore, PEG400 was further evaluated over a few concentrations to examine its effect on assay signal window and assay Z’ [<a class="bibr" href="#ml306.r24" rid="ml306.r24">24</a>]. It was found that at 0.1% concentration, PEG400 had minimal effect on the assay S:B or Z’, but a 1% concentration led to a decrease of S:B by more than 30% (data not shown). Additionally, the effect of 0.1% PEG400 was validated in an AmpC β-lactamase absorbance assay [<a class="bibr" href="#ml306.r25" rid="ml306.r25">25</a>], using a known aggregator, TIPP [<a class="bibr" href="#ml306.r26" rid="ml306.r26">26</a>]. It can be seen from <a class="figpopup" href="/books/NBK153223/figure/ml306.f4/?report=objectonly" target="object" rid-figpopup="figml306f4" rid-ob="figobml306f4">Figure 4C</a> that the addition of 0.1% PEG 400 exerted a similar effect as that of 0.01% Triton in the assay in that the apparent inhibitory effect observed in the very left figure in panel C was unmasked and TIPP was revealed as an inactive.</p><p>The above assay was used in a fully-integrated robotic screen of a library containing 351, 367 compounds tested at five concentrations ranging from 6.9 to 153 μM in a qHTS mode.[<a class="bibr" href="#ml306.r20" rid="ml306.r20">20</a>] The flexibility of choosing a biologically relevant compound concentration range for screening purpose is offered by the qHTS paradigm,[<a class="bibr" href="#ml306.r27" rid="ml306.r27">27</a>] and in this particular case, this range was selected based on the sensitivity of the assay. In other words, the relatively high concentration of apoferritin applied in the assay (10 μM) suggested that the lowest detection limit of assay would be in that range, rendering the screen of lower concentration plates (low single digit micromolar to submicromolar) unnecessary.</p><p>The screen was completed within 4 days. An average Z’ of 0.76 was achieved across the 1,509 plates screened, with those read on Envision reader 1 giving slightly higher Z’ than Envision reader 2 (<a class="figpopup" href="/books/NBK153223/figure/ml306.f5/?report=objectonly" target="object" rid-figpopup="figml306f5" rid-ob="figobml306f5">Figure 5A</a>). Low signal window plates were rejected, and in total, 1,228 plates passed quality control and were included in the final dataset. Data were further corrected against DMSO-containing plates and normalized against positive and negative controls for the establishment of dose-dependent concentration curves for each compound. EC<sub>50</sub> of each compound was directly determined from the primary screen. <a class="figpopup" href="/books/NBK153223/figure/ml306.f5/?report=objectonly" target="object" rid-figpopup="figml306f5" rid-ob="figobml306f5">Figure 5B</a> shows a 3D activity plot of the control titration (in green) along with potential inhibitors of apoferritin. The control propofol yielded a highly reproducible EC<sub>50</sub> with an average value of 23 μM. Samples that produced full or partial curves and had maximum response greater than six sigma activity (~60%) were declared as top actives. Additionally, top actives from normalized and uncorrected curve fits were included. All other compounds that resulted in signal decrease were grouped as weak inhibitors or inconclusives. Out of all the compounds screened, 0.64% were classified as top actives (<a class="figpopup" href="/books/NBK153223/figure/ml306.f5/?report=objectonly" target="object" rid-figpopup="figml306f5" rid-ob="figobml306f5">Figure 5B</a>, dark blue) and 6.7% were weak inhibitors or inconclusive (<a class="figpopup" href="/books/NBK153223/figure/ml306.f5/?report=objectonly" target="object" rid-figpopup="figml306f5" rid-ob="figobml306f5">Figure 5B</a>, light blue). Total actives shown in the 3D plot represent 7.3% of the entire chemical library screened.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml306f5" co-legend-rid="figlgndml306f5"><a href="/books/NBK153223/figure/ml306.f5/?report=objectonly" target="object" title="Figure 5" class="img_link icnblk_img figpopup" rid-figpopup="figml306f5" rid-ob="figobml306f5"><img class="small-thumb" src="/books/NBK153223/bin/ml306f5.gif" src-large="/books/NBK153223/bin/ml306f5.jpg" alt="Figure 5. Summary of apoferritin/1-AMA screening results." /></a><div class="icnblk_cntnt" id="figlgndml306f5"><h4 id="ml306.f5"><a href="/books/NBK153223/figure/ml306.f5/?report=objectonly" target="object" rid-ob="figobml306f5">Figure 5</a></h4><p class="float-caption no_bottom_margin">Summary of apoferritin/1-AMA screening results. A) scatter plot of Z’ values of the apoferritin/1-AMA assay across all screened plates (average Z’: 0.76); B) 3D plot of qHTS data with control titrations (shown in green), high confidence <a href="/books/NBK153223/figure/ml306.f5/?report=objectonly" target="object" rid-ob="figobml306f5">(more...)</a></p></div></div><p>A total of 2,563 top actives were clustered using Leadscope structural fingerprints. A tanimoto coefficient of 0.7 was used for clustering, and 261 clusters were identified. Additionally, 176 structurally diverse singletons were found. Compounds were chosen for follow-up based on structural diversity, structure activity relationships and property distributions such as MW, logP, and ligand efficiency. A collection of top 700 cherrypicked compounds were retested in the primary qHTS assay for activity confirmation. Ligand efficiency,[<a class="bibr" href="#ml306.r28" rid="ml306.r28">28</a>] a measure of binding affinity per heavy atom in a compound, was computed for all 700 compounds, and top 80 compounds were selected for confirmation in ITC assay for orthogonal assay (see <a class="figpopup" href="/books/NBK153223/figure/ml306.f6/?report=objectonly" target="object" rid-figpopup="figml306f6" rid-ob="figobml306f6">Figure 6</a> for assay work flow chart).</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml306f6" co-legend-rid="figlgndml306f6"><a href="/books/NBK153223/figure/ml306.f6/?report=objectonly" target="object" title="Figure 6" class="img_link icnblk_img figpopup" rid-figpopup="figml306f6" rid-ob="figobml306f6"><img class="small-thumb" src="/books/NBK153223/bin/ml306f6.gif" src-large="/books/NBK153223/bin/ml306f6.jpg" alt="Figure 6. Critical path work flow for the identification of small molecule inhibitors of apoferritin/1-AMA interaction that possess general anesthetic properties." /></a><div class="icnblk_cntnt" id="figlgndml306f6"><h4 id="ml306.f6"><a href="/books/NBK153223/figure/ml306.f6/?report=objectonly" target="object" rid-ob="figobml306f6">Figure 6</a></h4><p class="float-caption no_bottom_margin">Critical path work flow for the identification of small molecule inhibitors of apoferritin/1-AMA interaction that possess general anesthetic properties. </p></div></div><p>Of the 80 compounds, the 6-phenylpyridazin-3(2H)-one chemotype, as exemplified by CID-3244374 (<a class="figpopup" href="/books/NBK153223/figure/ml306.f7/?report=objectonly" target="object" rid-figpopup="figml306f7" rid-ob="figobml306f7">Figure 7</a>), emerged as highest in ligand efficiency and had nascent SAR directly from the primary screen. The 6-phenylpyridazin-3(2H)-one chemotype and its derivatives in the primary screen exhibited high ligand efficiency and good physicochemical properties. Given the compounds’ profiles and the initial qHTS SAR, the series was chosen for resynthesis, reconfirmation of purified actives, and confirmation in tadpole <i>in vivo</i> assays.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml306f7" co-legend-rid="figlgndml306f7"><a href="/books/NBK153223/figure/ml306.f7/?report=objectonly" target="object" title="Figure 7" class="img_link icnblk_img figpopup" rid-figpopup="figml306f7" rid-ob="figobml306f7"><img class="small-thumb" src="/books/NBK153223/bin/ml306f7.gif" src-large="/books/NBK153223/bin/ml306f7.jpg" alt="Figure 7. Initial hit identified from the qHTS and validated using apoferritin and tadpole assays." /></a><div class="icnblk_cntnt" id="figlgndml306f7"><h4 id="ml306.f7"><a href="/books/NBK153223/figure/ml306.f7/?report=objectonly" target="object" rid-ob="figobml306f7">Figure 7</a></h4><p class="float-caption no_bottom_margin">Initial hit identified from the qHTS and validated using apoferritin and tadpole assays. </p></div></div></div><div id="ml306.s21"><h3>3.2. Dose Response Curves for Probe</h3><div id="ml306.f8" class="figure bk_fig"><div class="graphic"><img src="/books/NBK153223/bin/ml306f8.jpg" alt="b2-g71" /></div><h3><span class="label">Figure 8</span><span class="title">Isothermal Titration Calorimetry (ITC) of the HSAF interaction with ML306 (K<sub>D</sub> = 8.2 μM)</span></h3></div></div><div id="ml306.s22"><h3>3.3. Scaffold/Moiety Chemical Liabilities</h3><p>One of the strengths of <a href="/pcsubstance/?term=ML306[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML306</a> and its probe series is the general drug-like nature of the 6-phenylpyridazin-3(2H)-one chemotype. Like many anesthetics, the probe and analogs are small in molecular weight and overall size and possess good physicochemical properties such as low number of hydrogen bond acceptors and donors and low log P. <a href="/pcsubstance/?term=ML306[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML306</a> does not contain any reactive functional groups and was found to be stable in both mouse plasma and PBS buffer conditions at various pH conditions. The probe has good <i>in vitro</i> ADME properties as well as good <i>in vivo</i> PK profile; microsomal stability with both human and mouse liver microsomes was assessed and <a href="/pcsubstance/?term=ML306[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML306</a> found to have a short half-life that is ideal for anesthetics. Lastly, the probe compound was found to have good BBB penetration. Overall, <a href="/pcsubstance/?term=ML306[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML306</a> represents an excellent starting point for further pre-clinical development of general anesthetics.</p></div><div id="ml306.s23"><h3>3.4. SAR Tables</h3><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml306t2"><a href="/books/NBK153223/table/ml306.t2/?report=objectonly" target="object" title="Table 2" class="img_link icnblk_img figpopup" rid-figpopup="figml306t2" rid-ob="figobml306t2"><img class="small-thumb" src="/books/NBK153223/table/ml306.t2/?report=thumb" src-large="/books/NBK153223/table/ml306.t2/?report=previmg" alt="Table 2. General anesthetic profile in tadpoles and inhibition of 1-AMA/Apofferitin interaction." /></a><div class="icnblk_cntnt"><h4 id="ml306.t2"><a href="/books/NBK153223/table/ml306.t2/?report=objectonly" target="object" rid-ob="figobml306t2">Table 2</a></h4><p class="float-caption no_bottom_margin">General anesthetic profile in tadpoles and inhibition of 1-AMA/Apofferitin interaction. Representative Analogs (modification at 6-position of the pyridazin-3-one). All analogs were synthesized at NCGC </p></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml306t3"><a href="/books/NBK153223/table/ml306.t3/?report=objectonly" target="object" title="Table 3" class="img_link icnblk_img figpopup" rid-figpopup="figml306t3" rid-ob="figobml306t3"><img class="small-thumb" src="/books/NBK153223/table/ml306.t3/?report=thumb" src-large="/books/NBK153223/table/ml306.t3/?report=previmg" alt="Table 3. General anesthetic profile in tadpoles and inhibition of 1-AMA/Apofferitin interaction." /></a><div class="icnblk_cntnt"><h4 id="ml306.t3"><a href="/books/NBK153223/table/ml306.t3/?report=objectonly" target="object" rid-ob="figobml306t3">Table 3</a></h4><p class="float-caption no_bottom_margin">General anesthetic profile in tadpoles and inhibition of 1-AMA/Apofferitin interaction. Representative Analogs (modification of the core). All analogs were synthesized at NCGC </p></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml306t4"><a href="/books/NBK153223/table/ml306.t4/?report=objectonly" target="object" title="Table 4" class="img_link icnblk_img figpopup" rid-figpopup="figml306t4" rid-ob="figobml306t4"><img class="small-thumb" src="/books/NBK153223/table/ml306.t4/?report=thumb" src-large="/books/NBK153223/table/ml306.t4/?report=previmg" alt="Table 4. General anesthetic profile in tadpoles and APO inhibition." /></a><div class="icnblk_cntnt"><h4 id="ml306.t4"><a href="/books/NBK153223/table/ml306.t4/?report=objectonly" target="object" rid-ob="figobml306t4">Table 4</a></h4><p class="float-caption no_bottom_margin">General anesthetic profile in tadpoles and APO inhibition. Representative Analogs (modification of the side chain). All analogs were synthesized at NCGC </p></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml306t5"><a href="/books/NBK153223/table/ml306.t5/?report=objectonly" target="object" title="Table 5" class="img_link icnblk_img figpopup" rid-figpopup="figml306t5" rid-ob="figobml306t5"><img class="small-thumb" src="/books/NBK153223/table/ml306.t5/?report=thumb" src-large="/books/NBK153223/table/ml306.t5/?report=previmg" alt="Table 5. General anesthetic profile in tadpoles and inhibition of 1-AMA/Apofferitin interaction." /></a><div class="icnblk_cntnt"><h4 id="ml306.t5"><a href="/books/NBK153223/table/ml306.t5/?report=objectonly" target="object" rid-ob="figobml306t5">Table 5</a></h4><p class="float-caption no_bottom_margin">General anesthetic profile in tadpoles and inhibition of 1-AMA/Apofferitin interaction. Representative Analogs (modification of the side chain). All analogs were synthesized at NCGC </p></div></div></div><div id="ml306.s24"><h3>3.5. <i>In Vivo</i> Activity, mouse model</h3><p><a href="/pcsubstance/?term=ML306[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML306</a> produced loss of righting reflex (LORR) in less than 20 seconds in mice, with durations that depended on dose. An 80 mg/kg injection iv produced an average time of 73 ± 45 seconds until mice were able to right themselves (n = 6). The response to this dose varied between 0 seconds (misplaced injection) and 256 seconds. Conversely, 100 mg/kg ivintravenous (IV) administration of <a href="/pcsubstance/?term=ML306[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML306</a> produced LORR in all animals (n = 3), with LORR ranging from 140 to 362 seconds. 40 mg/kg IV administration was determined to be ineffective in all mice tested (n = 4). Control injections with the vehicle solution ranged from 1304 mg HP-β-CD/kg body mass to 2557 mg/kg and produced no observable effects (n = 4). The latter dose approximates published data that suggests decreased activity and breathing irregularities following an intravenous injection of 2250 mg/kg in rats.[<a class="bibr" href="#ml306.r29" rid="ml306.r29">29</a>]</p><p>Upon recovery of righting reflex, the mice were subdued, exhibited slow exploratory behavior, and did not attempt to avoid the handler. Apparently normal behavior was observed within ten minutes following the injection. No apparent toxicity or residual effect of the injection was noted out to two weeks. Two weeks post injection, each mouse had gained a minimum of 0.4 grams of body mass, not different from the vehicle injected controls.</p><p>The molecular weight of the <a href="/pcsubstance/?term=ML306[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML306</a> (461 g/mol) salt is ~2.6 times that of propofol (178 g/mol). For comparison, a 20 mg/kg injection of propofol suspended in intralipid induces LORR for 216 ± 25 seconds. 100 mg/kg <a href="/pcsubstance/?term=ML306[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML306</a> is equal to 0.217 mmol/kg, whereas 20 mg/kg propofol is equal to 0.112 mmol/kg.</p></div><div id="ml306.s25"><h3>3.6. Profiling Assays</h3><div id="ml306.s26"><h4>Pharmacokinetic Profiling of Probe</h4><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml306t7"><a href="/books/NBK153223/table/ml306.t7/?report=objectonly" target="object" title="Table 7" class="img_link icnblk_img figpopup" rid-figpopup="figml306t7" rid-ob="figobml306t7"><img class="small-thumb" src="/books/NBK153223/table/ml306.t7/?report=thumb" src-large="/books/NBK153223/table/ml306.t7/?report=previmg" alt="Table 7. ADME profile for ML306." /></a><div class="icnblk_cntnt"><h4 id="ml306.t7"><a href="/books/NBK153223/table/ml306.t7/?report=objectonly" target="object" rid-ob="figobml306t7">Table 7</a></h4><p class="float-caption no_bottom_margin">ADME profile for ML306. All experiments were conducted at Pharmaron Inc </p></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml306t8"><a href="/books/NBK153223/table/ml306.t8/?report=objectonly" target="object" title="Table 8" class="img_link icnblk_img figpopup" rid-figpopup="figml306t8" rid-ob="figobml306t8"><img class="small-thumb" src="/books/NBK153223/table/ml306.t8/?report=thumb" src-large="/books/NBK153223/table/ml306.t8/?report=previmg" alt="Table 8. In vivo PK (mouse) at 40 mpk IV and 5 mpk IV." /></a><div class="icnblk_cntnt"><h4 id="ml306.t8"><a href="/books/NBK153223/table/ml306.t8/?report=objectonly" target="object" rid-ob="figobml306t8">Table 8</a></h4><p class="float-caption no_bottom_margin"><i>In vivo</i> PK (mouse) at 40 mpk IV and 5 mpk IV. All experiments were conducted at Pharmaron Inc. with male CD1 mice (6–8 weeks of age). Data was collected in triplicate at 8 time points over a 24 hr period </p></div></div><div id="ml306.f9" class="figure bk_fig"><div class="graphic"><img src="/books/NBK153223/bin/ml306f9.jpg" alt="Figure 9. (A) PK plasma profile for ML306." /></div><h3><span class="label">Figure 9</span></h3><div class="caption"><p><b>(A)</b> PK plasma profile for <a href="/pcsubstance/?term=ML306[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML306</a>. CD1 Mice IV (40 mpk (blue) and 5 mpk (red)) dosed as a solution with n = 3 for each time point. <b>(b)</b> PK brain profile for <a href="/pcsubstance/?term=ML306[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML306</a>. CD1 Mice IV (40 mpk) dosed as a solution with n = 3 for each time point.</p></div></div><p>See <a href="#ml306.s31">Section 4.2</a> “Mechanism of Action Studies”.</p></div></div></div><div id="ml306.s28"><h2 id="_ml306_s28_">4. Discussion</h2><div id="ml306.s29"><h3>Structure Activity Relationships of ML306</h3><p>A high-throughput screening campaign of a library containing 397,939 compounds in the 1-AMA/apoferritin assay and subsequent application of rigorous chemoinformatics analysis (see above for details) resulted in the selection of the 6-substituted pyridazin-3-one chemotype as our lead series (e.g. CID 3244374, <a class="figpopup" href="/books/NBK153223/figure/ml306.f7/?report=objectonly" target="object" rid-figpopup="figml306f7" rid-ob="figobml306f7">Figure 7</a>). Following confirmation of these pyridazin-3-one derivatives via re-synthesis in the qHTS assay, and synthesis of a small set of analogs (~10) we then profiled these compounds for anesthetic properties and toxicity in tadpole assay. In the tadpole assay, anesthetic profile was measured as % of immobility after 60 minutes at 10 μM (100% immobility is desired) and the toxicity was measured as % of immobility after 24 hr (0% immobility is desired). With a good correlation between 1-AMA/apoferritin inhibition and anesthetic profile for majority of the compounds in tadpoles, we planned more extensive systematic structural modifications to the 6-substituted pyridazin-3-ones in an effort to establish a full SAR profile. It should be noted that given the limitations of the qHTS assay sensitivity (~3 μM) and the fact that improving potency in this surrogate assay is not our ultimate goal, we chose to use the tadpole assay for SAR analysis. Though this clearly presents challenges for iterative medicinal chemistry optimization, we felt it was the most efficient way to discovery novel general anesthetics.