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<meta name="ncbi_pagename" content="Discovery of a novel structural class of M4 positive allosteric modulators: Characterization of ML293, N-(4-methoxy-7-methylbenzo[d]thiazol-2-yl)isonicotinamide, with CNS exposure in rats - Probe Reports from the NIH Molecular Libraries Program - NCBI Bookshelf">
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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 novel structural class of M4 positive allosteric modulators: Characterization of ML293, N-(4-methoxy-7-methylbenzo[d]thiazol-2-yl)isonicotinamide, with CNS exposure in rats - 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 novel structural class of M4 positive allosteric modulators: Characterization of ML293, N-(4-methoxy-7-methylbenzo[d]thiazol-2-yl)isonicotinamide, with CNS exposure in rats">
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<meta name="citation_publisher" content="National Center for Biotechnology Information (US)">
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<meta name="citation_date" content="2013/03/14">
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<meta name="citation_author" content="James M. Salovich">
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<meta name="citation_author" content="Douglas J. Sheffler">
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<meta name="citation_author" content="Paige N. Vinson">
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<meta name="citation_author" content="Atin Lamsal">
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<meta name="citation_author" content="Thomas J. Utley">
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<meta name="citation_author" content="Anna L. Blobaum">
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<meta name="citation_author" content="Thomas M. Bridges">
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<meta name="citation_author" content="Uyen Le">
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<meta name="citation_author" content="Carrie K. Jones">
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<meta name="citation_author" content="Michael R. Wood">
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<meta name="citation_author" content="J. Scott Daniels">
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<meta name="citation_author" content="P. Jeffrey Conn">
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<meta name="citation_author" content="Julie Engers">
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<meta name="citation_author" content="Colleen M. Niswender">
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<meta name="citation_author" content="Craig W. Lindsley">
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<meta name="citation_author" content="Corey R. Hopkins">
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<meta name="citation_pmid" content="23762944">
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<meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK143538/">
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<meta name="DC.Title" content="Discovery of a novel structural class of M4 positive allosteric modulators: Characterization of ML293, N-(4-methoxy-7-methylbenzo[d]thiazol-2-yl)isonicotinamide, with CNS exposure in rats">
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<meta name="DC.Contributor" content="James M. Salovich">
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<meta name="DC.Contributor" content="Douglas J. Sheffler">
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<meta name="DC.Contributor" content="Paige N. Vinson">
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<meta name="DC.Contributor" content="Atin Lamsal">
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<meta name="DC.Contributor" content="Thomas J. Utley">
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<meta name="DC.Contributor" content="Anna L. Blobaum">
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<meta name="DC.Contributor" content="Thomas M. Bridges">
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<meta name="DC.Contributor" content="Uyen Le">
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<meta name="DC.Contributor" content="Carrie K. Jones">
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<meta name="DC.Contributor" content="Michael R. Wood">
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<meta name="DC.Contributor" content="J. Scott Daniels">
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<meta name="DC.Contributor" content="P. Jeffrey Conn">
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<meta name="DC.Contributor" content="Julie Engers">
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<meta name="DC.Contributor" content="Colleen M. Niswender">
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<meta name="DC.Contributor" content="Craig W. Lindsley">
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<meta name="DC.Contributor" content="Corey R. Hopkins">
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<meta name="DC.Date" content="2013/03/14">
