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<script type="text/javascript" src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.boots.min.js"> </script><title>Discovery of a Highly Selective in vitro and in vivo M4 Positive Allosteric Modulator (PAM) - 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 a Highly Selective in vitro and in vivo M4 Positive Allosteric Modulator (PAM)">
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<meta name="citation_publisher" content="National Center for Biotechnology Information (US)">
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<meta name="citation_date" content="2010/10/20">
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<meta name="citation_author" content="L Michelle Lewis">
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<meta name="citation_author" content="Thomas M Bridges">
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<meta name="citation_author" content="Colleen M Niswender">
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<meta name="citation_author" content="C David Weaver">
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<meta name="citation_author" content="Craig W Lindsley">
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<meta name="citation_pmid" content="21433380">
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<meta name="DC.Title" content="Discovery of a Highly Selective in vitro and in vivo M4 Positive Allosteric Modulator (PAM)">
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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="L Michelle Lewis">
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<meta name="DC.Contributor" content="Thomas M Bridges">
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<meta name="DC.Contributor" content="Colleen M Niswender">
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<meta name="DC.Contributor" content="C David Weaver">
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<meta name="DC.Contributor" content="Craig W Lindsley">
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<meta name="DC.Date" content="2010/10/20">
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<meta name="description" content="Clinical trials with xanomeline, an M1/M4-preferring muscarinic acetylcholine receptor (mAChR) subtype orthosteric agonist, have demonstrated its efficacy as both a cognition-enhancing agent and an antipsychotic agent. Although multiple studies suggest that M1 may also play an important role in the antipsychotic effects of mAChR agonists, the relative contributions of M1 and M4 to the antipsychotic efficacy of xanomeline or antipsychotic-like effects of this compound in animal models remain relatively unknown. Unfortunately, highly selective centrally penetrant activators of either M1 or M4 have not as yet been made available to date, thus making it difficult to determine the in vivo effects of selective activation of these receptors. Only recently did we develop a highly selective M1 allosteric agonist probe (CID-25010775) to study the role of selective M1 activation in vitro and in vivo; however, no such probe exists for M4. The currently identified probe ML108 (CID-864492) possesses unprecedented selectivity for the M4 receptor against M1, M2, M3 and M5, as well as a large panel of G protein-coupled receptors (GPCRs), ion channels and transporters. Moreover, the probe is centrally penetrant, possesses excellent PK, is active in preclinical antipsychotic behavioral models, and shows good solubility in acceptable vehicles. Thus, ML108 can be used both in vitro and in vivo to study the role of selective M4 receptor activation. In conjunction with the M1 allosteric agonist probe, CID-25010775, this potent and selective M4 positive allosteric modulator (PAM) will enable the biomedical community to dissect the pharmacology of xanomeline, and determine the pharmacological and therapeutic potential of selective M1 and M4 activation.">
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<meta name="og:title" content="Discovery of a Highly Selective in vitro and in vivo M4 Positive Allosteric Modulator (PAM)">
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<meta name="og:description" content="Clinical trials with xanomeline, an M1/M4-preferring muscarinic acetylcholine receptor (mAChR) subtype orthosteric agonist, have demonstrated its efficacy as both a cognition-enhancing agent and an antipsychotic agent. Although multiple studies suggest that M1 may also play an important role in the antipsychotic effects of mAChR agonists, the relative contributions of M1 and M4 to the antipsychotic efficacy of xanomeline or antipsychotic-like effects of this compound in animal models remain relatively unknown. Unfortunately, highly selective centrally penetrant activators of either M1 or M4 have not as yet been made available to date, thus making it difficult to determine the in vivo effects of selective activation of these receptors. Only recently did we develop a highly selective M1 allosteric agonist probe (CID-25010775) to study the role of selective M1 activation in vitro and in vivo; however, no such probe exists for M4. The currently identified probe ML108 (CID-864492) possesses unprecedented selectivity for the M4 receptor against M1, M2, M3 and M5, as well as a large panel of G protein-coupled receptors (GPCRs), ion channels and transporters. Moreover, the probe is centrally penetrant, possesses excellent PK, is active in preclinical antipsychotic behavioral models, and shows good solubility in acceptable vehicles. Thus, ML108 can be used both in vitro and in vivo to study the role of selective M4 receptor activation. In conjunction with the M1 allosteric agonist probe, CID-25010775, this potent and selective M4 positive allosteric modulator (PAM) will enable the biomedical community to dissect the pharmacology of xanomeline, and determine the pharmacological and therapeutic potential of selective M1 and M4 activation.">
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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="_NBK50687_"><span class="title" itemprop="name">Discovery of a Highly Selective <i>in vitro</i> and <i>in vivo</i> M4 Positive Allosteric Modulator (PAM)</span></h1><p class="contribs">Lewis LM, Bridges TM, Niswender CM, et al.</p><p class="fm-aai"><a href="#_NBK50687_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>Clinical trials with xanomeline, an M1/M4-preferring muscarinic acetylcholine receptor (mAChR) subtype orthosteric agonist, have demonstrated its efficacy as both a cognition-enhancing agent and an antipsychotic agent. Although multiple studies suggest that M1 may also play an important role in the antipsychotic effects of mAChR agonists, the relative contributions of M1 and M4 to the antipsychotic efficacy of xanomeline or antipsychotic-like effects of this compound in animal models remain relatively unknown. Unfortunately, highly selective centrally penetrant activators of either M1 or M4 have not as yet been made available to date, thus making it difficult to determine the in vivo effects of selective activation of these receptors. Only recently did we develop a highly selective M1 allosteric agonist probe (CID-25010775) to study the role of selective M1 activation in vitro and in vivo; however, no such probe exists for M4. The currently identified probe ML108 (CID-864492) possesses unprecedented selectivity for the M4 receptor against M1, M2, M3 and M5, as well as a large panel of G protein-coupled receptors (GPCRs), ion channels and transporters. Moreover, the probe is centrally penetrant, possesses excellent PK, is active in preclinical antipsychotic behavioral models, and shows good solubility in acceptable vehicles. Thus, ML108 can be used both in vitro and in vivo to study the role of selective M4 receptor activation. In conjunction with the M1 allosteric agonist probe, CID-25010775, this potent and selective M4 positive allosteric modulator (PAM) will enable the biomedical community to dissect the pharmacology of xanomeline, and determine the pharmacological and therapeutic potential of selective M1 and M4 activation.</p></div><div class="h2"></div><p><b>Assigned Assay Grant #:</b> MH077607-1</p><p><b>Screening Center Name & PI:</b> Vanderbilt Screening Center for GPCRs, Ion Channels and Transporters, C. David Weaver</p><p><b>Chemistry Center Name & PI:</b> Vanderbilt Specialized Chemistry Center for Accelerated Probe Development, Craig W. Lindsley</p><p><b>Assay Submitter & Institution:</b> Colleen M. Niswender, Vanderbilt University</p><p><b>PubChem Summary Bioassay Identifier (AID):</b>
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<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2616" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-2616</a></p><div id="ml108.s2"><h2 id="_ml108_s2_">Probe Structure & Characteristics</h2><p>3-amino-<i>N</i>-(4-methoxybenzyl)-4,6-dimethylthieno[2,3-<i>b</i>] pyridine-2-carboxamide</p><p>MW = 341.4, logP = 3.6, tPSA = 76.7</p><div id="ml108.fu1" class="figure"><div class="graphic"><img src="/books/NBK50687/bin/ml108fu1.jpg" alt="Image ml108fu1" /></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml108tu1"><a href="/books/NBK50687/table/ml108.tu1/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figml108tu1" rid-ob="figobml108tu1"><img class="small-thumb" src="/books/NBK50687/table/ml108.tu1/?report=thumb" src-large="/books/NBK50687/table/ml108.tu1/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ml108.tu1"><a href="/books/NBK50687/table/ml108.tu1/?report=objectonly" target="object" rid-ob="figobml108tu1">Table</a></h4></div></div></div><div id="ml108.s3"><h2 id="_ml108_s3_">Recommendations for the scientific use of this probe</h2><p>This probe (CID 864492) can be used both <i>in vitro</i> and in vivo to study the role of selective M4 receptor activation. This probe possesses unprecedented selectivity versus M1, M2, M3 and M5, as well as a large panel of GPCRs, ion channels and transporters. Moreover, this probe is centrally penetrant, possesses excellent PK, and is active in preclinical antipsychotic behavioral models. CID 864492 shows good solubility in acceptable vehicles (>20 mg/mL in 20% β-cyclodextrin and >100 μM in DMSO.</p><div id="ml108.s4"><h3>Specific AIM</h3><p>To identify small molecule positive allosteric modulators and/or allosteric agonists of the M4 muscarinic acetylcholine receptor that are cell permeable, possess submicromolar potency and show greater than 10-fold selectivity over the other mAChRs (M1, M2, M3 and M5) employing a functional HTS approach.</p></div><div id="ml108.s5"><h3>Significance</h3><p>To date, five muscarinic acetylcholine receptor (mAChR) subtypes have been identified
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(M1–M5) and play important roles in mediating the actions of ACh in the peripheral and
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central nervous systems. (<a class="bibr" href="#ml108.r1" rid="ml108.r1">1</a>) Of these, M1 and M4 are the
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most heavily expressed in the CNS and represent attractive therapeutic targets for cognition,