</p><p>As shown in <a class="figpopup" href="/books/NBK153223/table/ml306.t2/?report=objectonly" target="object" rid-figpopup="figml306t2" rid-ob="figobml306t2">Table 2</a>, our initial exploration at 6-position of the pyridazin-3-one showed that smaller groups or rings are not well tolerated. For example, entries <b>1–3</b> (CID 45548816, CID 49704509, and CID 56643049) showed no activity in the HTS assay and had little or no effect on immobilizing the tadpoles. However, these modifications caused some toxicity (immobilization at 24 h). Similarly, replacing with more hydrophilic groups such as pyridine analogs <b>25</b>–<b>27</b> (CID 56643055, CID 56643062, and CID 56643057) and <i>N</i>,<i>N</i>-dimethylphenyl analog <b>17</b> (CID 56643068) resulted in diminished apoferritin activity and complete loss of activity in tadpoles. Phenyl or <i>para</i>-substituted phenyl groups improved the potency that is exemplified by the % of immobility of tadpoles at 10 μM and the HTS IC<sub>50</sub> values of compounds <b>7</b> (CID 5040404, R = 4-Me-phenyl), <b>10</b> (CID 4993789: R = 4-OMe-phenyl), <b>18–19</b> (CID 56643038 and CID 56643051) and <b>21</b> (CID 56643052: R = 4-<i>t</i>-butyl-phenyl). Further, these compounds showed minimal or no toxicity against tadpoles at 10 μM. Electron-donating lipophilic groups at the <i>para</i> position of the phenyl ring is preferred over <i>ortho</i> and <i>meta</i>-substitution. As shown in <a class="figpopup" href="/books/NBK153223/table/ml306.t2/?report=objectonly" target="object" rid-figpopup="figml306t2" rid-ob="figobml306t2">Table 2</a> compounds <b>7</b> & <b>10</b> (CID 5070704 and CID 4993789) displayed better potency both in tadpole assay and surrogate assay as compared to entries <b>8–9</b> (CID 56643035: R = <i>meta-</i>Me; and CID 7671962: R = <i>ortho-</i>Me, respectively) & <b>11–12</b> (CID 7665103: R = <i>meta</i>-OMe; CID 7665103: R = <i>ortho</i>-OMe, respectively) with <i>ortho</i> being the least potent. Further exploration with di-substituted phenyl analogs such as compounds <b>22</b> & <b>23</b> (CID 7663799 and CID 56643026) resulted in no activity in the tadpole assays despite good activity in the enzymatic assay. The 6-substitution pattern of the pyridazin-3-one appears to be essential for the modulation of anesthetic activity as evidenced by complete loss of potency for 5 and 4 substituted compounds <b>36</b>–<b>37</b> (CID 135363124 and CID 135363126). Given that the <i>p</i>-tolyl group at 6-position of the pyridazin-3-one appeared to provide maximal potency and minimal toxicity, it was held constant while other regions of the molecule were explored for SAR.</p><p>Although attempts to replace the pyridazin-3-one core with smaller or similar heterocycles provided several compounds with moderate activity as measured in the surrogate assay, these were shown to be inactive in the orthogonal tadpole assay (entries in <a class="figpopup" href="/books/NBK153223/table/ml306.t3/?report=objectonly" target="object" rid-figpopup="figml306t3" rid-ob="figobml306t3">Table 3</a>). This observation with these and several other analogs might be due to lack of necessary pharmacological properties essential to penetrate the target in the <i>in vivo</i> system. On the other hand, incorporation of an OMe-substituted phenyl ring, entry <b>33</b> (CID 56643065) retained the anesthetic profile but exhibited severe toxicity. Moreover, reduced activity for compound <b>40</b> (CID 135363121: 5-position = Me), suggests that further substitution in the pyridazin-3-one core is not tolerated.</p><p>Our next focus of SAR exploration was modification of the side chain at the 2-position as shown in <a class="figpopup" href="/books/NBK153223/table/ml306.t4/?report=objectonly" target="object" rid-figpopup="figml306t4" rid-ob="figobml306t4">Table 4</a> and <a class="figpopup" href="/books/NBK153223/table/ml306.t5/?report=objectonly" target="object" rid-figpopup="figml306t5" rid-ob="figobml306t5">Table 5</a> (only representative analogs are shown). We quickly learned that the amide linkage is critical for the anesthetic activity as evidenced by reduced potencies for compounds <b>63–67</b> in <a class="figpopup" href="/books/NBK153223/table/ml306.t5/?report=objectonly" target="object" rid-figpopup="figml306t5" rid-ob="figobml306t5">Table 5</a>. Introduction of other liphophilic groups such as phenyl, furan, thiophene, cycloalkyl (5,6 or 7-membered rings) greatly facilitated the potency in the 1-AMA/apoferritin assay and in tadpoles with diminished toxicity. Compounds <b>43–47</b> and <b>61</b> in <a class="figpopup" href="/books/NBK153223/table/ml306.t5/?report=objectonly" target="object" rid-figpopup="figml306t5" rid-ob="figobml306t5">table 5</a> displayed over 85% immobility at 10 μM without any toxicity. In contrast, a decreased activity for compounds <b>50</b> (CID 56643046) and <b>51</b> (CID 5099141), suggests that substitution of the phenyl ring is not well tolerated. Replacing the phenyl group with smaller groups such as a cyclopropyl moiety [compound <b>60</b> (CID 56643037)] or smaller alkyl group [compound <b>62</b> (CID 56643040)] also negates tadpole activity despite moderate activity in the HTS assay. Surprisingly, polar groups and/or heterocycles led to complete loss of anesthetic profile as evidenced by the % immobility and IC<sub>50</sub> values for compounds <b>54–59</b>. Finally, we turned our attention to optimization of the linker between the amide nitrogen and the phenyl ring. A two carbon linker is needed to manifest optimal anesthetic activity whereas a one carbon or ≥3 carbon linkers decreased the potency as shown for compounds <b>48</b> (CID 7662444) and <b>49</b> (CID 50925844), respectively. Therefore, our SAR exploration resulted in <i>para</i>-substituted phenyl group at 6-position with phenylethyl amide moiety side chain provided best anesthetic compounds with good potency and minimal toxicity. <a class="figpopup" href="/books/NBK153223/figure/ml306.f10/?report=objectonly" target="object" rid-figpopup="figml306f10" rid-ob="figobml306f10">Figure 10</a> provides a summary of the SAR assessed during the medicinal chemistry optimization. Compounds <b>7</b> (CID 5070704), <b>19</b> (CID 56643051), <b>43</b> (CID 56643048) and <b>44</b> (CID 56643036) are highlighted as some of the best candidates for further studies. However, we focused on compound <b>7</b> (<a href="/pcsubstance/?term=ML306[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML306</a>) because it exhibited better aqueous solubility than the other analogs.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml306f10" co-legend-rid="figlgndml306f10"><a href="/books/NBK153223/figure/ml306.f10/?report=objectonly" target="object" title="Figure 10" class="img_link icnblk_img figpopup" rid-figpopup="figml306f10" rid-ob="figobml306f10"><img class="small-thumb" src="/books/NBK153223/bin/ml306f10.gif" src-large="/books/NBK153223/bin/ml306f10.jpg" alt="Figure 10. SAR Summary." /></a><div class="icnblk_cntnt" id="figlgndml306f10"><h4 id="ml306.f10"><a href="/books/NBK153223/figure/ml306.f10/?report=objectonly" target="object" rid-ob="figobml306f10">Figure 10</a></h4><p class="float-caption no_bottom_margin">SAR Summary. </p></div></div><p>Having established compound <b>7</b> as a lead compound which exhibits favorable activity in the tadpole immobilization assay without any obvious adverse effects on the tadpoles viability (e.g. no acute toxicity) we were eager to progress this compound <i>in vivo</i> (mouse model, <a class="figpopup" href="/books/NBK153223/table/ml306.t6/?report=objectonly" target="object" rid-figpopup="figml306t6" rid-ob="figobml306t6">Table 6</a>). However, before doing so we investigated the <i>in vitro</i> ADME and <i>in vivo</i> PK properties of the molecule as shown in <a class="figpopup" href="/books/NBK153223/table/ml306.t7/?report=objectonly" target="object" rid-figpopup="figml306t7" rid-ob="figobml306t7">Tables 7</a> and <a class="figpopup" href="/books/NBK153223/table/ml306.t8/?report=objectonly" target="object" rid-figpopup="figml306t8" rid-ob="figobml306t8">8</a>. The probe compound exhibits favorable aqueous solubility (PBS buffer) of ~58 μM which is well above the concentration required for tadpole immobilization. This compound also displays favorable Caco-2 permeability of 8.2 and a minimal efflux ratio of 1.6 where anything <2 is considered desirable. Given that Caco-2 cells express Pgp, and Pgp efflux plays a well-known role in BBB permeability, this data can be used to predict BBB penetration of discovery compounds. We then wanted to examine whether the probe compound inhibits specific cytochrome P450 enzymes 2D6 and 3A4 as these two isoforms account for the metabolism of approximately 80% of drugs. To assess the potential for CYP inhibition and drug-drug interactions (DDI), we looked at the effect of co-incubation of our compound at 3 μM with known CYP substrates (2D6: dextromethorphan and 3A4:midazolam). We found that <a href="/pcsubstance/?term=ML306[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML306</a> exhibits modest CYP inhibition of 24% and 12% for 2D6 and 3A4 respectively. To further elucidate the potential for CYP liabilities, follow-up IC<sub>50</sub> values and testing of a more expansive representation of CYP isoforms will be required. <a href="/pcsubstance/?term=ML306[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML306</a> was also profiled for its microsomal stability with both human and mouse liver microsomes and was found to have a short half-life of 11 and 5.2 min, respectively. In most drug discovery programs such a result would be considered a liability, ideal general anesthetics are ones that are cleared rapidly as drugs with a slow metabolism are associated with a more prolonged “hangover effect” (e.g. fatigue, weakness, pain, nausea and vomiting). However, it should be noted that there is also a market for longer acting or slower metabolized compounds (i.e. sedation in the ICU). Lastly, <a href="/pcsubstance/?term=ML306[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML306</a> was profiled for its stability in both mouse plasma and PBS buffer and it was found to be stable in both media and at various pH’s (2, 7.4 and 9) as shown in <a class="figpopup" href="/books/NBK153223/figure/ml306.f3/?report=objectonly" target="object" rid-figpopup="figml306f3" rid-ob="figobml306f3">Figure 3</a>. With this <i>in vitro</i> ADME data in-hand we were eager to determine whether these results translated to appropriate <i>in vivo</i> exposure, namely T<sub>1/2</sub> and BBB penetration.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml306t6"><a href="/books/NBK153223/table/ml306.t6/?report=objectonly" target="object" title="Table 6" class="img_link icnblk_img figpopup" rid-figpopup="figml306t6" rid-ob="figobml306t6"><img class="small-thumb" src="/books/NBK153223/table/ml306.t6/?report=thumb" src-large="/books/NBK153223/table/ml306.t6/?report=previmg" alt="Table 6. ML306 In vivo loss of righting reflex (LORR) studies." /></a><div class="icnblk_cntnt"><h4 id="ml306.t6"><a href="/books/NBK153223/table/ml306.t6/?report=objectonly" target="object" rid-ob="figobml306t6">Table 6</a></h4><p class="float-caption no_bottom_margin">ML306 <i>In vivo</i> loss of righting reflex (LORR) studies. Standard error shown for LORR time </p></div></div><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml306f3" co-legend-rid="figlgndml306f3"><a href="/books/NBK153223/figure/ml306.f3/?report=objectonly" target="object" title="Figure 3" class="img_link icnblk_img figpopup" rid-figpopup="figml306f3" rid-ob="figobml306f3"><img class="small-thumb" src="/books/NBK153223/bin/ml306f3.gif" src-large="/books/NBK153223/bin/ml306f3.jpg" alt="Figure 3. Stability of ML306 in DPBS (pH 7." /></a><div class="icnblk_cntnt" id="figlgndml306f3"><h4 id="ml306.f3"><a href="/books/NBK153223/figure/ml306.f3/?report=objectonly" target="object" rid-ob="figobml306f3">Figure 3</a></h4><p class="float-caption no_bottom_margin">Stability of ML306 in DPBS (pH 7.4) buffer at room temperature over 48 hr (<i>Panel A</i>). Stability of ML306 at pH 9 (<i>Panel B</i>) and pH 2 at room temperature over 24 hr (<i>Panel C</i>). </p></div></div><p>As fast-acting general anesthetics are typically administered via IV (and inhalation for gases) we aimed to determine the in vivo PK profile of the probe compound at two different doses (5 mpk and 40 mpk) to ensure that a linear PK profile was observed. Our initial study used 5 mpk because we did not yet know the dose which would provide a general anesthetic effect to the mouse. After subsequent <i>in vivo</i> PD studies (<i>vide infra</i>) we chose a dose closer (40 mpk) to what is required for LORR (Loss of Righting Reflex) in the mouse model (<a class="figpopup" href="/books/NBK153223/table/ml306.t6/?report=objectonly" target="object" rid-figpopup="figml306t6" rid-ob="figobml306t6">Table 6</a>). These results are tabulated in <a class="figpopup" href="/books/NBK153223/table/ml306.t8/?report=objectonly" target="object" rid-figpopup="figml306t8" rid-ob="figobml306t8">Table 8</a> and closely mirror what we observed in the <i>in vitro</i> ADME studies. The T<sub>1/2</sub> in plasma was 17 min and 13 min for 5 and 40 mpk respectively, whereas the MRT in plamsa (mean residence time) was 16 min and 10 min, respectively. The T<sub>max</sub> in the brain was determined to be ~5 minutes. (40 mpk) with 30% of the compound remaining in the brain tissue after 15 min. Interestingly, others have tested propofol in mouse models (32 mpk) doses IV and found the T<sub>max</sub> to be ~3 minutes and the T<sub>1/2</sub> to be 9.6 minutes, which suggests that these compounds have similar residence in the brain tissue.[<a class="bibr" href="#ml306.r30" rid="ml306.r30">30</a>] <a href="/pcsubstance/?term=ML306[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML306</a> was found to have a linear PK profile in the brain that mimic that found in the plasma (<a class="figpopup" href="/books/NBK153223/figure/ml306.f9/?report=objectonly" target="object" rid-figpopup="figml306f9" rid-ob="figobml306f9">Figure 9A & B</a>) and had good BBB penetration with a P/B ratio of 2.4 and a C<sub>max</sub> of 22033 ng/g @ 40 mpk dose. We were encouraged to initiate preliminary <i>in vivo</i> PD studies with this compound by its favorable PK profile (short half-life, adequate brain exposure) and the fact that this brain profile closely resembles propofol.</p><p>The PK profile of <a href="/pcsubstance/?term=ML306[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML306</a> compares more favorably to that of propofol than it does to the general population of drugs but this should not be viewed as a deficiency, particularly given the early-stage status of this chemotype. The activity of many drugs and compounds do not translate well from mouse to human; however, general anesthetics are remarkable in that the concentrations necessary to produce immobility are conserved within a factor of 2–4 fold across all animal species. Even the very complex neurosteroid anesthetics produce immobility in tadpoles at concentrations comparable to that for both rodents and people. The concentrations of inhalational anesthetics required for mouse immobility are within 20% of those required in humans. This is also true for intravenous anesthetics, with the exception that bolus doses are larger due to pharmacokinetic considerations. Thus, the bolus dose of propofol in a human to produce unconsciousness is about 2 mg/kg, whereas that for a mouse is 20 mg/kg. The calculated concentrations at effect sites, however, are comparable. This is not to say that off-pathway effects are the same. In many cases, lack of lethality in the tadpole cannot be reproduced in the mouse. In light of this, our results to date indicate that <a href="/pcsubstance/?term=ML306[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML306</a> carries a sufficient promise to merit further development directed towards eventual human testing.</p></div><div id="ml306.s30"><h3>4.1. Comparison to Existing Art and How the New Probe is an Improvement</h3><p><a href="/pcsubstance/?term=ML306[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML306</a> and related analogs have reduced activity compared to propofol, in both the tadpole assay and the <i>in vivo</i> mouse model. However, the true goal of this project was to validate a novel approach to discover new general anesthetics. The field of general anesthetics has not seen a rationally designed approach or one that relying on HTS, but rather serendipitous discovery or structural modifications to known compounds. Thus, the probe compound presented herein represents validation of the first approach of this kind with demonstrated in vivo efficacy and a PK profile comparable to propofol.</p></div><div id="ml306.s31"><h3>4.2. Mechanism of Action Studies</h3><p>Propofol is, in part, thought to produce its effect by interacting with inhibitory cys-loop ligand-gated ion channels, although there exists evidence that it also has effects on other ion channels, such as the voltage gated cation channels. Although our surrogate screen is based an ability of apoferritin to mimic GABAergic allosteric binding, apoferritin clearly cannot mimic the ion channel activity of the GABA<sub>A</sub> receptor. This activity, however, is simply not amenable to high throughput screening as it requires an electrophysiology rig. One assay that more specifically evaluates GABA<sub>A</sub>R allosteric binding activity is the ability of compounds to enhance the binding of radiolabeled flunitrazepam. Preliminary results from Eckenhoff Lab show GABAergic activity for several members of the probe series. It is conceivable that a portion of the sedative action of members of the probe series is due to enhancement of GABAergic activity, as the original surrogate was designed to reveal. Although our preliminary results showed that the probe <a href="/pcsubstance/?term=ML306[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML306</a> was not active in the radiolabeled flunitrazepam assay, the fact that at the same time a number of its analogues did show activity comparable to propofol (data not shown), indicates that additional studies using the radiolabeled flunitrazepam, as well as alternative assay platforms to interrogate GABAergic activity, are warranted.</p><p>ITC against apoferritin was used only to confirm the qHTS results, since the latter may be contaminated by various optical effects, such as inner filter, FRET and so forth. ITC proved very difficult as the compounds were not available in sufficient mass in powder form to conduct several runs (which, given the expected micromolar K<sub>D</sub>, required the application of very high compound concentrations, beyond those supported by their aqueous solubilities) in the absence of DMSO. Cosolvents such as DMSO produce large heats of dilution which can obscure the often smaller heats of bimolecular binding interactions. Thus, after several attempts, the ITC confirmation of qHTS, even of the subsets, was abandoned in favor of the phenotype assays. However, <a href="/pcsubstance/?term=ML306[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML306</a> and the original hit CID-3244374 did prduce a binding isotherm in apoferritin ITC experiments, yielding K<sub>D</sub>’s of 8.2 μM (<a class="figpopup" href="/books/NBK153223/figure/ml306.f8/?report=objectonly" target="object" rid-figpopup="figml306f8" rid-ob="figobml306f8">Figure 8</a>) and 4.2 μM (<a class="figpopup" href="/books/NBK153223/figure/ml306.f9/?report=objectonly" target="object" rid-figpopup="figml306f9" rid-ob="figobml306f9">Figure 9</a>), respectively.</p><div id="ml306.s32"><h4>Pharmacological Profiling of Probe</h4><p><a href="/pcsubstance/?term=ML306[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML306</a> was submitted to the National Institute of Mental Health’s Psychoactive Drug Screening Program (PDSP) G protein-coupled receptor (GPCR) Panel, and the results were represented as a heatmap (<a class="figpopup" href="/books/NBK153223/table/ml306.t9/?report=objectonly" target="object" rid-figpopup="figml306t9" rid-ob="figobml306t9">Table 9</a>). <a href="/pcsubstance/?term=ML306[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML306</a> along with propofol were tested at 1 μM against a panel of 149 GPCRs. Compounds with <4-fold stimulation at 1 μM were considered uninteresting for further potency determination. Internal positive controls were used in the panel (data not shown). Surprisingly, both <a href="/pcsubstance/?term=ML306[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML306</a> and propofol were very clean with no significant activity against any of the tested GPCRs. Profiling against ligand gated voltage cannels and other selected receptors are ongoing. We were encouraged by this profile as it seems to indicate that the <i>in vivo</i> effect is not simply a result of promiscuous GPCR activity, however it also means that additional profiling must be done to help identify the target(s). It should be noted that such a task is a lofty goal given that researchers do not yet fully understand how known anesthetics work despite being studied extensively for decades.