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<meta name="description" content="This new M4 positive allosteric modulator (PAM) probe, ML293, is the result of an extended probe characterization project to improve in vivo PK properties and brain exposure. ML293 displayed modest potency at the human M4 receptor, EC50 = 1.3 μM, and excellent efficacy as noted by the leftward shift of the agonist concentration-response curve (14.6-fold). Importantly, ML293 displayed superior in vivo PK properties compared to the previous M4 probe molecules (ML108, ML173 and ML253) with low IV clearance (11.6 mL/min/kg) and excellent brain exposure (PO PBL, 10 mg/kg at 1 h, [Brain] = 10.3 μM, B:P = 0.85). Moreover, ML293 was selective for M4 (>30 μM versus, M1–3, M5), and possessed a clean ancillary pharmacological profile in a Ricerca radioligand binding panel of 68 G-protein-coupled receptors (GPCRs), ion channels and transporters with the exception of adenosine receptors. Here ML293 was found to be a potent ligand for antagonist of the A2A receptor; however the A2A antagonism will not confound in vivo evaluation of M4 PAM efficacy in schizophrenia models, whereas an A2A agonist could.">
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<meta name="og:description" content="This new M4 positive allosteric modulator (PAM) probe, ML293, is the result of an extended probe characterization project to improve in vivo PK properties and brain exposure. ML293 displayed modest potency at the human M4 receptor, EC50 = 1.3 μM, and excellent efficacy as noted by the leftward shift of the agonist concentration-response curve (14.6-fold). Importantly, ML293 displayed superior in vivo PK properties compared to the previous M4 probe molecules (ML108, ML173 and ML253) with low IV clearance (11.6 mL/min/kg) and excellent brain exposure (PO PBL, 10 mg/kg at 1 h, [Brain] = 10.3 μM, B:P = 0.85). Moreover, ML293 was selective for M4 (>30 μM versus, M1–3, M5), and possessed a clean ancillary pharmacological profile in a Ricerca radioligand binding panel of 68 G-protein-coupled receptors (GPCRs), ion channels and transporters with the exception of adenosine receptors. Here ML293 was found to be a potent ligand for antagonist of the A2A receptor; however the A2A antagonism will not confound in vivo evaluation of M4 PAM efficacy in schizophrenia models, whereas an A2A agonist could.">
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1,0-2,2l170,170m-91-117 110,110-26,26-110-110"></path></svg></a><a id="jr-fip-done" class="wsprkl btn" title="Dismiss find">✘</a></nav><nav 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="_NBK143538_"><span class="title" itemprop="name">Discovery of a novel structural class of M4 positive allosteric modulators: Characterization of ML293, <i>N</i>-(4-methoxy-7-methylbenzo[d]thiazol-2-yl)isonicotinamide, with CNS exposure in rats</span></h1><p class="contribs">Salovich JM, Sheffler DJ, Vinson PN, et al.</p><p class="fm-aai"><a href="#_NBK143538_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>This new M<sub>4</sub> positive allosteric modulator (PAM) probe, <a href="/pcsubstance/?term=ML293[synonym]" ref="pagearea=abstract&targetsite=entrez&targetcat=term&targettype=pubchem">ML293</a>, is the result of an extended probe characterization project to improve <i>in vivo</i> PK properties and brain exposure. <a href="/pcsubstance/?term=ML293[synonym]" ref="pagearea=abstract&targetsite=entrez&targetcat=term&targettype=pubchem">ML293</a> displayed modest potency at the human M4 receptor, EC<sub>50</sub> = 1.3 μM, and excellent efficacy as noted by the leftward shift of the agonist concentration-response curve (14.6-fold). Importantly, <a href="/pcsubstance/?term=ML293[synonym]" ref="pagearea=abstract&targetsite=entrez&targetcat=term&targettype=pubchem">ML293</a> displayed superior <i>in vivo</i> PK properties compared to the previous M<sub>4</sub> probe molecules (<a href="/pcsubstance/?term=ML108[synonym]" ref="pagearea=abstract&targetsite=entrez&targetcat=term&targettype=pubchem">ML108</a>, <a href="/pcsubstance/?term=ML173[synonym]" ref="pagearea=abstract&targetsite=entrez&targetcat=term&targettype=pubchem">ML173</a> and <a href="/pcsubstance/?term=ML253[synonym]" ref="pagearea=abstract&targetsite=entrez&targetcat=term&targettype=pubchem">ML253</a>) with low IV clearance (11.6 mL/min/kg) and excellent brain exposure (PO PBL, 10 mg/kg at 1 h, [Brain] = 10.3 μM, B:P = 0.85). Moreover, <a href="/pcsubstance/?term=ML293[synonym]" ref="pagearea=abstract&targetsite=entrez&targetcat=term&targettype=pubchem">ML293</a> was selective for M<sub>4</sub> (>30 μM versus, M<sub>1–3</sub>, M<sub>5</sub>), and possessed a clean ancillary pharmacological profile in a Ricerca radioligand binding panel of 68 G-protein-coupled receptors (GPCRs), ion channels and transporters with the exception of adenosine receptors. Here <a href="/pcsubstance/?term=ML293[synonym]" ref="pagearea=abstract&targetsite=entrez&targetcat=term&targettype=pubchem">ML293</a> was found to be a potent ligand for antagonist of the A<sub>2A</sub> receptor; however the A<sub>2A</sub> antagonism will not confound <i>in vivo</i> evaluation of M<sub>4</sub> PAM efficacy in schizophrenia models, whereas an A<sub>2A</sub> agonist could.</p></div><div class="h2"></div><p><b>Assigned Assay Grant #:</b> MH077607-1</p><p><b>Chemistry Center Name & PI:</b> Vanderbilt Specialized Chemistry Center, Craig 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">2616</a></p><div id="ml293.s1"><h2 id="_ml293_s1_">Probe Structure & Characteristics</h2><p><i>N</i>-(4-methoxy-7-methylbenzo[d]thiazol-2-yl)isonicotinamide, MW = 299.4, cLogP = 1.76, TPSA = 64.1.