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Alzheimer’s disease, and schizophrenia. (<a class="bibr" href="#ml108.r2" rid="ml108.r2 ml108.r3 ml108.r4">2–4</a>) In contrast, the adverse effects of cholinergic agents are
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thought to be primarily due to activation of peripheral M2 and M3 mAChRs. (<a class="bibr" href="#ml108.r5" rid="ml108.r5">5</a>,<a class="bibr" href="#ml108.r6" rid="ml108.r6">6</a>) Due to the high sequence
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homology and conservation of the orthosteric ACh binding site among the mAChR subtypes, development
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of chemical agents that are selective for a single subtype has been largely unsuccessful, and in the
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absence of highly selective activators of M4, it has been impossible to test the role of selective
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M4 activation. Clinical trials with xanomeline, a M1/M4-preferring orthosteric agonist, demonstrated
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efficacy as both a cognition-enhancing agent and an antipsychotic agent. (<a class="bibr" href="#ml108.r7" rid="ml108.r7 ml108.r8 ml108.r9">7–9</a>) In follow-up studies in rats, xanomeline displayed an antipsychotic-like profile comparable to clozapine. (<a class="bibr" href="#ml108.r10" rid="ml108.r10">10</a>) However, a long standing question concerned whether or not the antipsychotic efficacy or antipsychotic-like activity in animal models is mediated by activation of M1, M4, or a combination of both receptors. Data from mAChR knockout mice led to the suggestion that a selective M1 agonist would be beneficial for cognition, whereas an M4 agonist would provide antipsychotic activity for the treatment of schizophrenia. (<a class="bibr" href="#ml108.r5" rid="ml108.r5">5</a>,<a class="bibr" href="#ml108.r6" rid="ml108.r6">6</a>,<a class="bibr" href="#ml108.r11" rid="ml108.r11">11</a>) This proposal is further supported by recent studies demonstrating that M4 receptors modulate the dynamics of cholinergic and dopaminergic neurotransmission and that loss of M4 function results in a state of dopamine hyperfunction. (<a class="bibr" href="#ml108.r12" rid="ml108.r12">12</a>) These data, coupled with findings that schizophrenic patients have altered hippocampal M4 but not M1 receptor expression, (<a class="bibr" href="#ml108.r13" rid="ml108.r13">13</a>) suggest that selective activators of M4 may provide a novel treatment strategy for schizophrenia patients. However, multiple studies suggest that M1 may also play an important role in the antipsychotic effects of mAChR agonists and that the relative contributions of M1 and M4 to the antipsychotic efficacy of xanomeline or antipsychotic-like effects of this compound in animal models are not known. However, highly selective centrally penetrant activators of either M1 or M4 have not been available, making it impossible to determine the in vivo effects of selective activation of these receptors. Only recently did we develop a highly selective M1 allosteric agonist probe (CID 25010775) to study the role of selective M1 activation <i>in vitro</i> and <i>in vivo</i>; however, no such probe existed for M4.</p></div><div id="ml108.s6"><h3>Rationale</h3><p>In recent years, major advances have been made in the discovery of highly selective agonists of
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other GPCRs that act at an allosteric site rather than the orthosteric site, (<a class="bibr" href="#ml108.r14" rid="ml108.r14">14</a>) as well as positive allosteric modulators (PAMs). (<a class="bibr" href="#ml108.r15" rid="ml108.r15">15</a>,<a class="bibr" href="#ml108.r16" rid="ml108.r16">16</a>) By screening for compounds that act at an allosteric site on the receptor, it is anticipated that compounds that can selectively activate the M4 receptor versus the other mAChR subtypes may be identified. In conjunction with our MLPCN M1 allosteric agonist probe (CID 25010775), development of a potent and selective M4 allosteric agonist or PAM will enable the biomedical community to dissect the pharmacology of xanomeline and determine the pharmacology and therapeutic potential of selective M1 and M4 activation.</p></div></div><div id="ml108.s7"><h2 id="_ml108_s7_">Assay Implementation and Screening</h2><div id="ml108.s8"><h3>PubChem Bioassay Name</h3><p>Discovery of Novel Allosteric Agonists of the M4 Muscarinic Receptor: Primary Screen</p></div><div id="ml108.s9"><h3>List of PubChem bioassay identifiers generated for this screening project (AIDs)</h3><p><b><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1921" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1921</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1923" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1923</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1928" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1928</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1929" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1929</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1930" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1930</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1932" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1932</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1938" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1938</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1939" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1939</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2616" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-2616</a>,
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<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/626" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-626</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/643" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-643</a></b></p></div><div id="ml108.s10"><h3>PubChem Primary Assay Description</h3><p>Chinese hamster ovary (CHO K1) cells stably expressing rat (r)M1 were purchased from the American Type Culture Collection (ATCC, Manassas, VA) and cultured according to their recommendations. CHO cells stably expressing human (h) M2, hM3, and hM5 were generously provided by A. Levey (Emory University, Atlanta, GA); rM4 cDNA provided by T. I. Bonner (National Institutes of Health, Bethesda, MD) was used to stably transfect CHO-K1 cells purchased from the ATCC using Lipofectamine 2000. To make stable hM2 and rM4 cell lines for use in calcium mobilization assays, cell lines were cotransfected with a chimeric G protein (G<sub>qi5</sub>) using Lipofectamine 2000. rM2, hM3, and hM5 cells were grown in Ham’s F-12 medium containing 10% heat-inactivated fetal bovine serum, 2 mM GlutaMax I, 20 mM HEPES, and 50 μg/ml G418 sulfate. hM2-Gqi5 cells were grown in the same medium supplemented with 500 μg/ml hygromycin B. Stable rM4 cells were grown in Dulbecco’s modified Eagle’s medium containing 10% heat-inactivated fetal bovine serum, 2 mM GlutaMax I, 1 mM sodium pyruvate, 0.1 mM nonessential amino acids, 20 mM HEPES, and 400 μg/ml G418 sulfate; rM4-G<sub>qi5</sub> cells were grown in the same medium supplemented with 500 μg/ml hygromycin B. CHO cells stably expressing rM1, hM3, or hM5 were plated at a seeding density of 50,000 cells/100 μl/well. CHO cells stably coexpressing hM2/G<sub>qi5</sub> and ratM4/G<sub>qi5</sub> were plated at a seeding density of 60,000 cells/100 μl/well. For calcium mobilization, cells were incubated in antibiotic-free medium overnight at 37°C/5% CO<sub>2</sub> and assayed the next day.</p></div><div id="ml108.s11"><h3>Calcium Mobilization Assay</h3><p>Cells were loaded with calcium indicator dye [2 μM Fluo-4 acetoxymethyl ester (50 μl/well) prepared as a stock in DMSO and mixed in a 1:1 ratio with 10% Pluronic acid F-127 in assay buffer (1×Hanks’ balanced salt solution supplemented with 20 mM HEPES and 2.5 mM probenecid, pH 7.4)] for 45 min at 37°C. Dye was removed and replaced with the appropriate volume of assay buffer. All compounds were serially diluted in assay buffer for a final 2× stock in 0.6% DMSO. This stock was then added to the assay plate for a final DMSO concentration of 0.3%. Acetylcholine (EC<sub>20</sub> concentration or full dose-response curve) was prepared at a 10× stock solution in assay buffer before addition to assay plates. Calcium mobilization was measured at 25°C using a FLEXstation II (Molecular Devices, Sunnyvale, CA). Cells were preincubated with test compound (or vehicle) for 1.5 min before the addition of the agonist, acetylcholine. Cells were then stimulated for 50 s with a submaximal concentration (EC<sub>20</sub>) or a full dose-response curve of acetylcholine. The signal amplitude was first normalized to baseline and then as a percentage of the maximal response to acetylcholine.</p></div><div id="ml108.s12"><h3>Summary of Screen</h3><p>This screen was performed in the pilot phase, the MLSCN, when the MLSMR compound collection at Vanderbilt only contained 12,364 compounds. From the primary M4 screen of 12,364 compounds, 69 putative M4 activators were identified with an average Z′ score of 0.67±0.093. The confirmation screen (singles at 10 μM) produced 25 active compounds. After a selectivity screen versus M1, only 4 compounds (<a class="figpopup" href="/books/NBK50687/figure/ml108.f1/?report=objectonly" target="object" rid-figpopup="figml108f1" rid-ob="figobml108f1">Figure 1</a>) appeared to be M4 selective. Chemistry was pursued around these four screening hits <b>1–4</b>, and 48 analogs were synthesized (25 analogs of <b>1–3</b> and 23 analogs of <b>4</b>); unfortunately, none of these confirmed as selective M4 agonist or PAMs.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml108f1" co-legend-rid="figlgndml108f1"><a href="/books/NBK50687/figure/ml108.f1/?report=objectonly" target="object" title="Figure 1" class="img_link icnblk_img figpopup" rid-figpopup="figml108f1" rid-ob="figobml108f1"><img class="small-thumb" src="/books/NBK50687/bin/ml108f1.gif" src-large="/books/NBK50687/bin/ml108f1.jpg" alt="Figure 1. M4 HTS hits." /></a><div class="icnblk_cntnt" id="figlgndml108f1"><h4 id="ml108.f1"><a href="/books/NBK50687/figure/ml108.f1/?report=objectonly" target="object" rid-ob="figobml108f1">Figure 1</a></h4><p class="float-caption no_bottom_margin">M4 HTS hits. </p></div></div><p>The project was shelved until a preliminary report from Eli Lilly (C.C. Felder, Eli Lilly,
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personal communication) showed that a new compound, LY2033298, was a robust, but weak, M4 PAM that
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is highly selective for <i>human</i> M4 (<a class="figpopup" href="/books/NBK50687/figure/ml108.f2/?report=objectonly" target="object" rid-figpopup="figml108f2" rid-ob="figobml108f2">Figure
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2</a>). However, to study selective M4 activation in a preclinical, academic setting, we, and the
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biomedical community at large, require a potent and selective M4 for <i>rat</i> M4.
