125 lines
132 KiB
Text
125 lines
132 KiB
Text
<!DOCTYPE html>
|
|
<html xmlns="http://www.w3.org/1999/xhtml" xml:lang="en" class="no-js no-jr">
|
|
<head>
|
|
<!-- For pinger, set start time and add meta elements. -->
|
|
<script type="text/javascript">var ncbi_startTime = new Date();</script>
|
|
|
|
<!-- Logger begin -->
|
|
<meta name="ncbi_db" content="books">
|
|
<meta name="ncbi_pdid" content="book-part">
|
|
<meta name="ncbi_acc" content="NBK143193">
|
|
<meta name="ncbi_domain" content="mlprobe">
|
|
<meta name="ncbi_report" content="reader">
|
|
<meta name="ncbi_type" content="fulltext">
|
|
<meta name="ncbi_objectid" content="">
|
|
<meta name="ncbi_pcid" content="/NBK143193/?report=reader">
|
|
<meta name="ncbi_pagename" content="Development of the First Highly Selective mAChR 5 (M5) Positive Allosteric Modulator (PAM) - Probe Reports from the NIH Molecular Libraries Program - NCBI Bookshelf">
|
|
<meta name="ncbi_bookparttype" content="chapter">
|
|
<meta name="ncbi_app" content="bookshelf">
|
|
<!-- Logger end -->
|
|
|
|
<!--component id="Page" label="meta"/-->
|
|
<script type="text/javascript" src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.boots.min.js"> </script><title>Development of the First Highly Selective mAChR 5 (M5) Positive Allosteric Modulator (PAM) - Probe Reports from the NIH Molecular Libraries Program - NCBI Bookshelf</title>
|
|
<meta charset="utf-8">
|
|
<meta name="apple-mobile-web-app-capable" content="no">
|
|
<meta name="viewport" content="initial-scale=1,minimum-scale=1,maximum-scale=1,user-scalable=no">
|
|
<meta name="jr-col-layout" content="auto">
|
|
<meta name="jr-prev-unit" content="/books/n/mlprobe/ml173/?report=reader">
|
|
<meta name="jr-next-unit" content="/books/n/mlprobe/ml171/?report=reader">
|
|
<meta name="bk-toc-url" content="/books/n/mlprobe/?report=toc">
|
|
<meta name="robots" content="INDEX,FOLLOW,NOARCHIVE">
|
|
<meta name="citation_inbook_title" content="Probe Reports from the NIH Molecular Libraries Program [Internet]">
|
|
<meta name="citation_title" content="Development of the First Highly Selective mAChR 5 (M5) Positive Allosteric Modulator (PAM)">
|
|
<meta name="citation_publisher" content="National Center for Biotechnology Information (US)">
|
|
<meta name="citation_date" content="2013/03/14">
|
|
<meta name="citation_author" content="Thomas M. Bridges">
|
|
<meta name="citation_author" content="L. Michelle Lewis">
|
|
<meta name="citation_author" content="C. David Weaver">
|
|
<meta name="citation_author" content="Michael R. Wood">
|
|
<meta name="citation_author" content="J. Scott Daniels">
|
|
<meta name="citation_author" content="P. Jeffrey Conn">
|
|
<meta name="citation_author" content="Craig W. Lindsley">
|
|
<meta name="citation_pmid" content="23762960">
|
|
<meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK143193/">
|
|
<link rel="schema.DC" href="http://purl.org/DC/elements/1.0/">
|
|
<meta name="DC.Title" content="Development of the First Highly Selective mAChR 5 (M5) Positive Allosteric Modulator (PAM)">
|
|
<meta name="DC.Type" content="Text">
|
|
<meta name="DC.Publisher" content="National Center for Biotechnology Information (US)">
|
|
<meta name="DC.Contributor" content="Thomas M. Bridges">
|
|
<meta name="DC.Contributor" content="L. Michelle Lewis">
|
|
<meta name="DC.Contributor" content="C. David Weaver">
|
|
<meta name="DC.Contributor" content="Michael R. Wood">
|
|
<meta name="DC.Contributor" content="J. Scott Daniels">
|
|
<meta name="DC.Contributor" content="P. Jeffrey Conn">
|
|
<meta name="DC.Contributor" content="Craig W. Lindsley">
|
|
<meta name="DC.Date" content="2013/03/14">
|
|