</p><div id="ml293.fu1" class="figure"><div class="graphic"><img src="/books/NBK143538/bin/ml293fu1.jpg" alt="Image ml293fu1" /></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml293tu1"><a href="/books/NBK143538/table/ml293.tu1/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figml293tu1" rid-ob="figobml293tu1"><img class="small-thumb" src="/books/NBK143538/table/ml293.tu1/?report=thumb" src-large="/books/NBK143538/table/ml293.tu1/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ml293.tu1"><a href="/books/NBK143538/table/ml293.tu1/?report=objectonly" target="object" rid-ob="figobml293tu1">Table</a></h4></div></div></div><div id="ml293.s2"><h2 id="_ml293_s2_">1. Recommendations for Scientific Use of the Probe</h2><p>This extended probe (<a href="/pcsubstance/?term=ML293[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML293</a>, CID 56592940) can be used both <i>in vitro</i> and <i>in vivo</i> to study the role of selective M<sub>4</sub> receptor activation. This probe possesses excellent selectivity versus M<sub>1</sub>, M<sub>2</sub>, M<sub>3,</sub> and M<sub>5</sub>, as well as a large panel of GPCRs, ion channels, and transporters. The new probe molecule displays modest potency against hM<sub>4</sub>, EC<sub>50</sub> = 1.3 μM along with an excellent 14.6-fold shift of the acetylcholine CRC. In an <i>in vivo</i> IV clearance study in rat, <a href="/pcsubstance/?term=ML293[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML293</a> displayed superior clearance values versus the previous probe molecules (CL = 11.6 mL/min/kg) with a <i>t</i><sub>1/2</sub> = 57 min., and a mean resonance time = 85 min (previous probe molecules >100 mL/min/kg). In addition, an oral plasma:brain study for <a href="/pcsubstance/?term=ML293[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML293</a> showed a Brain<sub>AUC</sub>:Plasma<sub>AUC</sub> of 0.85, with excellent brain exposure (3093 ng/g, 10.3 μM), nearly 10 times higher than any of the previous probe molecules. Thus, <a href="/pcsubstance/?term=ML293[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML293</a> is a much improved M<sub>4</sub> PAM molecule in terms of <i>in vivo</i> PK properties, while maintaining modest <i>in vitro</i> potency and efficacy. Due to the significant improvement in the <i>in vivo</i> properties, we anticipate wide use of <a href="/pcsubstance/?term=ML293[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML293</a> in the M<sub>4</sub> community.</p></div><div id="ml293.s3"><h2 id="_ml293_s3_">2. Materials and Methods</h2><div id="ml293.s4"><h3>2.1. Assays</h3><ul><li class="half_rhythm"><div><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2616" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2616</a>: M4 PAM Summary AID</div></li><li class="half_rhythm"><div><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/623938" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 623938</a>: hM4_PAM_EC2_CRC (Potency)</div></li><li class="half_rhythm"><div><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/623924" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 623924</a>: hM1_PAM_EC2_CounterScreen</div></li><li class="half_rhythm"><div><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/623925" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 623925</a>: hM2_PAM_EC2_CounterScreen</div></li><li class="half_rhythm"><div><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/623926" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 623926</a>: hM3_PAM_EC2_CounterScreen</div></li><li class="half_rhythm"><div><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/623939" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 623939</a>: hM5_PAM_EC2_CounterScreen</div></li><li class="half_rhythm"><div><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/623940" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 623940</a>: rM1_PAM_EC2_CounterScreen</div></li><li class="half_rhythm"><div><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/623941" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 623941</a>: rM2_PAM_EC2_CounterScreen</div></li><li class="half_rhythm"><div><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/623943" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 623943</a>: rM3_PAM_EC2_CounterScreen</div></li><li class="half_rhythm"><div><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/623945" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 623945</a>: rM4_PAM_EC2_CounterScreen</div></li><li class="half_rhythm"><div><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/623946" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 623946</a>: rM5_PAM_EC2_CounterScreen</div></li><li class="half_rhythm"><div><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/623948" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 623948</a>: hM4_PAM_EC2_Fold_Shift</div></li><li class="half_rhythm"><div><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/623923" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 623923</a>: ML293_Riserca_Binding</div></li></ul></div><div id="ml293.s5"><h3>2.2. Probe Chemical Characterization</h3><p>Probe compound <a href="/pcsubstance/?term=ML293[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML293</a> (CID: 56592940, SID: <a href="https://pubchem.ncbi.nlm.nih.gov/substance/134220214" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">134220214</a>) was prepared according to the scheme in <a class="figpopup" href="/books/NBK143538/figure/ml293.f1/?report=objectonly" target="object" rid-figpopup="figml293f1" rid-ob="figobml293f1">Figure 1</a> and had the following characterization: <sup>1</sup>H NMR (400 MHz, DMSO-<i>d</i><sub>6</sub>): δ 8.82 (d, <i>J</i> = 6.0 Hz, 2H), 8.02 (d, <i>J</i> = 6.1 Hz, 2H), 7.11 (d, <i>J</i> = 8.1 Hz, 1H), 6.95 (d, <i>J</i> = 8.1 Hz, 1H), 3.90 (s, 3H), 2.45 (s, 3H). LC/MS: R<sub>T</sub> = 0.60 min., m/z = 300 [M + H]<sup>+</sup>.