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Therefore, we initiated a cheminformatics and database mining effort based on the LY2033298
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scaffold, to attempt to deliver a useful M4 PAM probe for the MLPCN Network that would possess
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appropriate potency (rM4 EC<sub>50</sub> < 500 nM), and be free from patent issues. (<a class="bibr" href="#ml108.r16" rid="ml108.r16">16</a>) A substructure search for commercially available compounds in the ChemBridge Corporation’s chemical database containing a core similar to LY2033298 delivered CID 714286 and related analogs, which were free of intellectual property issues. CID 714286 was a potent PAM of rat M4 (EC<sub>50</sub> = 400 nM) which induced a 47-fold leftward shift in the ACh CRC. Moreover, CID 714286 was highly selective for rat M4 (EC<sub>50</sub> > 50 μM for rM1, hM2, hM3 and hM5), binds at an allosteric site on the M4 receptor, increases affinity for ACh and increases coupling to G proteins. (<a class="bibr" href="#ml108.r17" rid="ml108.r17">17</a>) However, CID 714286 possessed a high log P (4.6) and was virtually insoluble in anything except DMSO. (<a class="bibr" href="#ml108.r17" rid="ml108.r17">17</a>)</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml108f2" co-legend-rid="figlgndml108f2"><a href="/books/NBK50687/figure/ml108.f2/?report=objectonly" target="object" title="Figure 2" class="img_link icnblk_img figpopup" rid-figpopup="figml108f2" rid-ob="figobml108f2"><img class="small-thumb" src="/books/NBK50687/bin/ml108f2.gif" src-large="/books/NBK50687/bin/ml108f2.jpg" alt="Figure 2. LY2033298 and cheminformatics and database mining approach leading to CID 714286." /></a><div class="icnblk_cntnt" id="figlgndml108f2"><h4 id="ml108.f2"><a href="/books/NBK50687/figure/ml108.f2/?report=objectonly" target="object" rid-ob="figobml108f2">Figure 2</a></h4><p class="float-caption no_bottom_margin">LY2033298 and cheminformatics and database mining approach leading to CID 714286. </p></div></div></div><div id="ml108.s13"><h3>Probe Chemical Lead Optimization Strategy</h3><p>For the chemical lead optimization of CID 714286, we employed a parallel synthesis approach to
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rapidly explore alternative amide moieties (<a class="figpopup" href="/books/NBK50687/figure/ml108.f3/?report=objectonly" target="object" rid-figpopup="figml108f3" rid-ob="figobml108f3">Figure 3</a>).
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Readily available acid <b>5</b> was treated with polymer-supported DCC, HOBt and one of 24
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different benzyl or heteroarylmethyl amines, followed by mass-directed preparative HPLC purification
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to deliver 24 analogs <b>6</b> of CID 714286. (<a class="bibr" href="#ml108.r18" rid="ml108.r18">18</a>)
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Clear SAR was observed for this set of analogs, with EC<sub>50</sub>s for rM4 potentiation ranging
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from 370 nM to >100 μM, and with fold-shifts ranging from 3.4- to 70-fold (<a class="figpopup" href="/books/NBK50687/table/ml108.t1/?report=objectonly" target="object" rid-figpopup="figml108t1" rid-ob="figobml108t1">Table 1</a>). Within this library, CID 713286, upon re-synthesis, displayed an EC<sub>50</sub> of 339 nM and 29-fold leftward shift of the ACh CRC. Attempts to install a basic nitrogen atom in the form of pyridyl analogs CID 44176129 and CID 20417337 to improve solubility led a diminution in rM4 potency (rM4 EC<sub>50</sub>s of 2.82 μM and 5.59 μM, respectively). Ultimately, ether-containing analogs such as CID 864492 (rM4EC<sub>50</sub> = 390 nM, 70-fold shift) and CID 1541501 (rM4EC<sub>50</sub> = 369 nM, 29-fold shift) emerged as attractive probe candidates, as they met the potency requirements for an MLPCN probe. Moreover, the log P values for both CID 864492 and CID 1541501 were measured as 3.4 – a full order of magnitude lower than the initial lead CID 714286. (<a class="bibr" href="#ml108.r18" rid="ml108.r18">18</a>) This reduced lipophilicity directly translated into improved solubility across a panel of 22 pharmaceutically acceptable vehicles – including aqueous vehicles such as 20% β-cyclodextrin, wherein both provided homogeneous solutions at 10 mg/mL. (<a class="bibr" href="#ml108.r18" rid="ml108.r18">18</a>)</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml108f3" co-legend-rid="figlgndml108f3"><a href="/books/NBK50687/figure/ml108.f3/?report=objectonly" target="object" title="Figure 3" class="img_link icnblk_img figpopup" rid-figpopup="figml108f3" rid-ob="figobml108f3"><img class="small-thumb" src="/books/NBK50687/bin/ml108f3.gif" src-large="/books/NBK50687/bin/ml108f3.jpg" alt="Figure 3. Optimization of CID 7142z86." /></a><div class="icnblk_cntnt" id="figlgndml108f3"><h4 id="ml108.f3"><a href="/books/NBK50687/figure/ml108.f3/?report=objectonly" target="object" rid-ob="figobml108f3">Figure 3</a></h4><p class="float-caption no_bottom_margin">Optimization of CID 7142z86. </p></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml108t1"><a href="/books/NBK50687/table/ml108.t1/?report=objectonly" target="object" title="Table 1" class="img_link icnblk_img figpopup" rid-figpopup="figml108t1" rid-ob="figobml108t1"><img class="small-thumb" src="/books/NBK50687/table/ml108.t1/?report=thumb" src-large="/books/NBK50687/table/ml108.t1/?report=previmg" alt="Table 1. Structures and SAR for Analogs of CID714286." /></a><div class="icnblk_cntnt"><h4 id="ml108.t1"><a href="/books/NBK50687/table/ml108.t1/?report=objectonly" target="object" rid-ob="figobml108t1">Table 1</a></h4><p class="float-caption no_bottom_margin">Structures and SAR for Analogs of CID714286. </p></div></div><p>Upon further study, both CID 864492 and CID 1541501 were found to be potent rM4 positive
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allosteric modulators, but due to the larger fold-shift observed with CID 864492 and the lack of
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significant ancillary pharmacology (<a class="figpopup" href="/books/NBK50687/table/ml108.t2/?report=objectonly" target="object" rid-figpopup="figml108t2" rid-ob="figobml108t2">Table 2</a>), we pursued CID 864492 as a potential MLPCN probe. As shown in <a class="figpopup" href="/books/NBK50687/figure/ml108.f4/?report=objectonly" target="object" rid-figpopup="figml108f4" rid-ob="figobml108f4">Figure 4A</a>, CID 864462 failed to elicit rM4 receptor activation in the absence of ACh (Flat line in A); however, when a submaximal (EC<sub>20</sub>) concentration of ACh is applied, concentration dependent rM4 activation is observed with an EC<sub>50</sub> of 390 nM. CID 864492 potentiates the response of rM4 to ACh, as manifested by a dose-dependent leftward shift of the ACh CRC. At the highest concentration tested (10 μM), CID 864492 induced a 70-fold shift of the ACh CRC. CID 864492 was also found to be highly selective for rM4 versus rM1, hM2, hM3 and hM5, as no shift in the ACh CRC was observed with 30 μM CID 864492 (<a class="figpopup" href="/books/NBK50687/figure/ml108.f5/?report=objectonly" target="object" rid-figpopup="figml108f5" rid-ob="figobml108f5">Figure 5A</a>).(<a class="bibr" href="#ml108.r18" rid="ml108.r18">18</a>)</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml108t2"><a href="/books/NBK50687/table/ml108.t2/?report=objectonly" target="object" title="Table 2" class="img_link icnblk_img figpopup" rid-figpopup="figml108t2" rid-ob="figobml108t2"><img class="small-thumb" src="/books/NBK50687/table/ml108.t2/?report=thumb" src-large="/books/NBK50687/table/ml108.t2/?report=previmg" alt="Table 2. MDS Lead Profiling Screen for CID 1541501 and CID 864492." /></a><div class="icnblk_cntnt"><h4 id="ml108.t2"><a href="/books/NBK50687/table/ml108.t2/?report=objectonly" target="object" rid-ob="figobml108t2">Table 2</a></h4><p class="float-caption no_bottom_margin">MDS Lead Profiling Screen for CID 1541501 and CID 864492. </p></div></div><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml108f4" co-legend-rid="figlgndml108f4"><a href="/books/NBK50687/figure/ml108.f4/?report=objectonly" target="object" title="Figure 4" class="img_link icnblk_img figpopup" rid-figpopup="figml108f4" rid-ob="figobml108f4"><img class="small-thumb" src="/books/NBK50687/bin/ml108f4.gif" src-large="/books/NBK50687/bin/ml108f4.jpg" alt="Figure 4. A) rM4 CRC in presence and absence of ACh EC20; B) ACh Fold-shift assay with CID 864492." /></a><div class="icnblk_cntnt" id="figlgndml108f4"><h4 id="ml108.f4"><a href="/books/NBK50687/figure/ml108.f4/?report=objectonly" target="object" rid-ob="figobml108f4">Figure 4</a></h4><p class="float-caption no_bottom_margin">A) rM4 CRC in presence and absence of ACh EC<sub>20</sub>; B) ACh Fold-shift assay with CID
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864492. </p></div></div><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml108f5" co-legend-rid="figlgndml108f5"><a href="/books/NBK50687/figure/ml108.f5/?report=objectonly" target="object" title="Figure 5" class="img_link icnblk_img figpopup" rid-figpopup="figml108f5" rid-ob="figobml108f5"><img class="small-thumb" src="/books/NBK50687/bin/ml108f5.gif" src-large="/books/NBK50687/bin/ml108f5.jpg" alt="Figure 5. A) mAChR selectivity of CID 864492 versus M1, M2, M3 and M5 at 30 μM; B) [3H]-NMS competition binding experiments with the orthosteric ligand atropine and CID 864492 and CID1541501." /></a><div class="icnblk_cntnt" id="figlgndml108f5"><h4 id="ml108.f5"><a href="/books/NBK50687/figure/ml108.f5/?report=objectonly" target="object" rid-ob="figobml108f5">Figure 5</a></h4><p class="float-caption no_bottom_margin">A) mAChR selectivity of CID 864492 versus M1, M2, M3 and M5 at 30 μM; B)
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[<sup>3</sup>H]-NMS competition binding experiments with the orthosteric ligand atropine and CID 864492 and CID1541501. </p></div></div><p><a class="figpopup" href="/books/NBK50687/figure/ml108.f5/?report=objectonly" target="object" rid-figpopup="figml108f5" rid-ob="figobml108f5">Figure 5B</a> shows that neither CID 864492 nor CID
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1541501 displace the mAChR orthosteric ligand [<sup>3</sup>H]-NMS in radioligand
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competition binding experiments (0.1 nM, [<sup>3</sup>H-NMS]), further supporting
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the allosteric mode of receptor activation, since the orthosteric antagonist readily competes for [<sup>3</sup>H-NMS] with a K<sub>i</sub> of 0.54 nM. (<a class="bibr" href="#ml108.r17" rid="ml108.r17">17</a>)</p><p>Due to the unprecedented mAChR and ancillary target selectivity, we felt that CID 864492, while a
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valuable <i>in vitro</i> probe to study selective rM4 activation, would be more valuable
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to the translational biomedical community if it were also an <i>in vivo</i> probe for rM4
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activation like our earlier M1 probes. Thus, we performed a brain/plasma study to determine if our rM4 PAM probe (CID 864492) was centrally penetrant after systemic dosing. When dosed at 56.6 mg/kg i.p. to male rats, CID 864492 displayed a 0.87 brain<sub>AUC</sub>/plasma<sub>AUC</sub> ratio (<a class="figpopup" href="/books/NBK50687/figure/ml108.f6/?report=objectonly" target="object" rid-figpopup="figml108f6" rid-ob="figobml108f6">Figure 6</a>) with comparable plasma t<sub>1/2</sub> (1.6 hr) to brain t<sub>1/2</sub> (1.25 hr). CID 864492 was cleared from plasma and brain after 4 hours with levels BLQ. The brain AUC far exceeded the 390 nM EC<sub>50</sub> for rM4 activation. This is an excellent profile for a CNS agent. Importantly, the animals were closely monitored, and were healthy, with no signs of classical pan-mAChR activation (SLUD – salivation, lacramation, urination and defecation), indicating that the <i>in vitro</i> selectivity profile was mirrored <i>in vivo</i>. (<a class="bibr" href="#ml108.r18" rid="ml108.r18">18</a>)</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml108f6" co-legend-rid="figlgndml108f6"><a href="/books/NBK50687/figure/ml108.f6/?report=objectonly" target="object" title="Figure 6" class="img_link icnblk_img figpopup" rid-figpopup="figml108f6" rid-ob="figobml108f6"><img class="small-thumb" src="/books/NBK50687/bin/ml108f6.gif" src-large="/books/NBK50687/bin/ml108f6.jpg" alt="Figure 6. Brain/plasma study with CID 864492 when dosed i.p. at 56.6 mg/kg." /></a><div class="icnblk_cntnt" id="figlgndml108f6"><h4 id="ml108.f6"><a href="/books/NBK50687/figure/ml108.f6/?report=objectonly" target="object" rid-ob="figobml108f6">Figure 6</a></h4><p class="float-caption no_bottom_margin">Brain/plasma study with CID 864492 when dosed i.p. at 56.6 mg/kg. </p></div></div><p>As an ongoing debate in the field has concerned the antipsychotic potential of selective M4