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml306t9"><a href="/books/NBK153223/table/ml306.t9/?report=objectonly" target="object" title="Table 9" class="img_link icnblk_img figpopup" rid-figpopup="figml306t9" rid-ob="figobml306t9"><img class="small-thumb" src="/books/NBK153223/table/ml306.t9/?report=thumb" src-large="/books/NBK153223/table/ml306.t9/?report=previmg" alt="Table 9. PDSP GPCR Profiling of ML306 and propofol tested at 1 μM concentration." /></a><div class="icnblk_cntnt"><h4 id="ml306.t9"><a href="/books/NBK153223/table/ml306.t9/?report=objectonly" target="object" rid-ob="figobml306t9">Table 9</a></h4><p class="float-caption no_bottom_margin">PDSP GPCR Profiling of ML306 and propofol tested at 1 μM concentration. White squares represent inactivity while blue squares represent fold stimulation at 1 μM </p></div></div></div></div><div id="ml306.s33"><h3>4.3. Planned Future Studies</h3><p>Future studies will be multi-pronged. First, it is likely that only a subset of the original apoferritin qHTS actives have anesthetic activity, and these may not be the very top hits in the primary screen (as primarily determined by the hits’ displacement IC<sub>50</sub> values in the apoferritin assay). We now know, for example, that the apoferritin “anesthetic” site is likely to be a fatty acid binding site.[<a class="bibr" href="#ml306.r31" rid="ml306.r31">31</a>] Thus, the overlap between anesthetics and fatty acid chemotypes is finite and is not likely to be large. Therefore, the original list of top actives needs to be revisited in an unbiased phenotype screen, such as the stereotypical photoresponses in the zebra fish embryo. We have initiated a collaboration with the Peterson Lab at Massachusetts General Hospital and Harvard Medical School to validate this approach using his medium throughput zebrafish screening operation. A second direction will be to focus further on the medicinal chemistry of the <a href="/pcsubstance/?term=ML306[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML306</a> series. It is likely that this modest sized compound can be further modified to produce greater activity. Our goal would be to exceed the potency of propofol in the tadpole assay by at least 10-fold. Moreover, we plan to test several of the other compounds with promising tadpole activity in the in vivo model to see if improved activity is observed (e.g. compounds <b>18</b>, <b>44</b>, <b>46</b>, <b>47</b> and <b>61</b>). A third direction is to use <a href="/pcsubstance/?term=ML306[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML306</a> as a probe to identify the mechanism of action for this compound and the members of its series. We will explore the mechanism through our own studies as well as collaborating with the Roth Laboratory at the University of North Carolina, Chapel Hill. These efforts include pull-down studies using light-activated analogs of <a href="/pcsubstance/?term=ML306[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML306</a>, similar to what the Eckenhoff lab has done for propofol (with m-Azipropofol) and/or additional profiling of potential targets. The SAR profile we have established through this project thus far should allow for such derivatives to be prepared without affecting the anesthetic properties.</p></div></div><div id="ml306.s34"><h2 id="_ml306_s34_">5. References</h2><dl class="temp-labeled-list"><dl class="bkr_refwrap"><dt>1.</dt><dd><div class="bk_ref" id="ml306.r1">Eckenhoff RG. Promiscuous ligands and attractive cavities: how do the inhaled anesthetics work? <span><span class="ref-journal">Mol Interv. </span>2001;<span class="ref-vol">1</span>(5):258–68.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/14993365" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 14993365</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>2.</dt><dd><div class="bk_ref" id="ml306.r2">Xie Z, et al. The inhalation anesthetic isoflurane induces a vicious cycle of apoptosis and amyloid beta-protein accumulation. <span><span class="ref-journal">J Neurosci. </span>2007;<span class="ref-vol">27</span>(6):1247–54.</span> [<a href="/pmc/articles/PMC6673586/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6673586</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/17287498" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17287498</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>3.</dt><dd><div class="bk_ref" id="ml306.r3">Eckenhoff RG, et al. Inhaled anesthetic enhancement of amyloid-beta oligomerization and cytotoxicity. <span><span class="ref-journal">Anesthesiology. </span>2004;<span class="ref-vol">101</span>(3):703–9.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15329595" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15329595</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>4.</dt><dd><div class="bk_ref" id="ml306.r4">Franks NP. General anaesthesia: from molecular targets to neuronal pathways of sleep and arousal. <span><span class="ref-journal">Nat Rev Neurosci. </span>2008;<span class="ref-vol">9</span>(5):370–86.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/18425091" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18425091</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>5.</dt><dd><div class="bk_ref" id="ml306.r5">Eckenhoff RG, Johansson JS. Molecular interactions between inhaled anesthetics and proteins. <span><span class="ref-journal">Pharmacol Rev. </span>1997;<span class="ref-vol">49</span>(4):343–67.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/9443162" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9443162</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>6.</dt><dd><div class="bk_ref" id="ml306.r6">Sigel E. Mapping of the benzodiazepine recognition site on GABA(A) receptors. <span><span class="ref-journal">Curr Top Med Chem. </span>2002;<span class="ref-vol">2</span>(8):833–9.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12171574" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12171574</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>7.</dt><dd><div class="bk_ref" id="ml306.r7">Santhakumar V, Wallner M, Otis TS. Ethanol acts directly on extrasynaptic subtypes of GABAA receptors to increase tonic inhibition. <span><span class="ref-journal">Alcohol. </span>2007;<span class="ref-vol">41</span>(3):211–21.</span> [<a href="/pmc/articles/PMC2040048/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2040048</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/17591544" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17591544</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>8.</dt><dd><div class="bk_ref" id="ml306.r8">Chiara DC, et al. Identification of nicotinic acetylcholine receptor amino acids photolabeled by the volatile anesthetic halothane. <span><span class="ref-journal">Biochemistry. </span>2003;<span class="ref-vol">42</span>(46):13457–67.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/14621991" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 14621991</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>9.</dt><dd><div class="bk_ref" id="ml306.r9">Mihic SJ, et al. Sites of alcohol and volatile anaesthetic action on GABA(A) and glycine receptors. <span><span class="ref-journal">Nature. </span>1997;<span class="ref-vol">389</span>(6649):385–9.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/9311780" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9311780</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>10.</dt><dd><div class="bk_ref" id="ml306.r10">Bali M, Jansen M, Akabas MH. GABA-induced intersubunit conformational movement in the GABAA receptor alpha 1M1-beta 2M3 transmembrane subunit interface: experimental basis for homology modeling of an intravenous anesthetic binding site. <span><span class="ref-journal">J Neurosci. </span>2009;<span class="ref-vol">29</span>(10):3083–92.</span> [<a href="/pmc/articles/PMC2677711/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2677711</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19279245" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19279245</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>11.</dt><dd><div class="bk_ref" id="ml306.r11">Franks NP, Lieb WR. Do general anaesthetics act by competitive binding to specific receptors? <span><span class="ref-journal">Nature. </span>1984;<span class="ref-vol">310</span>(5978):599–601.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/6462249" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 6462249</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>12.</dt><dd><div class="bk_ref" id="ml306.r12">Dubois BW, Cherian SF, Evers AS. Volatile anesthetics compete for common binding sites on bovine serum albumin: a 19F-NMR study. <span><span class="ref-journal">Proc Natl Acad Sci U S A. </span>1993;<span class="ref-vol">90</span>(14):6478–82.</span> [<a href="/pmc/articles/PMC46955/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC46955</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/8341659" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8341659</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>13.</dt><dd><div class="bk_ref" id="ml306.r13">Liu R, et al. Comparative binding character of two general anaesthetics for sites on human serum albumin. <span><span class="ref-journal">Biochem J. </span>2004;<span class="ref-vol">380</span>(Pt 1):147–52.</span> [<a href="/pmc/articles/PMC1224140/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1224140</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/14759223" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 14759223</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>14.</dt><dd><div class="bk_ref" id="ml306.r14">Johansson JS, et al. Binding of the volatile general anesthetics halothane and isoflurane to a mammalian beta-barrel protein. <span><span class="ref-journal">FEBS J. </span>2005;<span class="ref-vol">272</span>(2):573–81.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15654894" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15654894</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>15.</dt><dd><div class="bk_ref" id="ml306.r15">Liu R, Loll PJ, Eckenhoff RG. Structural basis for high-affinity volatile anesthetic binding in a natural 4-helix bundle protein. <span><span class="ref-journal">FASEB J. </span>2005;<span class="ref-vol">19</span>(6):567–76.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15791007" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15791007</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>16.</dt><dd><div class="bk_ref" id="ml306.r16">Vedula LS, et al. A unitary anesthetic binding site at high resolution. <span><span class="ref-journal">J Biol Chem. </span>2009;<span class="ref-vol">284</span>(36):24176–84.</span> [<a href="/pmc/articles/PMC2782011/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2782011</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19605349" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19605349</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>17.</dt><dd><div class="bk_ref" id="ml306.r17">Krasowski MD, et al. General anesthetic potencies of a series of propofol analogs correlate with potency for potentiation of gamma-aminobutyric acid (GABA) current at the GABA(A) receptor but not with lipid solubility. <span><span class="ref-journal">J Pharmacol Exp Ther. </span>2001;<span class="ref-vol">297</span>(1):338–51.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/11259561" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11259561</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>18.</dt><dd><div class="bk_ref" id="ml306.r18">Butts CA, et al. Identification of a fluorescent general anesthetic, 1-aminoanthracene. <span><span class="ref-journal">Proc Natl Acad Sci U S A. </span>2009;<span class="ref-vol">106</span>(16):6501–6.</span> [<a href="/pmc/articles/PMC2672486/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2672486</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19346473" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19346473</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>19.</dt><dd><div class="bk_ref" id="ml306.r19">James R, Glen JB. Synthesis, biological evaluation, and preliminary structure-activity considerations of a series of alkylphenols as intravenous anesthetic agents. <span><span class="ref-journal">J Med Chem. </span>1980;<span class="ref-vol">23</span>(12):1350–7.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/7452689" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7452689</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>20.</dt><dd><div class="bk_ref" id="ml306.r20">Inglese J, et al. Quantitative high-throughput screening: a titration-based approach that efficiently identifies biological activities in large chemical libraries. <span><span class="ref-journal">Proc Natl Acad Sci U S A. </span>2006;<span class="ref-vol">103</span>(31):11473–8.</span> [<a href="/pmc/articles/PMC1518803/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1518803</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/16864780" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16864780</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>21.</dt><dd><div class="bk_ref" id="ml306.r21">Lea WA, et al. A high-throughput approach for identification of novel general anesthetics. <span><span class="ref-journal">PLoS One. </span>2009;<span class="ref-vol">4</span>(9):e7150.</span> [<a href="/pmc/articles/PMC2746312/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2746312</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19777064" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19777064</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>22.</dt><dd><div class="bk_ref" id="ml306.r22">Simeonov A, et al. Fluorescence spectroscopic profiling of compound libraries. <span><span class="ref-journal">J Med Chem. </span>2008;<span class="ref-vol">51</span>(8):2363–71.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/18363325" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18363325</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>23.</dt><dd><div class="bk_ref" id="ml306.r23">Inglese J, et al. High-throughput screening assays for the identification of chemical probes. <span><span class="ref-journal">Nat Chem Biol. </span>2007;<span class="ref-vol">3</span>(8):466–79.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17637779" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17637779</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>24.</dt><dd><div class="bk_ref" id="ml306.r24">Zhang JH, Chung TD, Oldenburg KR. A Simple Statistical Parameter for Use in Evaluation and Validation of High Throughput Screening Assays. <span><span class="ref-journal">J Biomol Screen. </span>1999;<span class="ref-vol">4</span>(2):67–73.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/10838414" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10838414</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>25.</dt><dd><div class="bk_ref" id="ml306.r25">Feng BY, et al. A high-throughput screen for aggregation-based inhibition in a large compound library. <span><span class="ref-journal">J Med Chem. </span>2007;<span class="ref-vol">50</span>(10):2385–90.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17447748" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17447748</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>26.</dt><dd><div class="bk_ref" id="ml306.r26">Feng BY, Shoichet BK. A detergent-based assay for the detection of promiscuous inhibitors. <span><span class="ref-journal">Nat Protoc. </span>2006;<span class="ref-vol">1</span>(2):550–3.</span> [<a href="/pmc/articles/PMC1544377/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1544377</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/17191086" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17191086</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>27.</dt><dd><div class="bk_ref" id="ml306.r27">Yasgar A, et al. Compound Management for Quantitative High-Throughput Screening. <span><span class="ref-journal">JALA Charlottesv Va. </span>2008;<span class="ref-vol">13</span>(2):79–89.</span> [<a href="/pmc/articles/PMC2390859/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2390859</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/18496600" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18496600</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>28.</dt><dd><div class="bk_ref" id="ml306.r28">Hopkins AL, et al. Ligand efficiency: a useful metric for lead selection. <span><span class="ref-journal">Drug Discov Today. </span>2004;<span class="ref-vol">9</span>(10):430–1.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15109945" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15109945</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>29.</dt><dd><div class="bk_ref" id="ml306.r29">Gould S, Scott RC. 2-Hydroxypropyl-β-cyclodextrin (HP-beta-CD): A toxicology review. <span><span class="ref-journal">Food and Chemical Toxicology. </span>2005;<span class="ref-vol">43</span>:1451–1459.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16018907" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16018907</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>30.</dt><dd><div class="bk_ref" id="ml306.r30">Guan L, Wu XM, Jiang JY. Elimination half-life of propofol in effect-site of mice. <span><span class="ref-journal">Beijing Da Xue Xue Bao. </span>2005;<span class="ref-vol">37</span>:187–189.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15841152" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15841152</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>31.</dt><dd><div class="bk_ref" id="ml306.r31">Bu W, et al. Ferritin couples iron and fatty acid metabolism. <span><span class="ref-journal">FASEB J. </span>2012.</span> available online ahead of print. [<a href="/pmc/articles/PMC3360150/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3360150</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/22362897" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22362897</span></a>]</div></dd></dl></dl></div><div id="ml306.app1"><h2 id="_ml306_app1_">Appendix</h2><div id="ml306.s35"><h3>ML306 Probe Characterization</h3><p id="ml306.fu3"><a href="/books/NBK153223/figure/ml306.fu3/?report=objectonly" target="object" rid-ob="figobml306fu3" class="figpopup">Figure</a></p><p id="ml306.f13"><a href="/books/NBK153223/figure/ml306.f13/?report=objectonly" target="object" rid-ob="figobml306f13" class="figpopup">Figure A1. LC-MS purity analysis for ML306</a></p><p id="ml306.f14"><a href="/books/NBK153223/figure/ml306.f14/?report=objectonly" target="object" rid-ob="figobml306f14" class="figpopup">Figure A2. <sup>1</sup>H NMR spectrum of ML306</a></p><p id="ml306.f15"><a href="/books/NBK153223/figure/ml306.f15/?report=objectonly" target="object" rid-ob="figobml306f15" class="figpopup">Figure A3. <sup>13</sup>C NMR spectrum of ML306</a></p></div><div id="ml306.s36"><h3>Analog Characterization</h3><div id="ml306.fu4" class="figure"><div class="graphic"><img src="/books/NBK153223/bin/ml306fu42.jpg" alt="Image ml306fu42" /></div></div><p><b>CID 56643048:</b> LC-MS Retention Time: t<sub>1</sub> (Method 1) = 5.542 min and t<sub>2</sub> (Method 2) = x min; <sup>1</sup>H NMR (400 MHz, CDCl<sub>3</sub>) δ 1.48 (d, <i>J</i> = 6.3 Hz, 2 H), 1.65 (d, <i>J</i> = 5.9 Hz, 1 H), 2.39 (s, 3 H), 2.76 (s, 1 H), 2.89 (s, 2 H), 4.65 – 4.82 (m, 1 H), 5.03 (d, <i>J</i> = 15.3 Hz, 1 H), 5.23 – 5.41 (m, 1 H), 5.93 (q, <i>J</i> = 6.4 Hz, 1 H), 6.24 – 6.40 (m, 2 H), 6.77 (d, <i>J</i> = 9.4 Hz, 1 H), 7.23 (d, <i>J</i> = 7.0 Hz, 2 H), 7.32 – 7.42 (m, 2 H), 7.54 – 7.61 (m, 1 H), 7.70 (d, <i>J</i> = 9.4 Hz, 1 H); HRMS (ESI) <i>m/z</i> (M+H)<sup>+</sup> calcd. for C<sub>20</sub>H<sub>22</sub>N<sub>3</sub>O<sub>3</sub>, 352.1656; found 352.1656.</p><div id="ml306.fu5" class="figure"><div class="graphic"><img src="/books/NBK153223/bin/ml306fu43.jpg" alt="Image ml306fu43" /></div></div><p><b>CID 56643039:</b> LC-MS Retention Time: t<sub>1</sub> (Method 1) = 5.438 min and t<sub>2</sub> (Method 2) = 3.430 min; <sup>1</sup>H NMR (400 MHz, CDCl<sub>3</sub>) δ 1.48 (d, <i>J</i> = 7.0 Hz, 2 H), 1.65 (d, <i>J</i> = 6.7 Hz, 1 H), 2.40 (s, 3 H), 2.77 (s, 1 H), 2.84 (s, 2 H), 4.98 – 5.33 (m, 2 H), 5.95 (q, <i>J</i> =7.0 Hz, 1 H), 6.21 – 6.40 (m, 2 H), 7.05 (d, <i>J</i> = 9.4 Hz, 1 H), 7.25 (s, 1 H), 7.36 – 7.47 (m, 1 H), 7.66 – 7.71 (m, 3 H); HRMS (ESI) <i>m/z</i> (M+H)<sup>+</sup> calcd. for C<sub>21</sub>H<sub>23</sub>N<sub>2</sub>O<sub>3</sub>, 351.1703; found 351.1709.</p><div id="ml306.fu6" class="figure"><div class="graphic"><img src="/books/NBK153223/bin/ml306fu44.jpg" alt="Image ml306fu44" /></div></div><p><b>CID 56643058:</b> LC-MS Retention Time: t<sub>1</sub> (Method 1) = 5.455 min and t<sub>2</sub> (Method 2) = 3.334 min; <sup>1</sup>H NMR (400 MHz, CDCl<sub>3</sub>) δ 1.70 (dd, <i>J</i> = 15.5 and 6.9 Hz, 2 H), 2.47 (s, 3 H), 2.93 – 3.06 (m, 2 H), 5.50 (q, <i>J</i> = 6.3 Hz, 1 H), 6.16 – 6.21 (m, 1 H), 6.27 – 6.31 (m, 1 H), 6.39 – 6.42 (m, 1 H), 7.23 – 7.47 (m, 4 H), 7.81 – 7.91 (m, 1 H), 7.93 – 8.00 (m, 2 H), 8.45 (d, <i>J</i> = 8.6 Hz, 1 H); HRMS (ESI) <i>m/z</i> (M+H)<sup>+</sup> calcd. for C<sub>20</sub>H<sub>20</sub>N<sub>5</sub>O<sub>2</sub>, 362.1612; found 362.1616.</p><div id="ml306.fu7" class="figure"><div class="graphic"><img src="/books/NBK153223/bin/ml306fu45.jpg" alt="Image ml306fu45" /></div></div><p><b>CID 56643034:</b> LC-MS Retention Time: t<sub>1</sub> (Method 1) = 6.125 min and t<sub>2</sub> (Method 2) = 3.643 min; <sup>1</sup>H NMR (400 MHz, CDCl<sub>3</sub>) δ 1.32 – 1.84 (m, 12 H), 2.35 (s, 3 H), 2.72 (s, 1 H), 2.92 (s, 2 H), 3.79 – 3.84 (m, 1 H), 4.25 – 4.39 (m, 1 H), 4.94 – 5.08 (m, 2 H), 7.04 (d, <i>J</i> = 9.8 Hz, 1 H), 7.30 (d, <i>J</i> = 7.8 Hz, 2 H), 7.76 (d, <i>J</i> = 7.8 Hz, 2 H), 7.99 – 8.11 (m, 1 H); HRMS (ESI) <i>m/z</i> (M+H)<sup>+</sup> calcd. for C<sub>21</sub>H<sub>28</sub>N<sub>3</sub>O<sub>2</sub>, 354.2176; found 354.2179.</p><div id="ml306.fu8" class="figure"><div class="graphic"><img src="/books/NBK153223/bin/ml306fu46.jpg" alt="Image ml306fu46" /></div></div><p><b>CID 56643061:</b> LC-MS Retention Time: t<sub>1</sub> (Method 1) = 5.843 min and t<sub>2</sub> (Method 2) = 3.503 min; <sup>1</sup>H NMR (400 MHz, CDCl<sub>3</sub>) δ 1.54 (d, <i>J</i> = 7.4 Hz, 2 H), 1.72 (d, <i>J</i> = 6.7 Hz, 2 H), 2.41 (s, 3 H), 2.76 (s, 3 H), 5.02 – 5.28 (m, 2 H), 6.06 (q, <i>J</i>= 6.9 Hz, 1 H), 7.00 – 7.10 (m, 1 H), 7.24 – 7.43 (m, 7 H), 7.65 – 7.74 (m, 3 H); HRMS (ESI) <i>m/z</i> (M+H)<sup>+</sup> calcd. for C<sub>22</sub>H<sub>24</sub>N<sub>3</sub>O<sub>2</sub>, 362.1863; found 362.1866.</p></div></div><div style="display:none"><div style="display:none" id="figml306f8"><img alt="Image ml306f8" src-large="/books/NBK153223/bin/ml306f8.jpg" /></div><div style="display:none" id="figml306f9"><img alt="Image ml306f9" src-large="/books/NBK153223/bin/ml306f9.jpg" /></div></div><div id="bk_toc_contnr"></div></div></div><div class="fm-sec"><h2 id="_NBK153223_pubdet_">Publication Details</h2><h3>Author Information and Affiliations</h3><p class="contrib-group"><h4>Authors</h4><span itemprop="author">Ganesha Rai</span>,<sup>a</sup> <span itemprop="author">Weiming Bu</span>,<sup>b</sup> <span itemprop="author">Wendy A. Lea</span>,<sup>a</sup> <span itemprop="author">David Liang</span>,<sup>b</sup> <span itemprop="author">Brian Weiser</span>,<sup>b</sup> <span itemprop="author">Vince Setola</span>,<sup>c</sup> <span itemprop="author">Christopher P. Austin</span>,<sup>a</sup> <span itemprop="author">Anton Simeonov</span>,<sup>a</sup> <span itemprop="author">Ajit Jadhav</span>,<sup>a</sup> <span itemprop="author">Roderic Eckenhoff</span>,<sup>b</sup> and <span itemprop="author">David J. Maloney</span><sup>a</sup><sup>,*</sup>.</p><h4>Affiliations</h4><div class="affiliation"><sup>a</sup>