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml293f1" co-legend-rid="figlgndml293f1"><a href="/books/NBK143538/figure/ml293.f1/?report=objectonly" target="object" title="Figure 1" class="img_link icnblk_img figpopup" rid-figpopup="figml293f1" rid-ob="figobml293f1"><img class="small-thumb" src="/books/NBK143538/bin/ml293f1.gif" src-large="/books/NBK143538/bin/ml293f1.jpg" alt="Figure 1. Synthesis of ML293." /></a><div class="icnblk_cntnt" id="figlgndml293f1"><h4 id="ml293.f1"><a href="/books/NBK143538/figure/ml293.f1/?report=objectonly" target="object" rid-ob="figobml293f1">Figure 1</a></h4><p class="float-caption no_bottom_margin">Synthesis of ML293. </p></div></div><p><b>Solubility:</b> Solubility in PBS was determined to be 6.4 μM, which is ~5-fold higher than the EC<sub>50</sub> for M<sub>4</sub> activation and better than the previous M<sub>4</sub> probe compounds <a href="/pcsubstance/?term=ML108[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML108</a> (0.7 μM), <a href="/pcsubstance/?term=ML173[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML173</a> (<.10 μM) and <a href="/pcsubstance/?term=ML253[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML253</a> (0.86 μM).</p><p><b>Stability:</b> Stability was determined for <a href="/pcsubstance/?term=ML293[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML293</a> at 23°C in PBS (no antioxidants or other protectorants and DMSO concentration below 0.1%). After 48 hours, 42% of the initial concentration of <a href="/pcsubstance/?term=ML293[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML293</a> remained (see <a class="figpopup" href="/books/NBK143538/figure/ml293.f2/?report=objectonly" target="object" rid-figpopup="figml293f2" rid-ob="figobml293f2">Figure 2</a>).</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml293f2" co-legend-rid="figlgndml293f2"><a href="/books/NBK143538/figure/ml293.f2/?report=objectonly" target="object" title="Figure 2" class="img_link icnblk_img figpopup" rid-figpopup="figml293f2" rid-ob="figobml293f2"><img class="small-thumb" src="/books/NBK143538/bin/ml293f2.gif" src-large="/books/NBK143538/bin/ml293f2.jpg" alt="Figure 2. Stability of ML293." /></a><div class="icnblk_cntnt" id="figlgndml293f2"><h4 id="ml293.f2"><a href="/books/NBK143538/figure/ml293.f2/?report=objectonly" target="object" rid-ob="figobml293f2">Figure 2</a></h4><p class="float-caption no_bottom_margin">Stability of ML293. </p></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml293tu2"><a href="/books/NBK143538/table/ml293.tu2/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figml293tu2" rid-ob="figobml293tu2"><img class="small-thumb" src="/books/NBK143538/table/ml293.tu2/?report=thumb" src-large="/books/NBK143538/table/ml293.tu2/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ml293.tu2"><a href="/books/NBK143538/table/ml293.tu2/?report=objectonly" target="object" rid-ob="figobml293tu2">Table</a></h4></div></div><p><b>Compounds added to the SMR collection (MLS#s):</b> MLS004035815 (<a href="/pcsubstance/?term=ML293[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML293</a>, CID 56592940, 20 mg); MLS004035816 (CID 43988952, 8.2 mg); MLS004035817 (CID 7192507, 5.2 mg); MLS004035818 (CID 7193069, 6.0 mg); MLS004035819 (CID 56592899, 5.7 mg); MLS004035820 (CID 43988967, 5.3 mg).</p></div><div id="ml293.s6"><h3>2.3. Probe Preparation</h3><p><i>N</i>-(4-methoxy-7-methylbenzo[d]thiazol-2-yl)isonicotinamide, <a href="/pcsubstance/?term=ML293[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML293</a>: To a stirred solution of 4-methoxy-7-methylbenzo[d]thiazol-2-amine (0.050 g, 0.26 mmol) and DIEA (0.112 mL, 0.64 mmol) in DCM (1.3 mL) at 0 °C was added isonicotinoyl chloride hydrochloride (0.050 g, 0.28 mmol). The reaction was allowed to warm to room temperature and stir overnight. The reaction was concentrated under vacuum and the residue purified by reverse-phase HPLC to give 55 mg (71%) of the pure product.</p></div></div><div id="ml293.s7"><h2 id="_ml293_s7_">3. Discussion</h2><div id="ml293.s8"><h3>3.1. Dose Response Curves for Probe</h3><p><a href="/pcsubstance/?term=ML293[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML293</a>, in the abscence of ACh, did not activate human M<sub>4</sub> cells. In the presence of an ~EC<sub>20</sub> concentration of ACh <a href="/pcsubstance/?term=ML293[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML293</a> induced well-behaved positive allosteric modulator (PAM) CRCs (<a class="figpopup" href="/books/NBK143538/figure/ml293.f3/?report=objectonly" target="object" rid-figpopup="figml293f3" rid-ob="figobml293f3">Figure 3</a>) with high efficacy (65% of ACh max).