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activation, especially in light of the recent positive PhII data in schizophrenics with xanomeline,
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an M1/M4 preferring agonist,, we studied CID 864492 in a preclinical antipsychotic model
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(amphetamine-induced hyperlocomotion) were all known atypical and typical antipsychotic agents show
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efficacy. In the event, we dosed both CID 864492 and CID 1541501 at 56.6 mg/kg (the same dose that
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provided excellent brain levels in the brain/plasma study), and found that both compounds inhibit
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amphetamine-induced hyperlocomtion (<a class="figpopup" href="/books/NBK50687/figure/ml108.f7/?report=objectonly" target="object" rid-figpopup="figml108f7" rid-ob="figobml108f7">Figure 7</a>). In confirm
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efficacy, we ran, in parallel, a rotorod experiment with CID 864492 and CID 1541501 at doses of 30,
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56.6 and 100 mg/kg, and observed no sedation. Thus, CID 864492, a selective rM4 positive allosteric
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modulator, demonstrated that selective M4 activation has therapeutic potential for a novel mechanism for the treatment of schizophrenia. Thus, CID 864492 has utility as both an <i>in vitro</i> and <i>in vivo</i> probe for selective rat M4 activation by an alloosteric mechanism, positive allosteric modulation (PAM). (<a class="bibr" href="#ml108.r18" rid="ml108.r18">18</a>) This probe nicely compliments other highly selective M1 MPLCN probes: CID 25010775, an M1 allosteric agonist (<a class="bibr" href="#ml108.r19" rid="ml108.r19">19</a>) and CID 24768606, a highly selective M1 antagonist. (<a class="bibr" href="#ml108.r20" rid="ml108.r20">20</a>)</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml108f7" co-legend-rid="figlgndml108f7"><a href="/books/NBK50687/figure/ml108.f7/?report=objectonly" target="object" title="Figure 7" class="img_link icnblk_img figpopup" rid-figpopup="figml108f7" rid-ob="figobml108f7"><img class="small-thumb" src="/books/NBK50687/bin/ml108f7.gif" src-large="/books/NBK50687/bin/ml108f7.jpg" alt="Figure 7. Reversal of amphetamine-induced hyperlocomotion with CID 864492 and CID 1541501." /></a><div class="icnblk_cntnt" id="figlgndml108f7"><h4 id="ml108.f7"><a href="/books/NBK50687/figure/ml108.f7/?report=objectonly" target="object" rid-ob="figobml108f7">Figure 7</a></h4><p class="float-caption no_bottom_margin">Reversal of amphetamine-induced hyperlocomotion with CID 864492 and CID 1541501. </p></div></div></div><div id="ml108.s14"><h3>Synthetic procedure (large scale) and spectral data for CID 864492</h3><div id="ml108.fu2" class="figure"><div class="graphic"><img src="/books/NBK50687/bin/ml108fu20.jpg" alt="Image ml108fu20" /></div></div><div id="ml108.s15"><h4>CID 864492, 3-amino-<i>N</i>-(4-methoxybenzyl)-4,6-dimethylthieno[2,3-<i>b</i>] pyridine-2-carboxamide [<a href="/pcsubstance/?term=ML108[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML108</a>]</h4><p>The following components were added to a stirred solution of 3-amino-4,6-dimethylthioenol[2,3-<i>b</i>]-pyridine-2-carboxylic acid <b>5</b> (3.0 g, 13.51 mmol; ChemBridge Corporation) in CH<sub>2</sub>Cl<sub>2</sub> (90 ml) at 25°C under room atmosphere: <i>N</i>,<i>N</i>-diisopropylethylamine (10 ml, 56.66 mmol); 1-hydroxybenzotriazole hydrate (1.83 g, 13.51 mmol, 1.0 equivalents); 4-methoxybenzylamine (2.04 g, 14.86 mmol, 1.1 equivalents); and <i>N</i>-(3-dimethylaminopropyl)-<i>N</i>-ethyl-carbodiimide hydrochloride (5.18 g, 27.02 mmol, 2.0 equivalents). After 48 h, macroporous triethylammonium methylpolystyrene carbonate (4.4 g, 13.51 mmol, 3.077 mmol/g, 1.0 equivalents) was added to the solution, which was then stirred for 3 h at 25°C under room atmosphere. The solution was vacuum-filtered next, and the filtrate was separated with citric acid (1.0 M in water) and CH<sub>2</sub>Cl<sub>2</sub>. The organics were dried over MgSO<sub>4</sub> and concentrated <i>in vacuo</i> to produce a dark yellow solid. The solid was purified by column chromatography (silica gel, fixed 1:2 EtOAc/hexanes) to afford 2.5 g (7.33 mmol, 54%) of <b>CID 864492</b> as a bright yellow solid. Analytical LC/MS (J-Sphere80-S4, 3.0 × 50 mm, 4.0-min gradient, 5%[CH3CN]: 95%[0.1% trifluoroacetic acid/H2O] to 100%[CH3CN]): 2.773 min, 99% (214 nm and ELSD), M + 1 peak <i>m</i>/<i>e</i> 342.12; 1H NMR (400 MHz, DMSO-<i>d6</i>) δ 7.27 (d, <i>J</i> = 8.8 Hz, 2H), 6.89 (s, 1H), 6.86 (d, <i>J</i> =8.8 Hz, 2H), 6.34 (br s, 2H), 5.80 (s, 1H), 4.53 (d, <i>J</i> = 6.0 Hz, 2H), 3.79(s, 3H), 2.73 (s, 3H), 2.57 (s, 3H); 13C NMR (100 MHz, DMSO-<i>d6</i>) δ 165.9, 159.3, 159.2, 147.7, 143.9, 130.7, 129.3, 123.7, 122.4, 114.4, 98.5, 55.5, 43.3, 24.5, 20.4; high-resolution mass spectroscopy (QToF): <i>m/z</i> calc for C<sub>18</sub>H<sub>19</sub>N<sub>3</sub>O<sub>2</sub>S [M+H]: 342.1198; found, 342.1276.</p></div></div><div id="ml108.s16"><h3>MLS#s</h3><p>002474502 (CID 864492, 500 mg), 002474499, 002474500, 002474501</p></div></div><div id="ml108.rl1"><h2 id="_ml108_rl1_">Bibliography</h2><dl class="temp-labeled-list"><dl class="bkr_refwrap"><dt>1.</dt><dd><div class="bk_ref" id="ml108.r1">Wess J. <span><span class="ref-journal">Crit, Rev Neurobiol. </span>1996;<span class="ref-vol">10</span>:69–99.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/8853955" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8853955</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>2.</dt><dd><div class="bk_ref" id="ml108.r2">Bymaster FP, Felder C, Ahmed S, McKinzie D. <span><span class="ref-journal">Curr Drug Targets. </span>2002;<span class="ref-vol">1</span>:163–181.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12769625" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12769625</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>3.</dt><dd><div class="bk_ref" id="ml108.r3">Messer WS Jr. <span><span class="ref-journal">Curr Top Med Chem. </span>2002;<span class="ref-vol">2</span>:353–358.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/11966459" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11966459</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>4.</dt><dd><div class="bk_ref" id="ml108.r4">Raedler TJ, Bymaster FP, Tandon R, Copolov D, Dean B. <span><span class="ref-journal">Mol Psychiatry. </span>2007;<span class="ref-vol">12</span>:232–246.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17146471" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17146471</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>5.</dt><dd><div class="bk_ref" id="ml108.r5">Bymaster FP, Carter PA, Yamada M, Gomeza J, Wess J, Hamilton SE, Nathanson NM, McKinzie DL, Felder CC. <span><span class="ref-journal">Eur J Neurosci. </span>2003;<span class="ref-vol">17</span>:1403–1410.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12713643" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12713643</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>6.</dt><dd><div class="bk_ref" id="ml108.r6">Bymaster FP, McKinzie DL, Felder CC, Wess J. <span><span class="ref-journal">Neurochem Res. </span>2003;<span class="ref-vol">28</span>:437–442.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12675128" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12675128</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>7.</dt><dd><div class="bk_ref" id="ml108.r7">Bodick NC, Offen WW, Levey AI, Cutler NR, Gauthier SG, Satlin A, Shannon HE, Tollefson GD, Rasmussen K, Bymaster FP, et al. <span><span class="ref-journal">Arch Neurol. </span>1997;<span class="ref-vol">54</span>:465–473.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/9109749" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9109749</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>8.</dt><dd><div class="bk_ref" id="ml108.r8">Shekhar A, Potter WZ, Lienemann J, Sunblad K, Lightfoot J, Herrera J, Unverzagt F, Bymaster FP, Felder C. 40th Annual Meeting of American College of Neuropsychopharmacology; 2005 Dec 11–15; Waikoloa, HI. Nashville, TN: American College of Neuropsychopharmacology; 2001. </div></dd></dl><dl class="bkr_refwrap"><dt>9.</dt><dd><div class="bk_ref" id="ml108.r9">Shekhar A, Potter WZ, Lightfoot J, Lienemann J, Dube’ S, Mallinckrodt C, Bymaster FP, McKinzie DL, Felder CC. <span><span class="ref-journal">Am J Psychiatry. </span>2008;<span class="ref-vol">165</span>:1033–1039.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/18593778" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18593778</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>10.</dt><dd><div class="bk_ref" id="ml108.r10">Stanhope KJ, Mirza NR, Bickerdike MJ, Bright JL, Harrington NR, Hesselink MB, Kennett GA, Lightowler S, Sheardown MJ, Syed R, et al. <span><span class="ref-journal">J Pharmacol Exp Ther. </span>2001;<span class="ref-vol">299</span>:782–792.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/11602695" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11602695</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>11.</dt><dd><div class="bk_ref" id="ml108.r11">Felder CC, Porter AC, Skillman TL, Zhang L, Bymaster FP, Nathanson NM, Hamilton SE, Gomeza J, Wess J, McKinzie DL. <span><span class="ref-journal">Life Sci. </span>2001;<span class="ref-vol">68</span>:2605–2613.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/11392633" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11392633</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>12.</dt><dd><div class="bk_ref" id="ml108.r12">Tzavara ET, Bymaster FP, Davis RJ, Wade MR, Perry KW, Wess J, McKinzie DL, Felder C, Nomikos GG. <span><span class="ref-journal">FASEB J. </span>2004;<span class="ref-vol">18</span>:1410–1412.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15231726" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15231726</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>13.</dt><dd><div class="bk_ref" id="ml108.r13">Scarr E, Sundram S, Keriakous D, Dean B. <span><span class="ref-journal">Biol Psychiatry. </span>2007;<span class="ref-vol">61</span>:1161–1170.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17239354" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17239354</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>14.</dt><dd><div class="bk_ref" id="ml108.r14">Marino MJ, Williams DL Jr, O’Brien JA, Valenti O, McDonald TP, Clements MK, Wang R, DiLella AG, Hess JF, Kinney GG, et al. <span><span class="ref-journal">Proc Natl Acad Sci U S A. </span>2003;<span class="ref-vol">100</span>:13668–13673.</span> [<a href="/pmc/articles/PMC263871/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC263871</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/14593202" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 14593202</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>15.</dt><dd><div class="bk_ref" id="ml108.r15">Conn PJ, Jones C, Lindsley CW. <span><span class="ref-journal">Trends in Pharm Sci. </span>2009;<span class="ref-vol">30</span>:148–159.