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NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850.</div><div class="affiliation"><sup>b</sup>
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Department of Anesthesiology and Critical Care, University of Pennsylvania Perelman School of Medicine, 3620 Hamilton Walk, Philadelphia, PA 19104</div><div class="affiliation"><sup>c</sup>
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Department of Pharmacology, University of North Caroline, 4009 Genetics Medicine CB#7365 Chapel Hill NC 27599-7365</div><div class="affiliation">
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<sup>*</sup> To whom correspondence should be addressed: Email:
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<a href="mailto:dev@null" data-email="vog.hin.liam@dyenolam" class="oemail">vog.hin.liam@dyenolam</a></div><h3>Publication History</h3><p class="small">Received: <span itemprop="datePublished">April 16, 2012</span>; Last Update: <span itemprop="dateModified">May 8, 2013</span>.</p><h3>Copyright</h3><div><div class="half_rhythm"><a href="/books/about/copyright/">Copyright Notice</a></div></div><h3>Publisher</h3><p>National Center for Biotechnology Information (US), Bethesda (MD)</p><h3>NLM Citation</h3><p>Rai G, Bu W, Lea WA, et al. Discovery of Novel General Anesthetics Using Apoferritin as a Surrogate System. 2012 Apr 16 [Updated 2013 May 8]. In: Probe Reports from the NIH Molecular Libraries Program [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2010-. <span class="bk_cite_avail"></span></p></div><div class="small-screen-prev"><a href="/books/n/mlprobe/ml307/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M75,30 c-80,60 -80,0 0,60 c-30,-60 -30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Prev</text></svg></a></div><div class="small-screen-next"><a href="/books/n/mlprobe/ml304/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M25,30c80,60 80,0 0,60 c30,-60 30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Next</text></svg></a></div></article><article data-type="fig" id="figobml306fu1"><div id="ml306.fu1" class="figure"><div class="graphic"><img data-src="/books/NBK153223/bin/ml306fu1.jpg" alt="Image ml306fu1" /></div></div></article><article data-type="table-wrap" id="figobml306tu1"><div id="ml306.tu1" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK153223/table/ml306.tu1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml306.tu1_lrgtbl__"><table><thead><tr><th id="hd_h_ml306.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">CID/ML#</th><th id="hd_h_ml306.tu1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Target Name</th><th id="hd_h_ml306.tu1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">IC<sub>50</sub>/EC<sub>50</sub> (μM) [SID, AID]</th><th id="hd_h_ml306.tu1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Anti-target Name(s)</th><th id="hd_h_ml306.tu1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Toxicity (%) [SID, AID]</th><th id="hd_h_ml306.tu1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Fold Selective</th><th id="hd_h_ml306.tu1_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Secondary Assay(s) Name: Immobility (%) [SID, AID]</th></tr></thead><tbody><tr><td headers="hd_h_ml306.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">CID 5070704/<a href="/pcsubstance/?term=ML306[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML306</a></td><td headers="hd_h_ml306.tu1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Apoferritin (surrogate target)</td><td headers="hd_h_ml306.tu1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">qHTS: 3.04 [<a href="https://pubchem.ncbi.nlm.nih.gov/substance/24415651" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 24415651</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/489008" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 489008</a>]</td><td headers="hd_h_ml306.tu1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><i>In Vivo</i> Tadpole Toxicity</td><td headers="hd_h_ml306.tu1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0% at 10 μM [<a href="https://pubchem.ncbi.nlm.nih.gov/substance/134419032" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 134419032</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/624098" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 624098</a>]</td><td headers="hd_h_ml306.tu1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">>90</td><td headers="hd_h_ml306.tu1_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><i>In Vivo</i> Tadpole Assay: 90% Immobility [<a href="https://pubchem.ncbi.nlm.nih.gov/substance/134419032" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 134419032</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/624098" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 624098</a>]</td></tr></tbody></table></div></div></article><article data-type="fig" id="figobml306f1"><div id="ml306.f1" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK153223/bin/ml306f1.jpg" alt="Figure 1. Example general anesthetics propofol and etomidate." /></div><h3><span class="label">Figure 1</span><span class="title">Example general anesthetics propofol and etomidate</span></h3></div></article><article data-type="table-wrap" id="figobml306t1"><div id="ml306.t1" class="table"><h3><span class="label">Table 1</span><span class="title">Apoferritin qHTS assay protocol</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK153223/table/ml306.t1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml306.t1_lrgtbl__"><table class="no_top_margin"><thead><tr><th id="hd_h_ml306.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">Sequence</th><th id="hd_h_ml306.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">Parameter</th><th id="hd_h_ml306.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">Value</th><th id="hd_h_ml306.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">Description</th></tr></thead><tbody><tr><td headers="hd_h_ml306.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>1</b></td><td headers="hd_h_ml306.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Reagent</td><td headers="hd_h_ml306.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">3 μL</td><td headers="hd_h_ml306.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">10 μM apoferritin in 50% saturated aminoanthracene (AMA) in columns 1, 2, 5–48; 50% AMA in columns 3–4 as negative controls, 1X PBS pH 7.2, 0.1% PEG 400</td></tr><tr><td headers="hd_h_ml306.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>2a</b></td><td headers="hd_h_ml306.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Compound</td><td headers="hd_h_ml306.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">23 or 46 nL</td><td headers="hd_h_ml306.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Compound Library</td></tr><tr><td headers="hd_h_ml306.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>2b</b></td><td headers="hd_h_ml306.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Control</td><td headers="hd_h_ml306.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">23 or 46 nL</td><td headers="hd_h_ml306.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Propofol</td></tr><tr><td headers="hd_h_ml306.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>3</b></td><td headers="hd_h_ml306.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Time</td><td headers="hd_h_ml306.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">10 min</td><td headers="hd_h_ml306.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">RT Incubation</td></tr><tr><td headers="hd_h_ml306.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>4</b></td><td headers="hd_h_ml306.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Detector</td><td headers="hd_h_ml306.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">380 nm excitation/535 nm emission</td><td headers="hd_h_ml306.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">EnVision</td></tr></tbody></table></div></div></article><article data-type="fig" id="figobml306fu2"><div id="ml306.fu2" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK153223/bin/ml306fu2.jpg" alt="Probe Characterization of ML306." /></div><h3><span class="title">Probe Characterization of ML306</span></h3><div class="caption"><p>*Purity >95% as determined by LC/MS and <sup>1</sup>H NMR analyses.</p></div></div></article><article data-type="table-wrap" id="figobml306tu2"><div id="ml306.tu2" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK153223/table/ml306.tu2/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml306.tu2_lrgtbl__"><table><thead><tr><th id="hd_h_ml306.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Internal ID</th><th id="hd_h_ml306.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">MLS ID</th><th id="hd_h_ml306.tu2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">SID</th><th id="hd_h_ml306.tu2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">CID</th><th id="hd_h_ml306.tu2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">ML #</th><th id="hd_h_ml306.tu2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Type</th><th id="hd_h_ml306.tu2_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Source</th></tr></thead><tbody><tr><td headers="hd_h_ml306.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>NCGC00140268</b></td><td headers="hd_h_ml306.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">MLS004082015</td><td headers="hd_h_ml306.tu2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134419032" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134419032</a></td><td headers="hd_h_ml306.tu2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">5070704</td><td headers="hd_h_ml306.tu2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="/pcsubstance/?term=ML306[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML306</a></td><td headers="hd_h_ml306.tu2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Probe</td><td headers="hd_h_ml306.tu2_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">NCGC</td></tr><tr><td headers="hd_h_ml306.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>NCGC00189159</b></td><td headers="hd_h_ml306.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">MLS004082018</td><td headers="hd_h_ml306.tu2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134419034" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134419034</a></td><td headers="hd_h_ml306.tu2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">56643048</td><td headers="hd_h_ml306.tu2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></td><td headers="hd_h_ml306.tu2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Analog</td><td headers="hd_h_ml306.tu2_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">NCGC</td></tr><tr><td headers="hd_h_ml306.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>NCGC00250075</b></td><td headers="hd_h_ml306.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">MLS004082016</td><td headers="hd_h_ml306.tu2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134419045" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134419045</a></td><td headers="hd_h_ml306.tu2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">56643039</td><td headers="hd_h_ml306.tu2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></td><td headers="hd_h_ml306.tu2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Analog</td><td headers="hd_h_ml306.tu2_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">NCGC</td></tr><tr><td headers="hd_h_ml306.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>NCGC00249431</b></td><td headers="hd_h_ml306.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">MLS004082019</td><td headers="hd_h_ml306.tu2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134419039" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134419039</a></td><td headers="hd_h_ml306.tu2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">56643034</td><td headers="hd_h_ml306.tu2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></td><td headers="hd_h_ml306.tu2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Analog</td><td headers="hd_h_ml306.tu2_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">NCGC</td></tr><tr><td headers="hd_h_ml306.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>NCGC00249428</b></td><td headers="hd_h_ml306.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">MLS004082020</td><td headers="hd_h_ml306.tu2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134419037" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134419037</a></td><td headers="hd_h_ml306.tu2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">56643061</td><td headers="hd_h_ml306.tu2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></td><td headers="hd_h_ml306.tu2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Analog</td><td headers="hd_h_ml306.tu2_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">NCGC</td></tr><tr><td headers="hd_h_ml306.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>NCGC00249763</b></td><td headers="hd_h_ml306.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">MLS004082017</td><td headers="hd_h_ml306.tu2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134419043" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134419043</a></td><td headers="hd_h_ml306.tu2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">56643058</td><td headers="hd_h_ml306.tu2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></td><td headers="hd_h_ml306.tu2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Analog</td><td headers="hd_h_ml306.tu2_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">NCGC</td></tr></tbody></table></div></div></article><article data-type="fig" id="figobml306f2"><div id="ml306.f2" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%202.%20List%20and%20structures%20of%20probe%20and%20related%20analogs%20that%20have%20been%20submitted%20to%20the%20MLSMR.&p=BOOKS&id=153223_ml306f2.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK153223/bin/ml306f2.jpg" alt="Figure 2. List and structures of probe and related analogs that have been submitted to the MLSMR." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 2</span><span class="title">List and structures of probe and related analogs that have been submitted to the MLSMR</span></h3></div></article><article data-type="fig" id="figobml306f3"><div id="ml306.f3" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%203.%20Stability%20of%20ML306%20in%20DPBS%20(pH%207.&p=BOOKS&id=153223_ml306f3.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK153223/bin/ml306f3.jpg" alt="Figure 3. Stability of ML306 in DPBS (pH 7." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 3</span></h3><div class="caption"><p>Stability of <a href="/pcsubstance/?term=ML306[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML306</a> in DPBS (pH 7.4) buffer at room temperature over 48 hr (<i>Panel A</i>). Stability of <a href="/pcsubstance/?term=ML306[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML306</a> at pH 9 (<i>Panel B</i>) and pH 2 at room temperature over 24 hr (<i>Panel C</i>).</p></div></div></article><article data-type="fig" id="figobml306f11"><div id="ml306.f11" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK153223/bin/ml306f11.jpg" alt="Scheme 1. Synthetic route to probe ML306." /></div><h3><span class="label">Scheme 1</span><span class="title">Synthetic route to probe <b>ML306</b></span></h3></div></article><article data-type="fig" id="figobml306f12"><div id="ml306.f12" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK153223/bin/ml306f12.jpg" alt="Scheme 2. General synthetic routes to intermediates and analogs." /></div><h3><span class="label">Scheme 2</span><span class="title">General synthetic routes to intermediates and analogs</span></h3></div></article><article data-type="fig" id="figobml306f4"><div id="ml306.f4" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%204.%20Optimization%20of%20the%20apoferritin%2F1-AMA%20fluorescence%20assay.&p=BOOKS&id=153223_ml306f4.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK153223/bin/ml306f4.jpg" alt="Figure 4. Optimization of the apoferritin/1-AMA fluorescence assay." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 4</span><span class="title">Optimization of the apoferritin/1-AMA fluorescence assay</span></h3><div class="caption"><p>A) and B) are scatter plots of the top LOPAC concentration plate run on Envision (ex: 380 nm/em: 535 nm) and on ViewLux (ex: 340 nm/em: 530 nm), respectively; C) Effect of 0.1% PEG 400 in an AmpC β-lactamase absorbance assay using a known aggregator, TIPP</p></div></div></article><article data-type="fig" id="figobml306f5"><div id="ml306.f5" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK153223/bin/ml306f5.jpg" alt="Figure 5. Summary of apoferritin/1-AMA screening results." /></div><h3><span class="label">Figure 5</span><span class="title">Summary of apoferritin/1-AMA screening results</span></h3><div class="caption"><p>A) scatter plot of Z’ values of the apoferritin/1-AMA assay across all screened plates (average Z’: 0.76); B) 3D plot of qHTS data with control titrations (shown in green), high confidence actives (dark blue) and weak actives (light blue)</p></div></div></article><article data-type="fig" id="figobml306f6"><div id="ml306.f6" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK153223/bin/ml306f6.jpg" alt="Figure 6. Critical path work flow for the identification of small molecule inhibitors of apoferritin/1-AMA interaction that possess general anesthetic properties." /></div><h3><span class="label">Figure 6</span><span class="title">Critical path work flow for the identification of small molecule inhibitors of apoferritin/1-AMA interaction that possess general anesthetic properties</span></h3></div></article><article data-type="fig" id="figobml306f7"><div id="ml306.f7" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK153223/bin/ml306f7.jpg" alt="Figure 7. Initial hit identified from the qHTS and validated using apoferritin and tadpole assays." /></div><h3><span class="label">Figure 7</span><span class="title">Initial hit identified from the qHTS and validated using apoferritin and tadpole assays</span></h3></div></article><article data-type="fig" id="figobml306f8"><div id="ml306.f8" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK153223/bin/ml306f8.jpg" alt="b2-g71" /></div><h3><span class="label">Figure 8</span><span class="title">Isothermal Titration Calorimetry (ITC) of the HSAF interaction with ML306 (K<sub>D</sub> = 8.2 μM)</span></h3></div></article><article data-type="table-wrap" id="figobml306t2"><div id="ml306.t2" class="table"><h3><span class="label">Table 2</span><span class="title">General anesthetic profile in tadpoles and inhibition of 1-AMA/Apofferitin interaction</span></h3><div class="caption"><p>Representative Analogs (modification at 6-position of the pyridazin-3-one). All analogs were synthesized at NCGC</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK153223/table/ml306.t2/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml306.t2_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_ml306.t2_1_1_1_1" colspan="8" rowspan="1" style="text-align:center;vertical-align:top;">