</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml293f3" co-legend-rid="figlgndml293f3"><a href="/books/NBK143538/figure/ml293.f3/?report=objectonly" target="object" title="Figure 3" class="img_link icnblk_img figpopup" rid-figpopup="figml293f3" rid-ob="figobml293f3"><img class="small-thumb" src="/books/NBK143538/bin/ml293f3.gif" src-large="/books/NBK143538/bin/ml293f3.jpg" alt="Figure 3. Human M4 PAM CRCs of ML293." /></a><div class="icnblk_cntnt" id="figlgndml293f3"><h4 id="ml293.f3"><a href="/books/NBK143538/figure/ml293.f3/?report=objectonly" target="object" rid-ob="figobml293f3">Figure 3</a></h4><p class="float-caption no_bottom_margin">Human M<sub>4</sub> PAM CRCs of ML293. ML253 had an EC<sub>50</sub> of 1.3 μM (65% ACh Max) for human M<sub>4</sub>. </p></div></div></div><div id="ml293.s9"><h3>3.2. Cellular Activity</h3><p>The primary HTS assay and all secondary assays are cell-based assays, indicating that <a href="/pcsubstance/?term=ML293[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML293</a> can gain access to its molecular target when applied to cells. The compound did not exhibit acute toxicity in cell based assays at concentrations up to 30 μM.</p></div><div id="ml293.s10"><h3>3.3. Profiling Assays</h3><p>To more fully characterize this novel M<sub>4</sub> PAM, <a href="/pcsubstance/?term=ML293[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML293</a> was tested at Ricerca Biosciences against their Lead Profiling Screen – a radioligand binding assay panel of 68 GPCR’s, ion channels, and transporters screened at 10 μM. <a href="/pcsubstance/?term=ML293[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML293</a> was found to bind to four of the 68 targets in the assays conducted (positive binding assessed as >50% inhibition at 10 μM). These included the Adenosine receptor family (A<sub>1</sub>, 91%; A<sub>2A</sub>, 100%; A<sub>3</sub>, 99%) as well as serotonin (5-hydroxytryptamine) 5-HT<sub>2B</sub> at 70% (<a class="figpopup" href="/books/NBK143538/table/ml293.t1/?report=objectonly" target="object" rid-figpopup="figml293t1" rid-ob="figobml293t1">Table 1</a>). The molecular scaffold found in <a href="/pcsubstance/?term=ML293[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML293</a> is similar to that found in a number of known adenosine receptor antagonists; thus, this finding is not surprising. It also should be noted that these are only single-point values and that functional selectivity may be significantly better than suggested by these “% activities.” To better determine the activity against the adenosine A<sub>2A</sub> receptor, <a href="/pcsubstance/?term=ML293[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML293</a> was evaluated at Ricerca Biosciences for IC<sub>50</sub>/K<sub>i</sub> determination. <a href="/pcsubstance/?term=ML293[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML293</a> was shown to be active against adenosine A<sub>2A</sub> as an <i>antagonist</i> (IC<sub>50</sub> = 0.029 μM; K<sub>i</sub> = 0.016 μM). As stated previously, this is expected as the <a href="/pcsubstance/?term=ML293[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML293</a> scaffold is known to be an antagonist of A<sub>2A</sub>. However, the adenosine receptors should not pose an issue in interpretation of any <i>in vivo</i> data for <a href="/pcsubstance/?term=ML293[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML293</a>, as <i>agonists</i> of the adenosine A<sub>2A</sub> receptor have been shown to be active in pre-clinical animal models of schizophrenia, not antagonists. Indeed, several markets atypical antipsychotics possess A<sub>2A</sub> antagonism. [<a class="bibr" href="#ml293.r1" rid="ml293.r1">1</a>, <a class="bibr" href="#ml293.r2" rid="ml293.r2">2</a>]</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml293t1"><a href="/books/NBK143538/table/ml293.t1/?report=objectonly" target="object" title="Table 1" class="img_link icnblk_img figpopup" rid-figpopup="figml293t1" rid-ob="figobml293t1"><img class="small-thumb" src="/books/NBK143538/table/ml293.t1/?report=thumb" src-large="/books/NBK143538/table/ml293.t1/?report=previmg" alt="Table 1. Ricerca Profiling of SID 134220214/VU0409524-1." /></a><div class="icnblk_cntnt"><h4 id="ml293.t1"><a href="/books/NBK143538/table/ml293.t1/?report=objectonly" target="object" rid-ob="figobml293t1">Table 1</a></h4><p class="float-caption no_bottom_margin">Ricerca Profiling of SID 134220214/VU0409524-1. </p></div></div><p>In an effort to aid the muscarinic community in the use of the probe compound, we further profiled the probe molecule (<a href="/pcsubstance/?term=ML293[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML293</a>) in a number of Tier 1 <i>in vitro</i> pharmacokinetic assays. We first wanted to assess the molecule in an intrinsic clearance assay (CL<sub>INT</sub>) in hepatic microsomes to evaluate the compound’s proclivity to oxidative metabolism, which provides a prediction (CL<sub>HEP</sub>) for subsequent clearance in <i>in vivo</i> PK studies. <a href="/pcsubstance/?term=ML293[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML293</a> showed moderate predicted CL<sub>HEP</sub> values in both human and rat microsomes (16.7 and 35.9 mL/min/kg, respectively). <a href="/pcsubstance/?term=ML293[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML293</a> was also evaluated to determine free fraction (human and rat equilibrium dialysis plasma protein binding studies). <a href="/pcsubstance/?term=ML293[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML293</a> showed low free fraction in human studies (~1% unbound); however, <a href="/pcsubstance/?term=ML293[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML293</a> possessed a reasonable free fraction in rat studies (3.2%, unbound). Lastly, the compound was evaluated in a rat brain homogenate binding study to assess the free brain fraction. <a href="/pcsubstance/?term=ML293[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML293</a> showed a ~1% free fraction in this assay. Based on the <i>in vitro</i> PK profile of <a href="/pcsubstance/?term=ML293[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML293</a>, further <i>in vivo</i> PK studies were warranted.