</span> [<a href="/pmc/articles/PMC2907736/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2907736</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19201489" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19201489</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>16.</dt><dd><div class="bk_ref" id="ml108.r16">Conn PJ, Christopolous A, Lindsley CW. <span><span class="ref-journal">Nat Rev Drug Discov. </span>2009;<span class="ref-vol">8</span>:41–54.</span> [<a href="/pmc/articles/PMC2907734/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2907734</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19116626" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19116626</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>17.</dt><dd><div class="bk_ref" id="ml108.r17">Shirey JK, Xiang Z, Orton D, Brady AE, Johnson KA, Williams R, Ayala JE, Rodriguez AL, Wess J, Weaver D, et al. <span><span class="ref-journal">Nat Chem Biol. </span>2008;<span class="ref-vol">4</span>:42–50.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/18059262" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18059262</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>18.</dt><dd><div class="bk_ref" id="ml108.r18">Brady A, Jones CK, Bridges TM, Kennedy PJ, Thompson AD, Breininger ML, Gentry PR, Yin H, Jadhav SB, Shirey J, Conn PJ, Lindsley CW. <span><span class="ref-journal">J Pharm & Exp Ther. </span>2008;<span class="ref-vol">327</span>:941–953.</span> [<a href="/pmc/articles/PMC2745822/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2745822</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/18772318" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18772318</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>19.</dt><dd><div class="bk_ref" id="ml108.r19">Sheffler DJ, Williams R, Bridges TM, Lewis LM, Xiang Z, Zheng F, Kane AS, Byum NE, Jadhav S, Mock MM, Zheng F, Lewis LM, Jones CK, Niswender CM, Weaver CD, Conn PJ, Lindsley CW, Conn PJ. <span class="ref-journal">Mol Pharmacol.</span> Vol. 76. 2009. pp. 356–369. [<a href="/pmc/articles/PMC2713127/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2713127</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19407080" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19407080</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>20.</dt><dd><div class="bk_ref" id="ml108.r20">Lebois EP, Bridges TM, Dawson ES, Kennedy JP, Xiang Z, Jadhav SB, Yin H, Meiler J, Jones CK, Conn PJ, Weaver CD, Lindsley CW. <span><span class="ref-journal">ACS Chemical Neurosci. </span></span> ARTICLE ASAP, in press. [<a href="/pmc/articles/PMC3180826/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3180826</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21961051" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21961051</span></a>]</div></dd></dl></dl></div><div id="ml108.app1"><h2 id="_ml108_app1_">APPENDIX I. Solubility, Stability and Reactivity data as determined by Absorption Systems</h2><div id="ml108.s17"><h3>Solubility</h3><p>Solubility in PBS (at pH = 7.4) for <a href="/pcsubstance/?term=ML108[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML108</a> was 0.78 μM.</p></div><div id="ml108.s18"><h3>Stability</h3><p>Stability (at room temperature = 23 °C) for <a href="/pcsubstance/?term=ML108[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML108</a> in PBS (no antioxidants or other protectorants and DMSO concentration below 0.1%) is shown in the table below. After 48 hours, the percent of parent compound remaining was 102%, but the assay variability over the course of the experiment ranged from a low of 93% (at 1 hour) to a high of 102% (at 48 hours).</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml108tu2"><a href="/books/NBK50687/table/ml108.tu2/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figml108tu2" rid-ob="figobml108tu2"><img class="small-thumb" src="/books/NBK50687/table/ml108.tu2/?report=thumb" src-large="/books/NBK50687/table/ml108.tu2/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ml108.tu2"><a href="/books/NBK50687/table/ml108.tu2/?report=objectonly" target="object" rid-ob="figobml108tu2">Table</a></h4></div></div></div><div id="ml108.s19"><h3>Reactivity</h3><p>As assessed through a glutathione (GSH) trapping experiment in phosphate buffered saline (with a substrate concentration of typically 5–50 μM and a GSH concentration of 5 mM, at t = 60 minutes) <a href="/pcsubstance/?term=ML108[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML108</a> was found to not form any detectable GSH adducts.<sup><a href="#ml108.fn1">*</a></sup></p></div></div><div id="ml108.app2"><h2 id="_ml108_app2_">APPENDIX II. Liquid Chromatography-Mass Spectrometry (LCMS) and Nuclear Magnetic Resonance (NMR) as prepared by Vanderbilt Specialized Chemistry Center</h2><div id="ml108.fu3" class="figure"><div class="graphic"><img src="/books/NBK50687/bin/ml108fu21.jpg" alt="Image ml108fu21" /></div></div><div id="ml108.fu4" class="figure"><div class="graphic"><img src="/books/NBK50687/bin/ml108fu22.jpg" alt="Image ml108fu22" /></div></div></div><h2 id="NBK50687_footnotes">Footnotes</h2><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>*</dt><dd><div id="ml108.fn1"><p class="no_top_margin">Solubility (PBS at pH = 7.4), Stability and Reactivity experiments were conducted at Absorption Systems. For additional information see: <a href="https://www.absorption.com/site" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">https://www<wbr style="display:inline-block"></wbr>​.absorption.com/site</a></p></div></dd></dl></dl><div id="bk_toc_contnr"></div></div></div><div class="fm-sec"><h2 id="_NBK50687_pubdet_">Publication Details</h2><h3>Author Information and Affiliations</h3><p class="contrib-group"><h4>Authors</h4><span itemprop="author">L Michelle Lewis</span>, <span itemprop="author">Thomas M Bridges</span>, <span itemprop="author">Colleen M Niswender</span>, <span itemprop="author">C David Weaver</span>, and <span itemprop="author">Craig W Lindsley</span><sup>1</sup>.</p><h4>Contact</h4><div class="affiliation"><sup>1</sup> <span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ude.tlibrednav@yelsdnil.giarc" class="oemail">ude.tlibrednav@yelsdnil.giarc</a></div><h3>Publication History</h3><p class="small">Received: <span itemprop="datePublished">September 1, 2009</span>; Last Update: <span itemprop="dateModified">October 20, 2010</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>Lewis LM, Bridges TM, Niswender CM, et al. Discovery of a Highly Selective in vitro and in vivo M4 Positive Allosteric Modulator (PAM) 2009 Sep 1 [Updated 2010 Oct 20]. 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/ml109/?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/y1/?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="figobml108fu1"><div id="ml108.fu1" class="figure"><div class="graphic"><img data-src="/books/NBK50687/bin/ml108fu1.jpg" alt="Image ml108fu1" /></div></div></article><article data-type="table-wrap" id="figobml108tu1"><div id="ml108.tu1" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK50687/table/ml108.tu1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml108.tu1_lrgtbl__"><table><thead><tr><th id="hd_h_ml108.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">CID/ML#</th><th id="hd_h_ml108.tu1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Target Name</th><th id="hd_h_ml108.tu1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">IC50/EC50 (nM) [SID, AID]</th><th id="hd_h_ml108.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_ml108.tu1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">IC50/EC50 (μM) [SID, AID]</th><th id="hd_h_ml108.tu1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Selectivity</th><th id="hd_h_ml108.tu1_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Secondary Assay(s) Name: IC50/EC50 (nM) [SID, AID]</th></tr></thead><tbody><tr><td headers="hd_h_ml108.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">CID 864492<br /><a href="/pcsubstance/?term=ML108[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML108</a></td><td headers="hd_h_ml108.tu1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">M4</td><td headers="hd_h_ml108.tu1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">390 [<a href="https://pubchem.ncbi.nlm.nih.gov/substance/85163688" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID-85163688</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1923" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1923</a>]</td><td headers="hd_h_ml108.tu1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">M1, M2, M3, M5<br /><br />MDS Pharma</td><td headers="hd_h_ml108.tu1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">> 30 μM [<a href="https://pubchem.ncbi.nlm.nih.gov/substance/85163688" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID-85163688</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1921" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1921</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1928" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1928</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1929" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1929</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1930" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1930</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1932" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1932</a>]</td><td headers="hd_h_ml108.tu1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">>100</td><td headers="hd_h_ml108.tu1_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">[<sup>3</sup>H]-NMS Binding (> 30
|
|
μM)<br /><br />ACh Fold-shift (> 70-fold)<br /><br />[<a href="https://pubchem.ncbi.nlm.nih.gov/substance/85163688" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID-85163688</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1938" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1938</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1939" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1939</a>]</td></tr></tbody></table></div></div></article><article data-type="fig" id="figobml108f1"><div id="ml108.f1" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK50687/bin/ml108f1.jpg" alt="Figure 1. M4 HTS hits." /></div><h3><span class="label">Figure 1</span><span class="title">M4 HTS hits</span></h3></div></article><article data-type="fig" id="figobml108f2"><div id="ml108.f2" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK50687/bin/ml108f2.jpg" alt="Figure 2. LY2033298 and cheminformatics and database mining approach leading to CID 714286." /></div><h3><span class="label">Figure 2</span><span class="title">LY2033298 and cheminformatics and database mining approach leading to CID 714286</span></h3></div></article><article data-type="fig" id="figobml108f3"><div id="ml108.f3" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK50687/bin/ml108f3.jpg" alt="Figure 3. Optimization of CID 7142z86." /></div><h3><span class="label">Figure 3</span><span class="title">Optimization of CID 7142z86</span></h3></div></article><article data-type="table-wrap" id="figobml108t1"><div id="ml108.t1" class="table"><h3><span class="label">Table 1</span><span class="title">Structures and SAR for Analogs of CID714286</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK50687/table/ml108.t1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml108.t1_lrgtbl__"><table class="no_margin"><thead><tr><th id="hd_h_ml108.t1_1_1_1_1" colspan="4" rowspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50687/bin/ml108fu2.jpg" alt="Image ml108fu2.jpg" /></div><span class="hr"></span></th></tr><tr><th headers="hd_h_ml108.t1_1_1_1_1" id="hd_h_ml108.t1_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">CID</th><th headers="hd_h_ml108.t1_1_1_1_1" id="hd_h_ml108.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">R</th><th headers="hd_h_ml108.t1_1_1_1_1" id="hd_h_ml108.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">rat M4 EC<sub>50</sub> (μM)<sup>a</sup></th><th headers="hd_h_ml108.t1_1_1_1_1" id="hd_h_ml108.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">rat M4 ACh fold-shift</th></tr></thead><tbody><tr><td headers="hd_h_ml108.t1_1_1_1_1 hd_h_ml108.t1_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><b>734373</b></td><td headers="hd_h_ml108.t1_1_1_1_1 hd_h_ml108.