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<div class="graphic"><img src="/books/NBK153223/bin/ml306fu3.jpg" alt="Image ml306fu3.jpg" /></div></th></tr><tr><th headers="hd_h_ml306.t2_1_1_1_1" id="hd_h_ml306.t2_1_1_2_1" colspan="8" rowspan="1" style="text-align:left;vertical-align:top;">
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<span class="hr"></span></th></tr><tr><th headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1" id="hd_h_ml306.t2_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Entry</th><th headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1" id="hd_h_ml306.t2_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">CID</th><th headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1" id="hd_h_ml306.t2_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">SID</th><th headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1" id="hd_h_ml306.t2_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">NCGC IDs</th><th headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1" id="hd_h_ml306.t2_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">R</th><th headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1" id="hd_h_ml306.t2_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">IC<sub>50</sub> (μM)<sup>a</sup></th><th headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1" id="hd_h_ml306.t2_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">% immobility<sup>b</sup></th><th headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1" id="hd_h_ml306.t2_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">toxicity<sup>c</sup></th></tr></thead><tbody><tr><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>1</b></td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">45548816</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134419067" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134419067</a></td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">NCGC00262353</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>H</b></td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">inactive</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">5</td></tr><tr><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>2</b></td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">49704509</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134419066" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134419066</a></td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">NCGC00262352</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>CH</b><b><sub>3</sub></b></td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">24.2</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">5</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">15</td></tr><tr><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>3</b></td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">56643049</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134419068" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134419068</a></td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">NCGC00262354</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>isopropyl</b></td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">inactive</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">5</td></tr><tr><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>4</b></td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">56643049</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134419069" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134419069</a></td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">NCGC00262355</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>cyclopropyl</b></td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">inactive</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">5</td></tr><tr><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>5</b></td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">56643032</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134419051" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134419051</a></td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">NCGC00262337</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>cyclohexyl</b></td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">12.1</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">40</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">5</td></tr><tr><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>6</b></td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">5053472</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134419085" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134419085</a></td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">NCGC00262371</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>phenyl</b></td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">5.4</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">20</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">5</td></tr><tr><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>7</b></td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">5070704</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/13449032" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">13449032</a></td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">NCGC00140268</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>4-CH<sub>3</sub>-phenyl</b></td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">3.04</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">90</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td></tr><tr><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>8</b></td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">56643035</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134419049" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134419049</a></td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">NCGC00262335</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>3-CH<sub>3</sub>-phenyl</b></td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">3.4</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">20</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">5</td></tr><tr><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>9</b></td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">7671962</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134419050" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134419050</a></td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">NCGC00262336</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>2-CH<sub>3</sub>-phenyl</b></td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">19.2</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10</td></tr><tr><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>10</b></td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">4993789</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134419033" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134419033</a></td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">NCGC00140457</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>4-OCH<sub>3</sub>-phenyl</b></td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">4.3</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">75</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">5</td></tr><tr><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>11</b></td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">7665103</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134419055" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134419055</a></td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">NCGC00262341</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>3-OCH<sub>3</sub>-phenyl</b></td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">3.0</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">30</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10</td></tr><tr><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>12</b></td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">7665103</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134419054" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134419054</a></td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">NCGC00262340</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>2-OCH<sub>3</sub>-phenyl</b></td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">17.1</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">5</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">15</td></tr><tr><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>13</b></td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">7664506</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134419046" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134419046</a></td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">NCGC00262332</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>4-F-phenyl</b></td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">4.8</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">5</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td></tr><tr><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>14</b></td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">56643067</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134419087" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134419087</a></td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">NCGC00262373</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>4-CF<sub>3</sub>-phenyl</b></td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">9.6</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">5</td></tr><tr><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>15</b></td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">56643069</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134419089" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134419089</a></td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">NCGC00262375</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>4-CN-phenyl</b></td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">5.4</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">5</td></tr><tr><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>16</b></td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">56643059</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134419061" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134419061</a></td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">NCGC00262347</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>4-OCF<sub>3</sub>-phenyl</b></td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">13.6</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">80</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10</td></tr><tr><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>17</b></td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">56643068</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134419057" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134419057</a></td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">NCGC00262343</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>4-NMe<sub>2</sub>-phenyl</b></td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">3.8</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10</td></tr><tr><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>18</b></td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">56643038</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134419060" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134419060</a></td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">NCGC00262346</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>4-(2-PrO)-phenyl</b></td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">4.8</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">95</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">5</td></tr><tr><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>19</b></td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">56643051</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134419062" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134419062</a></td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">NCGC00262348</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>4-isobutyloxyphenyl</b></td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">13.6</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">100</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td></tr><tr><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>20</b></td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">56643060</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134419088" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134419088</a></td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">NCGC00262374</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>4-<i>n</i>-Bu-phenyl</b></td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">4.8</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">5</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">5</td></tr><tr><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>21</b></td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">56643052</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134419063" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134419063</a></td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">NCGC00262349</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>4-<i>t</i>-Bu-phenyl</b></td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">6.8</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">90</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10</td></tr><tr><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>22</b></td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">7663799</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134419047" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134419047</a></td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">NCGC00262333</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>3,4-methylenedioxyphenyl</b></td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">4.3</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td></tr><tr><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>23</b></td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">56643026</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134419053" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134419053</a></td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">NCGC00262339</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>4-CH<sub>3</sub>SO<sub>2</sub>-phenyl</b></td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">21.5</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">5</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">5</td></tr><tr><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>24</b></td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">7659957</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134419056" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134419056</a></td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">NCGC00262342</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>3,4-(OCH<sub>3</sub>)<sub>2</sub>-phenyl</b></td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10.8</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">15</td></tr><tr><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>25</b></td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">56643055</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134419048" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134419048</a></td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">NCGC00262334</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>4-pyridyl</b></td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">30.4</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">5</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10</td></tr><tr><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>26</b></td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">56643062</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134419064" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134419064</a></td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">NCGC00262350</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>3-pyridyl</b></td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">24.2</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">15</td></tr><tr><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>27</b></td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">56643057</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134419065" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134419065</a></td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">NCGC00262351</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>2-CH<sub>3</sub>-3-pyridyl</b></td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">5.4</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td><td headers="hd_h_ml306.t2_1_1_1_1 hd_h_ml306.t2_1_1_2_1 hd_h_ml306.t2_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>a</dt><dd><div id="ml306.tfn1"><p class="no_margin">qhts IC<sub>50</sub>;</p></div></dd></dl><dl class="bkr_refwrap"><dt>b</dt><dd><div id="ml306.tfn2"><p class="no_margin">Tadpole experiment immobility at 10 μM after 60 min;</p></div></dd></dl><dl class="bkr_refwrap"><dt>c</dt><dd><div id="ml306.tfn3"><p class="no_margin">% immobility after 24 h (10 μM)</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobml306t3"><div id="ml306.t3" class="table"><h3><span class="label">Table 3</span><span class="title">General anesthetic profile in tadpoles and inhibition of 1-AMA/Apofferitin interaction</span></h3><div class="caption"><p>Representative Analogs (modification of the core). All analogs were synthesized at NCGC</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK153223/table/ml306.t3/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml306.t3_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_ml306.t3_1_1_1_1" colspan="8" rowspan="1" style="text-align:center;vertical-align:top;">
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<span class="hr"></span></th></tr><tr><th headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1" id="hd_h_ml306.t3_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Entry</th><th headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1" id="hd_h_ml306.t3_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID</th><th headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1" id="hd_h_ml306.t3_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">SID</th><th headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1" id="hd_h_ml306.t3_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">NCGC IDs</th><th headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1" id="hd_h_ml306.t3_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">R</th><th headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1" id="hd_h_ml306.t3_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">IC<sub>50</sub> (μM)<sup>a</sup></th><th headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1" id="hd_h_ml306.t3_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">% immobility<sup>b</sup></th><th headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1" id="hd_h_ml306.t3_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">toxicity<sup>c</sup></th></tr></thead><tbody><tr><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>28</b></td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">56643042</td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134419074" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134419074</a></td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">NCGC00262360</td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