</p></div></div><div id="ml293.s11"><h2 id="_ml293_s11_">4. Discussion</h2><div id="ml293.s12"><h3>4.1. Comparison to Existing Art and How the New Probe is an Improvement</h3><p><a href="/pcsubstance/?term=ML293[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML293</a> has a superior PK profile when compared to all of the limited known art in the M<sub>4</sub> field, including <a href="/nuccore/1257965291" class="bk_tag" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=nuccore">LY293298</a>, <a href="/pcsubstance/?term=ML108[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML108</a>, <a href="/pcsubstance/?term=ML173[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML173</a> and <a href="/pcsubstance/?term=ML253[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML253</a> (<a class="figpopup" href="/books/NBK143538/figure/ml293.f4/?report=objectonly" target="object" rid-figpopup="figml293f4" rid-ob="figobml293f4">Figure 4</a>). Although the other compounds are more potent versus the hM<sub>4</sub> receptor, <a href="/pcsubstance/?term=ML293[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML293</a> represents a novel chemical scaffold which will help the muscarinic community as a starting point for new scaffold hopping strategies. <a href="/pcsubstance/?term=ML293[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML293</a> exhibits a dramatically improved <i>in vivo</i> PK profile over all of the existing M<sub>4</sub> PAM molecules. <a href="/pcsubstance/?term=ML293[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML293</a> displays a low hepatic clearance <i>in vivo</i> (11.6 mL/min/kg versus >100 mL/min/kg), allowing for a PO dosing regimen. CNS penetration with <a href="/pcsubstance/?term=ML293[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML293</a> is also superior to the prior art when comparing similar dosing schemes. Further studies are on-going at Vanderbilt to merge the scaffolds in order to maintain the superior <i>in vivo</i> PK profile of <a href="/pcsubstance/?term=ML293[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML293</a> while increasing the potency.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml293f4" co-legend-rid="figlgndml293f4"><a href="/books/NBK143538/figure/ml293.f4/?report=objectonly" target="object" title="Figure 4" class="img_link icnblk_img figpopup" rid-figpopup="figml293f4" rid-ob="figobml293f4"><img class="small-thumb" src="/books/NBK143538/bin/ml293f4.gif" src-large="/books/NBK143538/bin/ml293f4.jpg" alt="Figure 4. Comparison of the key profiles of the known M4 PAM art and ML293." /></a><div class="icnblk_cntnt" id="figlgndml293f4"><h4 id="ml293.f4"><a href="/books/NBK143538/figure/ml293.f4/?report=objectonly" target="object" rid-ob="figobml293f4">Figure 4</a></h4><p class="float-caption no_bottom_margin">Comparison of the key profiles of the known M<sub>4</sub> PAM art and ML293. </p></div></div></div></div><div id="ml293.s13"><h2 id="_ml293_s13_">5. References</h2><dl class="temp-labeled-list"><dl class="bkr_refwrap"><dt>1.</dt><dd><div class="bk_ref" id="ml293.r1">Rimondini R, Ferré S, Ögren SO, et al. Adenosine A<sub>2A</sub> agonists: a potential new type of atypical antipsychotic. <span><span class="ref-journal">Neuropharmacology. </span>1997;<span class="ref-vol">17</span>:82–91.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/9252983" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9252983</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>2.</dt><dd><div class="bk_ref" id="ml293.r2">Ferré S, O’Connor WT, Snaprud P, et al. Antagonistic
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interaction between adenosine A<sub>2A</sub> receptors and dopamine D<sub>2</sub> receptors in the ventral striopallidal system. Implications for the treatment of schizophrenia. <span><span class="ref-journal">Neuroscience. </span>1994;<span class="ref-vol">63</span>:765–73.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/7898676" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7898676</span></a>]</div></dd></dl></dl></div><div id="bk_toc_contnr"></div></div></div><div class="fm-sec"><h2 id="_NBK143538_pubdet_">Publication Details</h2><h3>Author Information and Affiliations</h3><p class="contrib-group"><h4>Authors</h4><span itemprop="author">James M. Salovich</span>, <span itemprop="author">Douglas J. Sheffler</span>, <span itemprop="author">Paige N. Vinson</span>, <span itemprop="author">Atin Lamsal</span>, <span itemprop="author">Thomas J. Utley</span>, <span itemprop="author">Anna L. Blobaum</span>, <span itemprop="author">Thomas M. Bridges</span>, <span itemprop="author">Uyen Le</span>, <span itemprop="author">Carrie K. Jones</span>, <span itemprop="author">Michael R. Wood</span>, <span itemprop="author">J. Scott Daniels</span>, <span itemprop="author">P. Jeffrey Conn</span>, <span itemprop="author">Julie Engers</span>, <span itemprop="author">Colleen M. Niswender</span>, <span itemprop="author">Craig W. Lindsley</span>, and <span itemprop="author">Corey R. Hopkins</span><sup>,<img src="/corehtml/pmc/pmcgifs/corrauth.gif" alt="corresponding author" /></sup>.