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><div class="graphic"><img src="/books/NBK50687/bin/ml108fu3.jpg" alt="Image ml108fu3.jpg" /></div></td><td headers="hd_h_ml108.t1_1_1_1_1 hd_h_ml108.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.69</td><td headers="hd_h_ml108.t1_1_1_1_1 hd_h_ml108.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">7.8</td></tr><tr><td headers="hd_h_ml108.t1_1_1_1_1 hd_h_ml108.t1_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><b>44176127</b></td><td headers="hd_h_ml108.t1_1_1_1_1 hd_h_ml108.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><div class="graphic"><img src="/books/NBK50687/bin/ml108fu4.jpg" alt="Image ml108fu4.jpg" /></div></td><td headers="hd_h_ml108.t1_1_1_1_1 hd_h_ml108.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.87</td><td headers="hd_h_ml108.t1_1_1_1_1 hd_h_ml108.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">3.4</td></tr><tr><td headers="hd_h_ml108.t1_1_1_1_1 hd_h_ml108.t1_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><b>1502242</b></td><td headers="hd_h_ml108.t1_1_1_1_1 hd_h_ml108.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><div class="graphic"><img src="/books/NBK50687/bin/ml108fu5.jpg" alt="Image ml108fu5.jpg" /></div></td><td headers="hd_h_ml108.t1_1_1_1_1 hd_h_ml108.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2.34</td><td headers="hd_h_ml108.t1_1_1_1_1 hd_h_ml108.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">ND</td></tr><tr><td headers="hd_h_ml108.t1_1_1_1_1 hd_h_ml108.t1_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><b>24769768</b></td><td headers="hd_h_ml108.t1_1_1_1_1 hd_h_ml108.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><div class="graphic"><img src="/books/NBK50687/bin/ml108fu6.jpg" alt="Image ml108fu6.jpg" /></div></td><td headers="hd_h_ml108.t1_1_1_1_1 hd_h_ml108.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">9.03</td><td headers="hd_h_ml108.t1_1_1_1_1 hd_h_ml108.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">ND</td></tr><tr><td headers="hd_h_ml108.t1_1_1_1_1 hd_h_ml108.t1_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><b>44176128</b></td><td headers="hd_h_ml108.t1_1_1_1_1 hd_h_ml108.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><div class="graphic"><img src="/books/NBK50687/bin/ml108fu7.jpg" alt="Image ml108fu7.jpg" /></div></td><td headers="hd_h_ml108.t1_1_1_1_1 hd_h_ml108.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">>100</td><td headers="hd_h_ml108.t1_1_1_1_1 hd_h_ml108.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">ND</td></tr><tr><td headers="hd_h_ml108.t1_1_1_1_1 hd_h_ml108.t1_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><b>44176129</b></td><td headers="hd_h_ml108.t1_1_1_1_1 hd_h_ml108.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><div class="graphic"><img src="/books/NBK50687/bin/ml108fu8.jpg" alt="Image ml108fu8.jpg" /></div></td><td headers="hd_h_ml108.t1_1_1_1_1 hd_h_ml108.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2.82</td><td headers="hd_h_ml108.t1_1_1_1_1 hd_h_ml108.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">ND</td></tr><tr><td headers="hd_h_ml108.t1_1_1_1_1 hd_h_ml108.t1_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><b>20417337</b></td><td headers="hd_h_ml108.t1_1_1_1_1 hd_h_ml108.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><div class="graphic"><img src="/books/NBK50687/bin/ml108fu9.jpg" alt="Image ml108fu9.jpg" /></div></td><td headers="hd_h_ml108.t1_1_1_1_1 hd_h_ml108.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">5.59</td><td headers="hd_h_ml108.t1_1_1_1_1 hd_h_ml108.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">ND</td></tr><tr><td headers="hd_h_ml108.t1_1_1_1_1 hd_h_ml108.t1_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><b>714286</b></td><td headers="hd_h_ml108.t1_1_1_1_1 hd_h_ml108.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><div class="graphic"><img src="/books/NBK50687/bin/ml108fu10.jpg" alt="Image ml108fu10.jpg" /></div></td><td headers="hd_h_ml108.t1_1_1_1_1 hd_h_ml108.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.33</td><td headers="hd_h_ml108.t1_1_1_1_1 hd_h_ml108.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">29</td></tr><tr><td headers="hd_h_ml108.t1_1_1_1_1 hd_h_ml108.t1_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><b>864491</b></td><td headers="hd_h_ml108.t1_1_1_1_1 hd_h_ml108.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><div class="graphic"><img src="/books/NBK50687/bin/ml108fu11.jpg" alt="Image ml108fu11.jpg" /></div></td><td headers="hd_h_ml108.t1_1_1_1_1 hd_h_ml108.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2.42</td><td headers="hd_h_ml108.t1_1_1_1_1 hd_h_ml108.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">ND</td></tr><tr><td headers="hd_h_ml108.t1_1_1_1_1 hd_h_ml108.t1_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><b>6757564</b></td><td headers="hd_h_ml108.t1_1_1_1_1 hd_h_ml108.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><div class="graphic"><img src="/books/NBK50687/bin/ml108fu12.jpg" alt="Image ml108fu12.jpg" /></div></td><td headers="hd_h_ml108.t1_1_1_1_1 hd_h_ml108.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2.42</td><td headers="hd_h_ml108.t1_1_1_1_1 hd_h_ml108.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">ND</td></tr><tr><td headers="hd_h_ml108.t1_1_1_1_1 hd_h_ml108.t1_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><b>44176130</b></td><td headers="hd_h_ml108.t1_1_1_1_1 hd_h_ml108.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><div class="graphic"><img src="/books/NBK50687/bin/ml108fu13.jpg" alt="Image ml108fu13.jpg" /></div></td><td headers="hd_h_ml108.t1_1_1_1_1 hd_h_ml108.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">5.16</td><td headers="hd_h_ml108.t1_1_1_1_1 hd_h_ml108.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">5.3</td></tr><tr><td headers="hd_h_ml108.t1_1_1_1_1 hd_h_ml108.t1_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><b>44176131</b></td><td headers="hd_h_ml108.t1_1_1_1_1 hd_h_ml108.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><div class="graphic"><img src="/books/NBK50687/bin/ml108fu14.jpg" alt="Image ml108fu14.jpg" /></div></td><td headers="hd_h_ml108.t1_1_1_1_1 hd_h_ml108.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">5.06</td><td headers="hd_h_ml108.t1_1_1_1_1 hd_h_ml108.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">ND</td></tr><tr><td headers="hd_h_ml108.t1_1_1_1_1 hd_h_ml108.t1_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><b>44176132</b></td><td headers="hd_h_ml108.t1_1_1_1_1 hd_h_ml108.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><div class="graphic"><img src="/books/NBK50687/bin/ml108fu15.jpg" alt="Image ml108fu15.jpg" /></div></td><td headers="hd_h_ml108.t1_1_1_1_1 hd_h_ml108.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">1.11</td><td headers="hd_h_ml108.t1_1_1_1_1 hd_h_ml108.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">ND</td></tr><tr><td headers="hd_h_ml108.t1_1_1_1_1 hd_h_ml108.t1_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><b>44176133</b></td><td headers="hd_h_ml108.t1_1_1_1_1 hd_h_ml108.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><div class="graphic"><img src="/books/NBK50687/bin/ml108fu16.jpg" alt="Image ml108fu16.jpg" /></div></td><td headers="hd_h_ml108.t1_1_1_1_1 hd_h_ml108.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">1.27</td><td headers="hd_h_ml108.t1_1_1_1_1 hd_h_ml108.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">ND</td></tr><tr><td headers="hd_h_ml108.t1_1_1_1_1 hd_h_ml108.t1_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><b>44176134</b></td><td headers="hd_h_ml108.t1_1_1_1_1 hd_h_ml108.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><div class="graphic"><img src="/books/NBK50687/bin/ml108fu17.jpg" alt="Image ml108fu17.jpg" /></div></td><td headers="hd_h_ml108.t1_1_1_1_1 hd_h_ml108.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.97</td><td headers="hd_h_ml108.t1_1_1_1_1 hd_h_ml108.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">12.4</td></tr><tr><td headers="hd_h_ml108.t1_1_1_1_1 hd_h_ml108.t1_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><b>864492</b></td><td headers="hd_h_ml108.t1_1_1_1_1 hd_h_ml108.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><div class="graphic"><img src="/books/NBK50687/bin/ml108fu18.jpg" alt="Image ml108fu18.jpg" /></div></td><td headers="hd_h_ml108.t1_1_1_1_1 hd_h_ml108.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.39</td><td headers="hd_h_ml108.t1_1_1_1_1 hd_h_ml108.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">70</td></tr><tr><td headers="hd_h_ml108.t1_1_1_1_1 hd_h_ml108.t1_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><b>1541501</b></td><td headers="hd_h_ml108.t1_1_1_1_1 hd_h_ml108.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><div class="graphic"><img src="/books/NBK50687/bin/ml108fu19.jpg" alt="Image ml108fu19.jpg" /></div></td><td headers="hd_h_ml108.t1_1_1_1_1 hd_h_ml108.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.37</td><td headers="hd_h_ml108.t1_1_1_1_1 hd_h_ml108.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">29</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="ml108.tfn1"><p class="no_margin">EC<sub>50</sub>s and fold-shifts are an average of at least 3 determinations;</p></div></dd></dl><dl class="bkr_refwrap"><dt></dt><dd><div id="ml108.tfn2"><p class="no_margin">ND, not determined</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobml108t2"><div id="ml108.t2" class="table"><h3><span class="label">Table 2</span><span class="title">MDS Lead Profiling Screen for CID 1541501 and CID 864492</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK50687/table/ml108.t2/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml108.t2_lrgtbl__"><table class="no_top_margin"><thead><tr><th id="hd_h_ml108.t2_1_1_1_1" rowspan="2" colspan="1" headers="hd_h_ml108.t2_1_1_1_1" style="text-align:center;vertical-align:bottom;">Target</th><th id="hd_h_ml108.t2_1_1_1_2" rowspan="2" colspan="1" headers="hd_h_ml108.t2_1_1_1_2" style="text-align:left;vertical-align:bottom;">Species</th><th id="hd_h_ml108.t2_1_1_1_3" colspan="2" rowspan="1" style="text-align:center;vertical-align:bottom;">% Inhibition<span class="hr"></span></th></tr><tr><th headers="hd_h_ml108.t2_1_1_1_3" id="hd_h_ml108.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">CID 1541501</th><th headers="hd_h_ml108.t2_1_1_1_3" id="hd_h_ml108.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">CID 864492</th></tr></thead><tbody><tr><td headers="hd_h_ml108.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Adenosine A1</td><td headers="hd_h_ml108.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">human</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">28</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">−1</td></tr><tr><td headers="hd_h_ml108.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Adenosine A2</td><td headers="hd_h_ml108.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">human</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">46</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">43</td></tr><tr><td headers="hd_h_ml108.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Adenosine A3</td><td headers="hd_h_ml108.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">human</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">28</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">40</td></tr><tr><td headers="hd_h_ml108.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Adrenergic<i>α</i><sub>1A</sub></td><td headers="hd_h_ml108.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">rat</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">9</td></tr><tr><td headers="hd_h_ml108.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Adrenergic<i>α</i><sub>1B</sub></td><td headers="hd_h_ml108.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">rat</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">−7</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">−7</td></tr><tr><td headers="hd_h_ml108.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Adrenergic<i>α</i><sub>1C</sub></td><td headers="hd_h_ml108.