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<div class="graphic"><img src="/books/NBK153223/bin/ml306fu4.jpg" alt="Image ml306fu4.jpg" /></div></td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">4.3</td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td></tr><tr><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>29</b></td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">56643028</td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134419071" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134419071</a></td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">NCGC00262357</td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
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<div class="graphic"><img src="/books/NBK153223/bin/ml306fu5.jpg" alt="Image ml306fu5.jpg" /></div></td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">3.0</td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td></tr><tr><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>30</b></td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">56643041</td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134419073" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134419073</a></td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">NCGC00262359</td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
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<div class="graphic"><img src="/books/NBK153223/bin/ml306fu6.jpg" alt="Image ml306fu6.jpg" /></div></td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">12.1</td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td></tr><tr><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>31</b></td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">56643047</td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134419076" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134419076</a></td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">NCGC00262362</td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
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<div class="graphic"><img src="/books/NBK153223/bin/ml306fu7.jpg" alt="Image ml306fu7.jpg" /></div></td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">24.1</td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">5</td></tr><tr><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>32</b></td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">56643030</td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134419075" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134419075</a></td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">NCGC00262361</td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
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<div class="graphic"><img src="/books/NBK153223/bin/ml306fu8.jpg" alt="Image ml306fu8.jpg" /></div></td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">inactive</td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td></tr><tr><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>33</b></td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">56643065</td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134419042" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134419042</a></td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">NCGC00249440</td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
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<div class="graphic"><img src="/books/NBK153223/bin/ml306fu9.jpg" alt="Image ml306fu9.jpg" /></div></td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">4.8</td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">95</td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">45</td></tr><tr><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>34</b></td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">135363127</td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/56844190" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">56844190</a></td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">NCGC00250074</td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
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<div class="graphic"><img src="/books/NBK153223/bin/ml306fu4.jpg" alt="Image ml306fu4.jpg" /></div></td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">14.5</td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10</td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td></tr><tr><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>35</b></td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">56643039</td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134419045" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134419045</a></td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">NCGC00250075</td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
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<div class="graphic"><img src="/books/NBK153223/bin/ml306fu5.jpg" alt="Image ml306fu5.jpg" /></div></td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">6.1</td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td></tr><tr><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>36</b></td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">135363124</td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/56844193" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">56844193</a></td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">NCGC00250071</td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
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<div class="graphic"><img src="/books/NBK153223/bin/ml306fu6.jpg" alt="Image ml306fu6.jpg" /></div></td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">14.5</td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td></tr><tr><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>37</b></td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">135363126</td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/56844195" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">56844195</a></td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">NCGC00250073</td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
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<div class="graphic"><img src="/books/NBK153223/bin/ml306fu10.jpg" alt="Image ml306fu10.jpg" /></div></td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">inactive</td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td></tr><tr><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>38</b></td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">135363128</td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/56844194" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">56844194</a></td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">NCGC00250077</td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
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<div class="graphic"><img src="/books/NBK153223/bin/ml306fu7.jpg" alt="Image ml306fu7.jpg" /></div></td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">inactive</td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10</td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td></tr><tr><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>39</b></td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">135363123</td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/56844191" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">56844191</a></td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">NCGC00250070</td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
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<div class="graphic"><img src="/books/NBK153223/bin/ml306fu8.jpg" alt="Image ml306fu8.jpg" /></div></td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">inactive</td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td></tr><tr><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>40</b></td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">135363121</td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/56844197" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">56844197</a></td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">NCGC00249762</td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
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<div class="graphic"><img src="/books/NBK153223/bin/ml306fu11.jpg" alt="Image ml306fu11.jpg" /></div></td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">9. 2</td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10</td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td></tr><tr><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>41</b></td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">56643058</td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134419043" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134419043</a></td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">NCGC00249763</td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
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<div class="graphic"><img src="/books/NBK153223/bin/ml306fu12.jpg" alt="Image ml306fu12.jpg" /></div></td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">21.5</td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td></tr><tr><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>42</b></td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">135363125</td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/56844196" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">56844196</a></td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">NCGC00250072</td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
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<div class="graphic"><img src="/books/NBK153223/bin/ml306fu13.jpg" alt="Image ml306fu13.jpg" /></div></td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">18.2</td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td><td headers="hd_h_ml306.t3_1_1_1_1 hd_h_ml306.t3_1_1_2_1 hd_h_ml306.t3_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>a</dt><dd><div id="ml306.tfn4"><p class="no_margin">qhts IC<sub>50</sub>;</p></div></dd></dl><dl class="bkr_refwrap"><dt>b</dt><dd><div id="ml306.tfn5"><p class="no_margin">Tadpole experiment immobility at 10 μM over 60 min;</p></div></dd></dl><dl class="bkr_refwrap"><dt>c</dt><dd><div id="ml306.tfn6"><p class="no_margin">% immobility at 24 h (10 μM)</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobml306t4"><div id="ml306.t4" class="table"><h3><span class="label">Table 4</span><span class="title">General anesthetic profile in tadpoles and APO inhibition</span></h3><div class="caption"><p>Representative Analogs (modification of the side chain). All analogs were synthesized at NCGC</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK153223/table/ml306.t4/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml306.t4_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_ml306.t4_1_1_1_1" colspan="8" rowspan="1" style="text-align:center;vertical-align:top;">
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<div class="graphic"><img src="/books/NBK153223/bin/ml306fu14.jpg" alt="Image ml306fu14.jpg" /></div></th></tr><tr><th headers="hd_h_ml306.t4_1_1_1_1" id="hd_h_ml306.t4_1_1_2_1" colspan="8" rowspan="1" style="text-align:left;vertical-align:top;">
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<span class="hr"></span></th></tr><tr><th headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1" id="hd_h_ml306.t4_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Entry</th><th headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1" id="hd_h_ml306.t4_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">CID</th><th headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1" id="hd_h_ml306.t4_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">SID</th><th headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1" id="hd_h_ml306.t4_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">NCGC IDs</th><th headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1" id="hd_h_ml306.t4_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">R</th><th headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1" id="hd_h_ml306.t4_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">IC<sub>50</sub> (μM)<sup>a</sup></th><th headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1" id="hd_h_ml306.t4_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">% immobility<sup>b</sup></th><th headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1" id="hd_h_ml306.t4_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">toxicity<sup>c</sup></th></tr></thead><tbody><tr><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>43</b></td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">56643048</td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134419034" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134419034</a></td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">NCGC00189159</td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
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<div class="graphic"><img src="/books/NBK153223/bin/ml306fu15.jpg" alt="Image ml306fu15.jpg" /></div></td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">5.0</td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">90</td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td></tr><tr><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>44</b></td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">56643036</td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134419035" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134419035</a></td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">NCGC00249422</td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
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<div class="graphic"><img src="/books/NBK153223/bin/ml306fu16.jpg" alt="Image ml306fu16.jpg" /></div></td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">3.0</td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">95</td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td></tr><tr><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>45</b></td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">49852991</td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/104224352" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">104224352</a></td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">NCGC00189154</td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
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<div class="graphic"><img src="/books/NBK153223/bin/ml306fu17.jpg" alt="Image ml306fu17.jpg" /></div></td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">30.4</td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">85</td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td></tr><tr><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>46</b></td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">56643061</td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134419037" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134419037</a></td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">NCGC00249428</td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
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<div class="graphic"><img src="/books/NBK153223/bin/ml306fu18.jpg" alt="Image ml306fu18.jpg" /></div></td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">3.4</td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">85</td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td></tr><tr><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>47</b></td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">56643031</td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134419038" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134419038</a></td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">NCGC00249429</td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
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<div class="graphic"><img src="/books/NBK153223/bin/ml306fu19.jpg" alt="Image ml306fu19.jpg" /></div></td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">3.4</td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">85</td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td></tr><tr><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>48</b></td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">7662444</td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134419082" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134419082</a></td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">NCGC00262368</td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
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<div class="graphic"><img src="/books/NBK153223/bin/ml306fu20.jpg" alt="Image ml306fu20.jpg" /></div></td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">3.4</td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10</td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">5</td></tr><tr><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>49</b></td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">50925844</td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134419077" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134419077</a></td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">NCGC00262363</td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
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<div class="graphic"><img src="/books/NBK153223/bin/ml306fu21.jpg" alt="Image ml306fu21.jpg" /></div></td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">3.4</td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">65</td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td></tr><tr><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>50</b></td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">56643046</td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134419052" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134419052</a></td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">NCGC00262338</td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
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<div class="graphic"><img src="/books/NBK153223/bin/ml306fu22.jpg" alt="Image ml306fu22.jpg" /></div></td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">3. 0</td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">5</td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">20</td></tr><tr><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>51</b></td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">5099141</td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134419084" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134419084</a></td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">NCGC00262370</td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
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<div class="graphic"><img src="/books/NBK153223/bin/ml306fu23.jpg" alt="Image ml306fu23.jpg" /></div></td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">17.1</td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">5</td></tr><tr><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>52</b></td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">49852775</td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/104224356" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">104224356</a></td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">NCGC00189158</td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
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<div class="graphic"><img src="/books/NBK153223/bin/ml306fu24.jpg" alt="Image ml306fu24.jpg" /></div></td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">15.2</td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td></tr><tr><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>53</b></td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">56643034</td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134419039" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134419039</a></td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">NCGC00249431</td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