</p><h4>Affiliations</h4><div class="affiliation"><sup>1</sup> Vanderbilt Specialized Chemistry Center, Vanderbilt University Medical Center</div><div class="affiliation"><sup><img src="/corehtml/pmc/pmcgifs/corrauth.gif" alt="corresponding author" /></sup><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ude.tlibrednav@snikpoh.r.yeroc" class="oemail">ude.tlibrednav@snikpoh.r.yeroc</a></div><h3>Publication History</h3><p class="small">Received: <span itemprop="datePublished">April 2, 2012</span>; Last Update: <span itemprop="dateModified">March 14, 2013</span>.</p><h3>Copyright</h3><div><div class="half_rhythm"><a href="/books/about/copyright/">Copyright Notice</a></div></div><h3>Publisher</h3><p>National Center for Biotechnology Information (US), Bethesda (MD)</p><h3>NLM Citation</h3><p>Salovich JM, Sheffler DJ, Vinson PN, et al. Discovery of a novel structural class of M4 positive allosteric modulators: Characterization of ML293, N-(4-methoxy-7-methylbenzo[d]thiazol-2-yl)isonicotinamide, with CNS exposure in rats. 2012 Apr 2 [Updated 2013 Mar 14]. 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/ml294/?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/ml292/?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="figobml293fu1"><div id="ml293.fu1" class="figure"><div class="graphic"><img data-src="/books/NBK143538/bin/ml293fu1.jpg" alt="Image ml293fu1" /></div></div></article><article data-type="table-wrap" id="figobml293tu1"><div id="ml293.tu1" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK143538/table/ml293.tu1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml293.tu1_lrgtbl__"><table><thead><tr><th id="hd_h_ml293.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CID/ML#</th><th id="hd_h_ml293.tu1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Target Name</th><th id="hd_h_ml293.tu1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">EC<sub>50</sub>/(μM) [SID, AID]</th><th id="hd_h_ml293.tu1_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Anti-target Name(s)</th><th id="hd_h_ml293.tu1_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">EC<sub>50</sub> (μM) [SID, AID]</th><th id="hd_h_ml293.tu1_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Fold Selective</th><th id="hd_h_ml293.tu1_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Secondary Assay(s) Name: Ach-Fold Shift [SID, AID]</th></tr></thead><tbody><tr><td headers="hd_h_ml293.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CID 56592940/<a href="/pcsubstance/?term=ML293[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML293</a></td><td headers="hd_h_ml293.tu1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">M<sub>4</sub></td><td headers="hd_h_ml293.tu1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hM<sub>4</sub> = 1.30 ±0.05 [<a href="https://pubchem.ncbi.nlm.nih.gov/substance/134220214" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 134220214</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/623938" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 623938</a>]</td><td headers="hd_h_ml293.tu1_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hM<sub>1–3</sub>,hM<sub>5</sub></td><td headers="hd_h_ml293.tu1_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">>30 [<a href="https://pubchem.ncbi.nlm.nih.gov/substance/134220214" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 134220214</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/623924" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 623924</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/623925" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 623925</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/623926" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 623926</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/623939" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 623939</a>]</td><td headers="hd_h_ml293.tu1_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">>20</td><td headers="hd_h_ml293.tu1_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">14.6-fold [<a href="https://pubchem.ncbi.nlm.nih.gov/substance/134220214" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 134220214</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/623948" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 623948</a>]</td></tr></tbody></table></div></div></article><article data-type="fig" id="figobml293f1"><div id="ml293.f1" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK143538/bin/ml293f1.jpg" alt="Figure 1. Synthesis of ML293." /></div><h3><span class="label">Figure 1</span><span class="title">Synthesis of ML293</span></h3></div></article><article data-type="table-wrap" id="figobml293tu2"><div id="ml293.tu2" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK143538/table/ml293.tu2/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml293.tu2_lrgtbl__"><table><thead><tr><th id="hd_h_ml293.