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">human</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">1</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">1</td></tr><tr><td headers="hd_h_ml108.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Adrenergic<i>α</i><sub>2A</sub></td><td headers="hd_h_ml108.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">human</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">7</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">17</td></tr><tr><td headers="hd_h_ml108.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Adrenergic<i>β</i><sub>1</sub></td><td headers="hd_h_ml108.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">human</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">17</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">17</td></tr><tr><td headers="hd_h_ml108.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Adrenergic<i>β</i><sub>2</sub></td><td headers="hd_h_ml108.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">human</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">30</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">35</td></tr><tr><td headers="hd_h_ml108.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Androgen (testosterone)AR</td><td headers="hd_h_ml108.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">rat</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">6</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">6</td></tr><tr><td headers="hd_h_ml108.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Bradykinin B<sub>1</sub></td><td headers="hd_h_ml108.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">human</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">13</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">1</td></tr><tr><td headers="hd_h_ml108.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Bradykinin B<sub>2</sub></td><td headers="hd_h_ml108.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">human</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">−5</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">−9</td></tr><tr><td headers="hd_h_ml108.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Calcium channel L-type, benzothiazepine</td><td headers="hd_h_ml108.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">rat</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">13</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">7</td></tr><tr><td headers="hd_h_ml108.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Calcium channel L-type, dihydropyridine</td><td headers="hd_h_ml108.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">rat</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">21</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">17</td></tr><tr><td headers="hd_h_ml108.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Calcium channel N-type</td><td headers="hd_h_ml108.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">rat</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">−8</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">−4</td></tr><tr><td headers="hd_h_ml108.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Dopamine D<sub>1</sub></td><td headers="hd_h_ml108.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">human</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">6</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">7</td></tr><tr><td headers="hd_h_ml108.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Dopamine D<sub>2</sub></td><td headers="hd_h_ml108.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">human</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td></tr><tr><td headers="hd_h_ml108.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Dopamine D<sub>3</sub></td><td headers="hd_h_ml108.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">human</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">−1</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">5</td></tr><tr><td headers="hd_h_ml108.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Dopamine D<sub>4</sub></td><td headers="hd_h_ml108.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">human</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">−13</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">−11</td></tr><tr><td headers="hd_h_ml108.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Endothelin ET<sub>A</sub></td><td headers="hd_h_ml108.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">human</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">−8</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">−8</td></tr><tr><td headers="hd_h_ml108.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Endothelin ET<sub>B</sub></td><td headers="hd_h_ml108.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">human</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">−4</td></tr><tr><td headers="hd_h_ml108.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Epidermal Growth Factor (EGF)</td><td headers="hd_h_ml108.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">human</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">9</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">−5</td></tr><tr><td headers="hd_h_ml108.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Estrogen ER<i>α</i></td><td headers="hd_h_ml108.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">human</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">−1</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">−1</td></tr><tr><td headers="hd_h_ml108.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">G protein-coupled receptor GPR103</td><td headers="hd_h_ml108.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">human</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">−3</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">−4</td></tr><tr><td headers="hd_h_ml108.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">GABA<sub>A</sub> Flunitrazepam, central</td><td headers="hd_h_ml108.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">rat</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">51</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">43</td></tr><tr><td headers="hd_h_ml108.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">GABA<sub>A</sub> Muscimol, central</td><td headers="hd_h_ml108.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">rat</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">6</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">9</td></tr><tr><td headers="hd_h_ml108.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">GABA<sub>B,A</sub></td><td headers="hd_h_ml108.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">human</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">−7</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">12</td></tr><tr><td headers="hd_h_ml108.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Glucocorticoid</td><td headers="hd_h_ml108.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">human</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">−3</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">8</td></tr><tr><td headers="hd_h_ml108.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Glutamate, Kainate</td><td headers="hd_h_ml108.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">rat</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">3</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">−15</td></tr><tr><td headers="hd_h_ml108.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Glutamate, NMDA, Agonism</td><td headers="hd_h_ml108.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">rat</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">17</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">22</td></tr><tr><td headers="hd_h_ml108.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Glutamate, NMDA, Glycine</td><td headers="hd_h_ml108.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">rat</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">3</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td></tr><tr><td headers="hd_h_ml108.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Glutamate, NMDA. Phencydidine</td><td headers="hd_h_ml108.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">rat</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">3</td></tr><tr><td headers="hd_h_ml108.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Histamine H<sub>1</sub></td><td headers="hd_h_ml108.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">human</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">14</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">7</td></tr><tr><td headers="hd_h_ml108.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Histamine H<sub>2</sub></td><td headers="hd_h_ml108.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">human</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">7</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10</td></tr><tr><td headers="hd_h_ml108.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Histamine H<sub>3</sub></td><td headers="hd_h_ml108.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">human</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">9</td></tr><tr><td headers="hd_h_ml108.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Imidazoline I<sub>1</sub> Central</td><td headers="hd_h_ml108.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">rat</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">7</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">8</td></tr><tr><td headers="hd_h_ml108.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">lnterleukin IL-1</td><td headers="hd_h_ml108.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">mouse</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">−19</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">−4</td></tr><tr><td headers="hd_h_ml108.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Leukotriene, Cysteinyl Cys LT</td><td headers="hd_h_ml108.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">human</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">−4</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">−6</td></tr><tr><td headers="hd_h_ml108.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Melatonin MT<sub>1</sub></td><td headers="hd_h_ml108.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">human</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">15</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">20</td></tr><tr><td headers="hd_h_ml108.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Muscarinic M<sub>1</sub></td><td headers="hd_h_ml108.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">human</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">−3</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td></tr><tr><td headers="hd_h_ml108.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Muscarinic M<sub>2</sub></td><td headers="hd_h_ml108.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">human</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">−1</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">−4</td></tr><tr><td headers="hd_h_ml108.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Muscarinic M<sub>3</sub></td><td headers="hd_h_ml108.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">human</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">−1</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">−2</td></tr><tr><td headers="hd_h_ml108.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Neuropeptide YY<sub>1</sub></td><td headers="hd_h_ml108.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">human</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">9</td></tr><tr><td headers="hd_h_ml108.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Neuropeptide YY<sub>2</sub></td><td headers="hd_h_ml108.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">human</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">−2</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td></tr><tr><td headers="hd_h_ml108.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Nicotinic Acetylcholine</td><td headers="hd_h_ml108.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">human</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">6</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">−6</td></tr><tr><td headers="hd_h_ml108.