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<div class="graphic"><img src="/books/NBK153223/bin/ml306fu25.jpg" alt="Image ml306fu25.jpg" /></div></td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10.2</td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">100</td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">100</td></tr><tr><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>54</b></td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">4582591</td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/104224364" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">104224364</a></td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">NCGC00189166</td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
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<div class="graphic"><img src="/books/NBK153223/bin/ml306fu26.jpg" alt="Image ml306fu26.jpg" /></div></td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">31. 6</td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">-</td></tr><tr><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>55</b></td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">49853286</td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/104224370" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">104224370</a></td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">NCGC00189172</td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
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<div class="graphic"><img src="/books/NBK153223/bin/ml306fu27.jpg" alt="Image ml306fu27.jpg" /></div></td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">29.2</td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">-</td></tr><tr><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>56</b></td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">3241729</td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/104223755" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">104223755</a></td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">NCGC00050102</td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
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<div class="graphic"><img src="/books/NBK153223/bin/ml306fu28.jpg" alt="Image ml306fu28.jpg" /></div></td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">35.5</td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">-</td></tr><tr><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>57</b></td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">56643066</td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134419078" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134419078</a></td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">NCGC00262364</td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
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<div class="graphic"><img src="/books/NBK153223/bin/ml306fu29.jpg" alt="Image ml306fu29.jpg" /></div></td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">15.2</td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td></tr><tr><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>58</b></td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">56643054</td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134419083" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134419083</a></td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">NCGC00262369</td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
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<div class="graphic"><img src="/books/NBK153223/bin/ml306fu30.jpg" alt="Image ml306fu30.jpg" /></div></td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">8.6</td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">5</td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td></tr><tr><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>59</b></td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">56643063</td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134419086" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134419086</a></td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">NCGC00262372</td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
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<div class="graphic"><img src="/books/NBK153223/bin/ml306fu31.jpg" alt="Image ml306fu31.jpg" /></div></td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">inactive</td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td></tr><tr><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>60</b></td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">56643037</td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134419081" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134419081</a></td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">NCGC00262367</td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
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<div class="graphic"><img src="/books/NBK153223/bin/ml306fu32.jpg" alt="Image ml306fu32.jpg" /></div></td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">3.0</td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">5</td></tr><tr><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>61</b></td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">56643027</td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134419040" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134419040</a></td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">NCGC00249436</td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
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<div class="graphic"><img src="/books/NBK153223/bin/ml306fu33.jpg" alt="Image ml306fu33.jpg" /></div></td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10.8</td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">95</td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td></tr><tr><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>62</b></td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">56643040</td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134419041" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134419041</a></td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">NCGC00249437</td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
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<div class="graphic"><img src="/books/NBK153223/bin/ml306fu34.jpg" alt="Image ml306fu34.jpg" /></div></td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">12.1</td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td><td headers="hd_h_ml306.t4_1_1_1_1 hd_h_ml306.t4_1_1_2_1 hd_h_ml306.t4_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>a</dt><dd><div id="ml306.tfn7"><p class="no_margin">qhts IC<sub>50</sub>;</p></div></dd></dl><dl class="bkr_refwrap"><dt>b</dt><dd><div id="ml306.tfn8"><p class="no_margin">Tadpole experiment immobility at 10 μM over 60 min;</p></div></dd></dl><dl class="bkr_refwrap"><dt>c</dt><dd><div id="ml306.tfn9"><p class="no_margin">% immobility at 24 h (10 μM)</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobml306t5"><div id="ml306.t5" class="table"><h3><span class="label">Table 5</span><span class="title">General anesthetic profile in tadpoles and inhibition of 1-AMA/Apofferitin interaction</span></h3><div class="caption"><p>Representative Analogs (modification of the side chain). All analogs were synthesized at NCGC</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK153223/table/ml306.t5/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml306.t5_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_ml306.t5_1_1_1_1" colspan="8" rowspan="1" style="text-align:center;vertical-align:top;">
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<div class="graphic"><img src="/books/NBK153223/bin/ml306fu35.jpg" alt="Image ml306fu35.jpg" /></div></th></tr><tr><th headers="hd_h_ml306.t5_1_1_1_1" id="hd_h_ml306.t5_1_1_2_1" colspan="8" rowspan="1" style="text-align:left;vertical-align:top;">
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<span class="hr"></span></th></tr><tr><th headers="hd_h_ml306.t5_1_1_1_1 hd_h_ml306.t5_1_1_2_1" id="hd_h_ml306.t5_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Entry</th><th headers="hd_h_ml306.t5_1_1_1_1 hd_h_ml306.t5_1_1_2_1" id="hd_h_ml306.t5_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">CID</th><th headers="hd_h_ml306.t5_1_1_1_1 hd_h_ml306.t5_1_1_2_1" id="hd_h_ml306.t5_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">SID</th><th headers="hd_h_ml306.t5_1_1_1_1 hd_h_ml306.t5_1_1_2_1" id="hd_h_ml306.t5_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">NCGC IDs</th><th headers="hd_h_ml306.t5_1_1_1_1 hd_h_ml306.t5_1_1_2_1" id="hd_h_ml306.t5_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">R</th><th headers="hd_h_ml306.t5_1_1_1_1 hd_h_ml306.t5_1_1_2_1" id="hd_h_ml306.t5_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">I C<sub>50</sub> (mM)<sup>a</sup></th><th headers="hd_h_ml306.t5_1_1_1_1 hd_h_ml306.t5_1_1_2_1" id="hd_h_ml306.t5_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">% immobility<sup>b</sup></th><th headers="hd_h_ml306.t5_1_1_1_1 hd_h_ml306.t5_1_1_2_1" id="hd_h_ml306.t5_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">toxicity<sup>c</sup></th></tr></thead><tbody><tr><td headers="hd_h_ml306.t5_1_1_1_1 hd_h_ml306.t5_1_1_2_1 hd_h_ml306.t5_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>63</b></td><td headers="hd_h_ml306.t5_1_1_1_1 hd_h_ml306.t5_1_1_2_1 hd_h_ml306.t5_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">135363119</td><td headers="hd_h_ml306.t5_1_1_1_1 hd_h_ml306.t5_1_1_2_1 hd_h_ml306.t5_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/56844198" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">56844198</a></td><td headers="hd_h_ml306.t5_1_1_1_1 hd_h_ml306.t5_1_1_2_1 hd_h_ml306.t5_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">NCGC00249760</td><td headers="hd_h_ml306.t5_1_1_1_1 hd_h_ml306.t5_1_1_2_1 hd_h_ml306.t5_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
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<div class="graphic"><img src="/books/NBK153223/bin/ml306fu36.jpg" alt="Image ml306fu36.jpg" /></div></td><td headers="hd_h_ml306.t5_1_1_1_1 hd_h_ml306.t5_1_1_2_1 hd_h_ml306.t5_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">inactive</td><td headers="hd_h_ml306.t5_1_1_1_1 hd_h_ml306.t5_1_1_2_1 hd_h_ml306.t5_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td><td headers="hd_h_ml306.t5_1_1_1_1 hd_h_ml306.t5_1_1_2_1 hd_h_ml306.t5_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td></tr><tr><td headers="hd_h_ml306.t5_1_1_1_1 hd_h_ml306.t5_1_1_2_1 hd_h_ml306.t5_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>64</b></td><td headers="hd_h_ml306.t5_1_1_1_1 hd_h_ml306.t5_1_1_2_1 hd_h_ml306.t5_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">3245279</td><td headers="hd_h_ml306.t5_1_1_1_1 hd_h_ml306.t5_1_1_2_1 hd_h_ml306.t5_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/4251618" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">4251618</a></td><td headers="hd_h_ml306.t5_1_1_1_1 hd_h_ml306.t5_1_1_2_1 hd_h_ml306.t5_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">NCGC00065315</td><td headers="hd_h_ml306.t5_1_1_1_1 hd_h_ml306.t5_1_1_2_1 hd_h_ml306.t5_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
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<div class="graphic"><img src="/books/NBK153223/bin/ml306fu37.jpg" alt="Image ml306fu37.jpg" /></div></td><td headers="hd_h_ml306.t5_1_1_1_1 hd_h_ml306.t5_1_1_2_1 hd_h_ml306.t5_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">18.2</td><td headers="hd_h_ml306.t5_1_1_1_1 hd_h_ml306.t5_1_1_2_1 hd_h_ml306.t5_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td><td headers="hd_h_ml306.t5_1_1_1_1 hd_h_ml306.t5_1_1_2_1 hd_h_ml306.t5_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td></tr><tr><td headers="hd_h_ml306.t5_1_1_1_1 hd_h_ml306.t5_1_1_2_1 hd_h_ml306.t5_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>65</b></td><td headers="hd_h_ml306.t5_1_1_1_1 hd_h_ml306.t5_1_1_2_1 hd_h_ml306.t5_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">135363122</td><td headers="hd_h_ml306.t5_1_1_1_1 hd_h_ml306.t5_1_1_2_1 hd_h_ml306.t5_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/51663603" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">51663603</a></td><td headers="hd_h_ml306.t5_1_1_1_1 hd_h_ml306.t5_1_1_2_1 hd_h_ml306.t5_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">NCGC00249765</td><td headers="hd_h_ml306.t5_1_1_1_1 hd_h_ml306.t5_1_1_2_1 hd_h_ml306.t5_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
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<div class="graphic"><img src="/books/NBK153223/bin/ml306fu38.jpg" alt="Image ml306fu38.jpg" /></div></td><td headers="hd_h_ml306.t5_1_1_1_1 hd_h_ml306.t5_1_1_2_1 hd_h_ml306.t5_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">inactive</td><td headers="hd_h_ml306.t5_1_1_1_1 hd_h_ml306.t5_1_1_2_1 hd_h_ml306.t5_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td><td headers="hd_h_ml306.t5_1_1_1_1 hd_h_ml306.t5_1_1_2_1 hd_h_ml306.t5_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10</td></tr><tr><td headers="hd_h_ml306.t5_1_1_1_1 hd_h_ml306.t5_1_1_2_1 hd_h_ml306.t5_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>66</b></td><td headers="hd_h_ml306.t5_1_1_1_1 hd_h_ml306.t5_1_1_2_1 hd_h_ml306.t5_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">135363120</td><td headers="hd_h_ml306.t5_1_1_1_1 hd_h_ml306.t5_1_1_2_1 hd_h_ml306.t5_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/56844192" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">56844192</a></td><td headers="hd_h_ml306.t5_1_1_1_1 hd_h_ml306.t5_1_1_2_1 hd_h_ml306.t5_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">NCGC00249761</td><td headers="hd_h_ml306.t5_1_1_1_1 hd_h_ml306.t5_1_1_2_1 hd_h_ml306.t5_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
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<div class="graphic"><img src="/books/NBK153223/bin/ml306fu39.jpg" alt="Image ml306fu39.jpg" /></div></td><td headers="hd_h_ml306.t5_1_1_1_1 hd_h_ml306.t5_1_1_2_1 hd_h_ml306.t5_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">18.2</td><td headers="hd_h_ml306.t5_1_1_1_1 hd_h_ml306.t5_1_1_2_1 hd_h_ml306.t5_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td><td headers="hd_h_ml306.t5_1_1_1_1 hd_h_ml306.t5_1_1_2_1 hd_h_ml306.t5_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td></tr><tr><td headers="hd_h_ml306.t5_1_1_1_1 hd_h_ml306.t5_1_1_2_1 hd_h_ml306.t5_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>67</b></td><td headers="hd_h_ml306.t5_1_1_1_1 hd_h_ml306.t5_1_1_2_1 hd_h_ml306.t5_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">56643045</td><td headers="hd_h_ml306.t5_1_1_1_1 hd_h_ml306.t5_1_1_2_1 hd_h_ml306.t5_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134419044" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134419044</a></td><td headers="hd_h_ml306.t5_1_1_1_1 hd_h_ml306.t5_1_1_2_1 hd_h_ml306.t5_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">NCGC00249766</td><td headers="hd_h_ml306.t5_1_1_1_1 hd_h_ml306.t5_1_1_2_1 hd_h_ml306.t5_1_1_3_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
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<div class="graphic"><img src="/books/NBK153223/bin/ml306fu40.jpg" alt="Image ml306fu40.jpg" /></div></td><td headers="hd_h_ml306.t5_1_1_1_1 hd_h_ml306.t5_1_1_2_1 hd_h_ml306.t5_1_1_3_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">21.5</td><td headers="hd_h_ml306.t5_1_1_1_1 hd_h_ml306.t5_1_1_2_1 hd_h_ml306.t5_1_1_3_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td><td headers="hd_h_ml306.t5_1_1_1_1 hd_h_ml306.t5_1_1_2_1 hd_h_ml306.t5_1_1_3_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>a</dt><dd><div id="ml306.tfn10"><p class="no_margin">qhts IC<sub>50</sub>;</p></div></dd></dl><dl class="bkr_refwrap"><dt>b</dt><dd><div id="ml306.tfn11"><p class="no_margin">Tadpole experiment immobility at 10 μM over 60 min;</p></div></dd></dl><dl class="bkr_refwrap"><dt>c</dt><dd><div id="ml306.tfn12"><p class="no_margin">% immobility at 24 h (10 μM)</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobml306t7"><div id="ml306.t7" class="table"><h3><span class="label">Table 7</span><span class="title">ADME profile for ML306</span></h3><div class="caption"><p>All experiments were conducted at Pharmaron Inc</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK153223/table/ml306.t7/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml306.t7_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_ml306.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Compound</th><th id="hd_h_ml306.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Solubility<sup>a</sup></th><th id="hd_h_ml306.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Caco-2 Permeability (10<sup>−6</sup> cm/s)</th><th id="hd_h_ml306.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Efflux Ratio</th><th id="hd_h_ml306.t7_1_1_1_5" colspan="2" rowspan="1" style="text-align:center;vertical-align:middle;">Microsomal Stability T<sub>1/2</sub> (min)<sup>b</sup></th><th id="hd_h_ml306.t7_1_1_1_6" colspan="2" rowspan="1" style="text-align:center;vertical-align:middle;">% CYP Inhibition @ 3 μM</th><th id="hd_h_ml306.t7_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Plasma Stability (mouse) % remaining (2 hr)</th><th id="hd_h_ml306.t7_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">PBS Buffer Stability % remaining (2 hr)</th></tr></thead><tbody><tr><td headers="hd_h_ml306.t7_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="/pcsubstance/?term=ML306[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML306</a></td><td headers="hd_h_ml306.t7_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">57.9 μM</td><td headers="hd_h_ml306.t7_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">8.2</td><td headers="hd_h_ml306.t7_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1.6</td><td headers="hd_h_ml306.t7_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">11 (human)</td><td headers="hd_h_ml306.t7_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">5.2 (mouse)</td><td headers="hd_h_ml306.t7_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">24 (2D6)<sup>c</sup></td><td headers="hd_h_ml306.t7_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">12 (3A4)<sup>d</sup></td><td headers="hd_h_ml306.t7_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">98.9</td><td headers="hd_h_ml306.t7_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">100%</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>a</dt><dd><div id="ml306.tfn13"><p class="no_margin">represents the kinetic solubility in PBS buffer (pH = 7.4).</p></div></dd></dl><dl class="bkr_refwrap"><dt>b</dt><dd><div id="ml306.tfn14"><p class="no_margin">represents the stability in the presence of NADPH. The probe compound showed no degradation without NADPH present over a 1 hr period.</p></div></dd></dl><dl class="bkr_refwrap"><dt>c</dt><dd><div id="ml306.tfn15"><p class="no_margin">dextromethorphan was used as the substrate.</p></div></dd></dl><dl class="bkr_refwrap"><dt>d</dt><dd><div id="ml306.tfn16"><p class="no_margin">midazolam was used as the substrate.