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;"></th><th id="hd_h_ml293.tu2_1_1_1_2" colspan="6" rowspan="1" style="text-align:center;vertical-align:bottom;">Percent Remaining (%)</th></tr><tr><th headers="hd_h_ml293.tu2_1_1_1_1" id="hd_h_ml293.tu2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">Compound</th><th headers="hd_h_ml293.tu2_1_1_1_2" id="hd_h_ml293.tu2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">0 Min</th><th headers="hd_h_ml293.tu2_1_1_1_2" id="hd_h_ml293.tu2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">15 Min</th><th headers="hd_h_ml293.tu2_1_1_1_2" id="hd_h_ml293.tu2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">30 Min</th><th headers="hd_h_ml293.tu2_1_1_1_2" id="hd_h_ml293.tu2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">90 Min</th><th headers="hd_h_ml293.tu2_1_1_1_2" id="hd_h_ml293.tu2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">24 Hour</th><th headers="hd_h_ml293.tu2_1_1_1_2" id="hd_h_ml293.tu2_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">48 Hour</th></tr></thead><tbody><tr><td headers="hd_h_ml293.tu2_1_1_1_1 hd_h_ml293.tu2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="/pcsubstance/?term=ML293[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML293</a>, CID 56592940</td><td headers="hd_h_ml293.tu2_1_1_1_2 hd_h_ml293.tu2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">100</td><td headers="hd_h_ml293.tu2_1_1_1_2 hd_h_ml293.tu2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">95</td><td headers="hd_h_ml293.tu2_1_1_1_2 hd_h_ml293.tu2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">90</td><td headers="hd_h_ml293.tu2_1_1_1_2 hd_h_ml293.tu2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">90</td><td headers="hd_h_ml293.tu2_1_1_1_2 hd_h_ml293.tu2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">58</td><td headers="hd_h_ml293.tu2_1_1_1_2 hd_h_ml293.tu2_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">42</td></tr></tbody></table></div></div></article><article data-type="fig" id="figobml293f2"><div id="ml293.f2" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK143538/bin/ml293f2.jpg" alt="Figure 2. Stability of ML293." /></div><h3><span class="label">Figure 2</span><span class="title">Stability of ML293</span></h3></div></article><article data-type="fig" id="figobml293f3"><div id="ml293.f3" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK143538/bin/ml293f3.jpg" alt="Figure 3. Human M4 PAM CRCs of ML293." /></div><h3><span class="label">Figure 3</span><span class="title">Human M<sub>4</sub> PAM CRCs of ML293</span></h3><div class="caption"><p><a href="/pcsubstance/?term=ML253[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML253</a> had an EC<sub>50</sub> of 1.3 μM (65% ACh Max) for human M<sub>4</sub>.</p></div></div></article><article data-type="table-wrap" id="figobml293t1"><div id="ml293.t1" class="table"><h3><span class="label">Table 1</span><span class="title">Ricerca Profiling of SID 134220214/VU0409524-1</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK143538/table/ml293.t1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml293.t1_lrgtbl__"><table class="no_top_margin"><thead><tr><th id="hd_h_ml293.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">CID/ML</th><th id="hd_h_ml293.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">Structure</th><th id="hd_h_ml293.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">Primary Biochemical Assay</th><th id="hd_h_ml293.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">Species</th><th id="hd_h_ml293.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">% inhibition @ 10 μM</th></tr></thead><tbody><tr><td headers="hd_h_ml293.t1_1_1_1_1" rowspan="4" colspan="1" style="text-align:center;vertical-align:middle;">CID 56592940/<a href="/pcsubstance/?term=ML293[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML293</a></td><td headers="hd_h_ml293.t1_1_1_1_2" rowspan="4" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143538/bin/ml293fu2.jpg" alt="Image ml293fu2.jpg" /></div></td><td headers="hd_h_ml293.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Adenosine A<sub>1</sub></td><td headers="hd_h_ml293.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Human</td><td headers="hd_h_ml293.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">91</td></tr><tr><td headers="hd_h_ml293.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Adenosine A<sub>2A</sub></td><td headers="hd_h_ml293.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Human</td><td headers="hd_h_ml293.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">100</td></tr><tr><td headers="hd_h_ml293.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Adenosine A<sub>3</sub></td><td headers="hd_h_ml293.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Human</td><td headers="hd_h_ml293.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">99</td></tr><tr><td headers="hd_h_ml293.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Serotonine (5-Hydroxytryptamine) 5-HT<sub>2B</sub></td><td headers="hd_h_ml293.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Human</td><td headers="hd_h_ml293.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">70</td></tr></tbody></table></div></div></article><article data-type="fig" id="figobml293f4"><div id="ml293.f4" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%204.%20Comparison%20of%20the%20key%20profiles%20of%20the%20known%20M4%20PAM%20art%20and%20ML293.&p=BOOKS&id=143538_ml293f4.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK143538/bin/ml293f4.jpg" alt="Figure 4. Comparison of the key profiles of the known M4 PAM art and ML293." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 4</span><span class="title">Comparison of the key profiles of the known M<sub>4</sub> PAM art and ML293</span></h3></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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