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Nicotinic Acetylcholine, Bungarotoxin</td><td headers="hd_h_ml108.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">human</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">−10</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">−4</td></tr><tr><td headers="hd_h_ml108.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Opiateδ (OP1, DOP)</td><td headers="hd_h_ml108.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">human</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">−13</td></tr><tr><td headers="hd_h_ml108.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Opiateκ (OP2, KOP)</td><td headers="hd_h_ml108.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">human</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">5</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td></tr><tr><td headers="hd_h_ml108.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Opiate μ (OP3, MOP)</td><td headers="hd_h_ml108.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">human</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">−2</td></tr><tr><td headers="hd_h_ml108.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Phorbol Ester</td><td headers="hd_h_ml108.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">mouse</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">4</td></tr><tr><td headers="hd_h_ml108.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Platelet Activating Factor (PAF)</td><td headers="hd_h_ml108.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">human</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">13</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">22</td></tr><tr><td headers="hd_h_ml108.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Potassium Channel [K<sub>ATP</sub>]</td><td headers="hd_h_ml108.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hamster</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">3</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">6</td></tr><tr><td headers="hd_h_ml108.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Potassium Channel hERG</td><td headers="hd_h_ml108.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">human</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">5</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">5</td></tr><tr><td headers="hd_h_ml108.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Prostanoid EP</td><td headers="hd_h_ml108.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">human</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">15</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">7</td></tr><tr><td headers="hd_h_ml108.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Purinergic P<sub>2X</sub></td><td headers="hd_h_ml108.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">rabbit</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">6</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">−4</td></tr><tr><td headers="hd_h_ml108.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Purinergic P<sub>2Y</sub></td><td headers="hd_h_ml108.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">rat</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">15</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">14</td></tr><tr><td headers="hd_h_ml108.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Rollpram</td><td headers="hd_h_ml108.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">rat</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">36</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">29</td></tr><tr><td headers="hd_h_ml108.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serotonin (5-Hydroxytryptamine) 5-HT<sub>A</sub></td><td headers="hd_h_ml108.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">human</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td></tr><tr><td headers="hd_h_ml108.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serotonin (5-Hydroxytryptamine) 5-HT<sub>B</sub></td><td headers="hd_h_ml108.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">human</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">−2</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">14</td></tr><tr><td headers="hd_h_ml108.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Sigmaσ<sub>1</sub></td><td headers="hd_h_ml108.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">human</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">6</td></tr><tr><td headers="hd_h_ml108.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Sigmaσ<sub>2</sub></td><td headers="hd_h_ml108.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">rat</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">−8</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">−3</td></tr><tr><td headers="hd_h_ml108.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Sodium Channel, Site 2</td><td headers="hd_h_ml108.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">rat</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">11</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">20</td></tr><tr><td headers="hd_h_ml108.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Tachykinin NK<sub>1</sub></td><td headers="hd_h_ml108.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">human</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">−15</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">−18</td></tr><tr><td headers="hd_h_ml108.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Thyroid Hormone</td><td headers="hd_h_ml108.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">rat</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">−1</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td></tr><tr><td headers="hd_h_ml108.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Transporter, Dopamine (DAT)</td><td headers="hd_h_ml108.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">human</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">27</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">46</td></tr><tr><td headers="hd_h_ml108.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Transporter, GABA</td><td headers="hd_h_ml108.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">rat</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">26</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">13</td></tr><tr><td headers="hd_h_ml108.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Transporter, Norepinephrine (NET)</td><td headers="hd_h_ml108.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">human</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">34</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">22</td></tr><tr><td headers="hd_h_ml108.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Transporter, Serotonin (5-Hydroxytryptamine) (SERT)</td><td headers="hd_h_ml108.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">human</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0</td><td headers="hd_h_ml108.t2_1_1_1_3 hd_h_ml108.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">4</td></tr></tbody></table></div></div></article><article data-type="fig" id="figobml108f4"><div id="ml108.f4" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK50687/bin/ml108f4.jpg" alt="Figure 4. A) rM4 CRC in presence and absence of ACh EC20; B) ACh Fold-shift assay with CID 864492." /></div><h3><span class="label">Figure 4</span></h3><div class="caption"><p>A) rM4 CRC in presence and absence of ACh EC<sub>20</sub>; B) ACh Fold-shift assay with CID
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864492.</p></div></div></article><article data-type="fig" id="figobml108f5"><div id="ml108.f5" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK50687/bin/ml108f5.jpg" alt="Figure 5. A) mAChR selectivity of CID 864492 versus M1, M2, M3 and M5 at 30 μM; B) [3H]-NMS competition binding experiments with the orthosteric ligand atropine and CID 864492 and CID1541501." /></div><h3><span class="label">Figure 5</span></h3><div class="caption"><p>A) mAChR selectivity of CID 864492 versus M1, M2, M3 and M5 at 30 μM; B)
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[<sup>3</sup>H]-NMS competition binding experiments with the orthosteric ligand atropine and CID 864492 and CID1541501.</p></div></div></article><article data-type="fig" id="figobml108f6"><div id="ml108.f6" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK50687/bin/ml108f6.jpg" alt="Figure 6. Brain/plasma study with CID 864492 when dosed i.p. at 56.6 mg/kg." /></div><h3><span class="label">Figure 6</span><span class="title">Brain/plasma study with CID 864492 when dosed i.p. at 56.6 mg/kg</span></h3></div></article><article data-type="fig" id="figobml108f7"><div id="ml108.f7" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK50687/bin/ml108f7.jpg" alt="Figure 7. Reversal of amphetamine-induced hyperlocomotion with CID 864492 and CID 1541501." /></div><h3><span class="label">Figure 7</span><span class="title">Reversal of amphetamine-induced hyperlocomotion with CID 864492 and CID 1541501</span></h3></div></article><article data-type="fig" id="figobml108fu2"><div id="ml108.fu2" class="figure"><div class="graphic"><img data-src="/books/NBK50687/bin/ml108fu20.jpg" alt="Image ml108fu20" /></div></div></article><article data-type="table-wrap" id="figobml108tu2"><div id="ml108.tu2" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK50687/table/ml108.tu2/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml108.tu2_lrgtbl__"><table><thead><tr><th id="hd_h_ml108.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;"></th><th id="hd_h_ml108.tu2_1_1_1_2" colspan="7" rowspan="1" style="text-align:center;vertical-align:bottom;">Percent Remaining (%)</th></tr><tr><th headers="hd_h_ml108.tu2_1_1_1_1" id="hd_h_ml108.tu2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">Compound</th><th headers="hd_h_ml108.tu2_1_1_1_2" id="hd_h_ml108.tu2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">0 Min</th><th headers="hd_h_ml108.tu2_1_1_1_2" id="hd_h_ml108.tu2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">15 Min</th><th headers="hd_h_ml108.tu2_1_1_1_2" id="hd_h_ml108.tu2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">30 Min</th><th headers="hd_h_ml108.tu2_1_1_1_2" id="hd_h_ml108.tu2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">1 Hour</th><th headers="hd_h_ml108.tu2_1_1_1_2" id="hd_h_ml108.tu2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">2 Hour</th><th headers="hd_h_ml108.tu2_1_1_1_2" id="hd_h_ml108.tu2_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">24 Hour</th><th headers="hd_h_ml108.tu2_1_1_1_2" id="hd_h_ml108.tu2_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">48 Hour</th></tr></thead><tbody><tr><td headers="hd_h_ml108.tu2_1_1_1_1 hd_h_ml108.tu2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="/pcsubstance/?term=ML108[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML108</a></td><td headers="hd_h_ml108.tu2_1_1_1_2 hd_h_ml108.tu2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">---</td><td headers="hd_h_ml108.tu2_1_1_1_2 hd_h_ml108.tu2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">100</td><td headers="hd_h_ml108.tu2_1_1_1_2 hd_h_ml108.tu2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">101</td><td headers="hd_h_ml108.tu2_1_1_1_2 hd_h_ml108.tu2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">93</td><td headers="hd_h_ml108.tu2_1_1_1_2 hd_h_ml108.tu2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">98</td><td headers="hd_h_ml108.tu2_1_1_1_2 hd_h_ml108.tu2_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">97</td><td headers="hd_h_ml108.tu2_1_1_1_2 hd_h_ml108.tu2_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">102</td></tr></tbody></table></div></div></article><article data-type="fig" id="figobml108fu3"><div id="ml108.fu3" class="figure"><div class="graphic"><img data-src="/books/NBK50687/bin/ml108fu21.jpg" alt="Image ml108fu21" /></div></div></article><article data-type="fig" id="figobml108fu4"><div id="ml108.fu4" class="figure"><div class="graphic"><img data-src="/books/NBK50687/bin/ml108fu22.jpg" alt="Image ml108fu22" /></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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