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobml306t8"><div id="ml306.t8" class="table"><h3><span class="label">Table 8</span><span class="title"><i>In vivo</i> PK (mouse) at 40 mpk IV and 5 mpk IV</span></h3><div class="caption"><p>All experiments were conducted at Pharmaron Inc. with male CD1 mice (6–8 weeks of age). Data was collected in triplicate at 8 time points over a 24 hr period</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK153223/table/ml306.t8/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml306.t8_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_ml306.t8_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Compound</th><th id="hd_h_ml306.t8_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Route<sup>a</sup></th><th id="hd_h_ml306.t8_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">T<sub>1/2</sub> (h)</th><th id="hd_h_ml306.t8_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">C<sub>o</sub> (ng/mL)</th><th id="hd_h_ml306.t8_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">AUC<sub>inf</sub> (h*ng/mL)</th><th id="hd_h_ml306.t8_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">C<sub>max</sub> (brain) (ng/g)</th><th id="hd_h_ml306.t8_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">T<sub>max</sub> (brain) (hr)</th><th id="hd_h_ml306.t8_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">MRT<sup>b</sup> (hr)</th><th id="hd_h_ml306.t8_1_1_1_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Cl (mL/min/kg)</th><th id="hd_h_ml306.t8_1_1_1_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">P/B Ratio<sup>c</sup></th></tr></thead><tbody><tr><td headers="hd_h_ml306.t8_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="/pcsubstance/?term=ML306[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML306</a></td><td headers="hd_h_ml306.t8_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">IV (5 mpk)</td><td headers="hd_h_ml306.t8_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.28</td><td headers="hd_h_ml306.t8_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">7878</td><td headers="hd_h_ml306.t8_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">1508</td><td headers="hd_h_ml306.t8_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">ND</td><td headers="hd_h_ml306.t8_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">ND</td><td headers="hd_h_ml306.t8_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.27</td><td headers="hd_h_ml306.t8_1_1_1_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">56.5</td><td headers="hd_h_ml306.t8_1_1_1_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">ND</td></tr><tr><td headers="hd_h_ml306.t8_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="/pcsubstance/?term=ML306[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML306</a></td><td headers="hd_h_ml306.t8_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">IV (40 mpk)</td><td headers="hd_h_ml306.t8_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.21</td><td headers="hd_h_ml306.t8_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">65162</td><td headers="hd_h_ml306.t8_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">11596</td><td headers="hd_h_ml306.t8_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">22033</td><td headers="hd_h_ml306.t8_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.08</td><td headers="hd_h_ml306.t8_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.17</td><td headers="hd_h_ml306.t8_1_1_1_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">58.1</td><td headers="hd_h_ml306.t8_1_1_1_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2.4</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>a</dt><dd><div id="ml306.tfn17"><p class="no_margin">Both formulated as a solution [HP-β-CD in saline (1 g/mL)].</p></div></dd></dl><dl class="bkr_refwrap"><dt>b</dt><dd><div id="ml306.tfn18"><p class="no_margin">Mean residence time (the time for elimination of 63.2% of the IV dose).</p></div></dd></dl><dl class="bkr_refwrap"><dt>c</dt><dd><div id="ml306.tfn19"><p class="no_margin">Plasma to brain ratio [AUC<sub>last</sub>(plasma)/AUC<sub>last</sub>(brain)].</p></div></dd></dl></dl></div></div></div></article><article data-type="fig" id="figobml306f9"><div id="ml306.f9" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK153223/bin/ml306f9.jpg" alt="Figure 9. (A) PK plasma profile for ML306." /></div><h3><span class="label">Figure 9</span></h3><div class="caption"><p><b>(A)</b> PK plasma profile for <a href="/pcsubstance/?term=ML306[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML306</a>. CD1 Mice IV (40 mpk (blue) and 5 mpk (red)) dosed as a solution with n = 3 for each time point. <b>(b)</b> PK brain profile for <a href="/pcsubstance/?term=ML306[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML306</a>. CD1 Mice IV (40 mpk) dosed as a solution with n = 3 for each time point.</p></div></div></article><article data-type="fig" id="figobml306f10"><div id="ml306.f10" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK153223/bin/ml306f10.jpg" alt="Figure 10. SAR Summary." /></div><h3><span class="label">Figure 10</span><span class="title">SAR Summary</span></h3></div></article><article data-type="table-wrap" id="figobml306t6"><div id="ml306.t6" class="table"><h3><span class="label">Table 6</span><span class="title">ML306 <i>In vivo</i> loss of righting reflex (LORR) studies</span></h3><div class="caption"><p>Standard error shown for LORR time</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK153223/table/ml306.t6/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml306.t6_lrgtbl__"><table><thead><tr><th id="hd_h_ml306.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"># Mice</th><th id="hd_h_ml306.t6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Compound (mg/kg)</th><th id="hd_h_ml306.t6_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">HP-β-CD (mg/kg)</th><th id="hd_h_ml306.t6_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Injection volume (μL)</th><th id="hd_h_ml306.t6_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Average LORR (s)</th></tr></thead><tbody><tr><td headers="hd_h_ml306.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">4</td><td headers="hd_h_ml306.t6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0</td><td headers="hd_h_ml306.t6_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1304–2557</td><td headers="hd_h_ml306.t6_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">50–92.5</td><td headers="hd_h_ml306.t6_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N/A</td></tr><tr><td headers="hd_h_ml306.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">4</td><td headers="hd_h_ml306.t6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">40</td><td headers="hd_h_ml306.t6_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">815–890</td><td headers="hd_h_ml306.t6_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">25–32.5</td><td headers="hd_h_ml306.t6_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">N/A</td></tr><tr><td headers="hd_h_ml306.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">6</td><td headers="hd_h_ml306.t6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">80</td><td headers="hd_h_ml306.t6_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1647–1672</td><td headers="hd_h_ml306.t6_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">60–70</td><td headers="hd_h_ml306.t6_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">73 ± 45</td></tr><tr><td headers="hd_h_ml306.t6_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">3</td><td headers="hd_h_ml306.t6_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">100</td><td headers="hd_h_ml306.t6_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2098–2100</td><td headers="hd_h_ml306.t6_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">70–88.5</td><td headers="hd_h_ml306.t6_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">245 ± 64</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobml306t9"><div id="ml306.t9" class="table"><h3><span class="label">Table 9</span><span class="title">PDSP GPCR Profiling of ML306 and propofol tested at 1 μM concentration</span></h3><div class="caption"><p>White squares represent inactivity while blue squares represent fold stimulation at 1 μM</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK153223/table/ml306.t9/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml306.t9_lrgtbl__"><table><tbody><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">ADRB3</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">PTGIR</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">P2RY11</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">TSHR</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">LHCGR</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CALCRB</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">LTB4R2B</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">ADRA1B</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">GPR77</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">LPAR2</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">LPAR5</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">ADORA2B</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">GNRHR</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">UTS2R</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">HTR2CVSV</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">AVPR1A</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">ADRB2</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MC2R</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">OXTR</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SSTR3</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">OPRL1</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">AVPR1B</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">GRM2</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MC3R</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">NPY4R</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">PTGER1</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">DRD5</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">OXER1</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MCHR2</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">TRHR</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">HTR7</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">PTHR1</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CHRM3</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CYSLTR1</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CHRM4</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MLNR</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">NMUR1</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="/pcsubstance/?term=ML306[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML306</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="background-color:#16365C;color:#FFFFFF;text-align:left;vertical-align:top;">2.38</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="background-color:#16365C;color:#FFFFFF;text-align:left;vertical-align:top;">2.6</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="background-color:#16365C;color:#FFFFFF;text-align:left;vertical-align:top;">2.29</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><b>Propofol</b></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td rowspan="2" colspan="1" style="text-align:left;vertical-align:top;"></td><td colspan="37" rowspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MC1R</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MCHR1</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">DRD3</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">NPY1R</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">DRD1</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">LTB4R</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">GRM1</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">NPY2R</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">HCTR2</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">F2RL3</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CNR2</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">C3AR1</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">GRM7</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">PTGDR</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">ADORA2A</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">GHRHR</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MTNR1B</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">ADRA1A</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">HTR2CVGV</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">VIPR2</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">HCTR1</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">FSHR</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CNR1</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">DRD2</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">PTGER2</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">S1PR3</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">F2R</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">GRPR</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">HRH2</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">HTR2CINI</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">F2RL1</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">LPAR6</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">PTGFR</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">GRM6</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">GCGR</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">HTR2CVNV</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SSTR5</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="/pcsubstance/?term=ML306[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML306</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="background-color:#16365C;color:#FFFFFF;text-align:left;vertical-align:top;">2.07</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><b>Propofol</b></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="background-color:#16365C;color:#FFFFFF;text-align:left;vertical-align:top;">2.01</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="background-color:#16365C;color:#FFFFFF;text-align:left;vertical-align:top;">2.05</td></tr><tr><td rowspan="2" colspan="1" style="text-align:left;vertical-align:top;"></td><td colspan="37" rowspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">HTR6</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">GRM8</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">NTSR2</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">GIPR</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">GLP2R</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">PTH2R</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">BDKBR1</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">VIPR1</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CCKAR</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SSTR2</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">AGTR1</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">S1PR2</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">P2RY12</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">EDNRA</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">GLP1R</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">P2RY2</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SSTR4</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">OPRK1</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">S1PR5</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">GLP1R</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">S1PR1</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">GRM4</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">LPAR1</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">NMUR2</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CHRM2</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">HRH3</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CRHR2</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SCTR</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">NPY5R</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MC4R</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">ADRA2B</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">BDKBR2</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">DRD4</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">PTGER2</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">TACR2</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">OPRD1</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">GPR44</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="/pcsubstance/?term=ML306[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML306</a></td><td rowspan="1" colspan="1" style="background-color:#16365C;color:#FFFFFF;text-align:left;vertical-align:top;">2.22</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><b>Propofol</b></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td rowspan="2" colspan="1" style="text-align:left;vertical-align:top;"></td><td colspan="37" rowspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">PTGER4</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">HRH4</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MC5R</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CYSLTR2</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">NMBR</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CCKBR</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">GAL1</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">F2RL2</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SSTR1</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">TACR3</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MTNR1A</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">TACR1</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">HTR1A</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">AVPR2</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">S1PR4</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">HTR1D</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CHRM5</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">HTR2A</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CHRM1</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">AGTR2</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">P2RY6</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">P2RY4</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">ADORA1</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">PTAFR</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">P2RY1</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">HTR1B</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">P2RY13</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">HTR1F</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">HTR2B</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">HRH1</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">P2RY14</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">HTR5</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">GHSR</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">NTSR1</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">HTR1E</td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">HTR4</td><td rowspan="3" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="/pcsubstance/?term=ML306[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML306</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><b>Propofol</b></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr></tbody></table></div></div></article><article data-type="fig" id="figobml306fu3"><div id="ml306.fu3" class="figure"><div class="graphic"><img data-src="/books/NBK153223/bin/ml306fu41.jpg" alt="Image ml306fu41" /></div></div></article><article data-type="fig" id="figobml306f13"><div id="ml306.f13" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%20A1.%20LC-MS%20purity%20analysis%20for%20ML306.&p=BOOKS&id=153223_ml306f13.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK153223/bin/ml306f13.jpg" alt="Figure A1. LC-MS purity analysis for ML306." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure A1</span><span class="title">LC-MS purity analysis for ML306</span></h3></div></article><article data-type="fig" id="figobml306f14"><div id="ml306.f14" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%20A2.%201H%20NMR%20spectrum%20of%20ML306.&p=BOOKS&id=153223_ml306f14.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK153223/bin/ml306f14.jpg" alt="Figure A2. 1H NMR spectrum of ML306." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure A2</span><span class="title"><sup>1</sup>H NMR spectrum of ML306</span></h3></div></article><article data-type="fig" id="figobml306f15"><div id="ml306.f15" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%20A3.%2013C%20NMR%20spectrum%20of%20ML306.&p=BOOKS&id=153223_ml306f15.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK153223/bin/ml306f15.jpg" alt="Figure A3. 13C NMR spectrum of ML306." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure A3</span><span class="title"><sup>13</sup>C NMR spectrum of ML306</span></h3></div></article><article data-type="fig" id="figobml306fu4"><div id="ml306.fu4" class="figure"><div class="graphic"><img data-src="/books/NBK153223/bin/ml306fu42.jpg" alt="Image ml306fu42" /></div></div></article><article data-type="fig" id="figobml306fu5"><div id="ml306.fu5" class="figure"><div class="graphic"><img data-src="/books/NBK153223/bin/ml306fu43.jpg" alt="Image ml306fu43" /></div></div></article><article data-type="fig" id="figobml306fu6"><div id="ml306.fu6" class="figure"><div class="graphic"><img data-src="/books/NBK153223/bin/ml306fu44.jpg" alt="Image ml306fu44" /></div></div></article><article data-type="fig" id="figobml306fu7"><div id="ml306.fu7" class="figure"><div class="graphic"><img data-src="/books/NBK153223/bin/ml306fu45.jpg" alt="Image ml306fu45" /></div></div></article><article data-type="fig" id="figobml306fu8"><div id="ml306.fu8" class="figure"><div class="graphic"><img data-src="/books/NBK153223/bin/ml306fu46.jpg" alt="Image ml306fu46" /></div></div></article></div><div id="jr-scripts"><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/libs.min.js"> </script><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.min.js"> </script></div></div>
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