<meta name="DC.Identifier" content="https://www.ncbi.nlm.nih.gov/books/NBK143193/">
|
|
<meta name="description" content="This probe (ML172, CID 44602489), which possesses improved muscarinic selectivity over our previous M5 positive allosteric modulator (PAM) probe (ML129, CID 42633508), can be used for in vitro molecular pharmacology and electrophysiology experiments to study the role of selective M5 receptor activation. This probe possesses unprecedented selectivity versus M1, M2, M3 and M4. The probe (ML172, CID 44602489) is not readily CNS penetrant, and so would need to be administered i.c.v. to study the role of central M5 activation in vivo.">
|
|
<meta name="og:title" content="Development of the First Highly Selective mAChR 5 (M5) Positive Allosteric Modulator (PAM)">
|
|
<meta name="og:type" content="book">
|
|
<meta name="og:description" content="This probe (ML172, CID 44602489), which possesses improved muscarinic selectivity over our previous M5 positive allosteric modulator (PAM) probe (ML129, CID 42633508), can be used for in vitro molecular pharmacology and electrophysiology experiments to study the role of selective M5 receptor activation. This probe possesses unprecedented selectivity versus M1, M2, M3 and M4. The probe (ML172, CID 44602489) is not readily CNS penetrant, and so would need to be administered i.c.v. to study the role of central M5 activation in vivo.">
|
|
<meta name="og:url" content="https://www.ncbi.nlm.nih.gov/books/NBK143193/">
|
|
<meta name="og:site_name" content="NCBI Bookshelf">
|
|
<meta name="og:image" content="https://www.ncbi.nlm.nih.gov/corehtml/pmc/pmcgifs/bookshelf/thumbs/th-mlprobe-lrg.png">
|
|
<meta name="twitter:card" content="summary">
|
|
<meta name="twitter:site" content="@ncbibooks">
|
|
<meta name="bk-non-canon-loc" content="/books/n/mlprobe/ml172/?report=reader">
|
|
<link rel="canonical" href="https://www.ncbi.nlm.nih.gov/books/NBK143193/">
|
|
<link href="https://fonts.googleapis.com/css?family=Archivo+Narrow:400,700,400italic,700italic&subset=latin" rel="stylesheet" type="text/css">
|
|
<link rel="stylesheet" href="/corehtml/pmc/jatsreader/ptpmc_3.22/css/libs.min.css">
|
|
<link rel="stylesheet" href="/corehtml/pmc/jatsreader/ptpmc_3.22/css/jr.min.css">
|
|
<meta name="format-detection" content="telephone=no">
|
|
<link rel="stylesheet" href="/corehtml/pmc/css/bookshelf/2.26/css/books.min.css" type="text/css">
|
|
<link rel="stylesheet" href="/corehtml/pmc/css/bookshelf/2.26/css//books_print.min.css" type="text/css" media="print">
|
|
<link rel="stylesheet" href="/corehtml/pmc/css/bookshelf/2.26/css/books_reader.min.css" type="text/css">
|
|
<style type="text/css">p a.figpopup{display:inline !important} .bk_tt {font-family: monospace} .first-line-outdent .bk_ref {display: inline} .body-content h2, .body-content .h2 {border-bottom: 1px solid #97B0C8} .body-content h2.inline {border-bottom: none} a.page-toc-label , .jig-ncbismoothscroll a {text-decoration:none;border:0 !important} .temp-labeled-list .graphic {display:inline-block !important} .temp-labeled-list img{width:100%}</style>
|
|
|
|
<link rel="shortcut icon" href="//www.ncbi.nlm.nih.gov/favicon.ico">
|
|
<meta name="ncbi_phid" content="CE8B33C87D663EB10000000000760066.m_5">
|
|
<meta name='referrer' content='origin-when-cross-origin'/><link type="text/css" rel="stylesheet" href="//static.pubmed.gov/portal/portal3rc.fcgi/4216699/css/3852956/3849091.css"></head>
|
|
<body>
|
|
<!-- Book content! -->
|
|
|
|
|
|
<div id="jr" data-jr-path="/corehtml/pmc/jatsreader/ptpmc_3.22/"><div class="jr-unsupported"><table class="modal"><tr><td><span class="attn inline-block"></span><br />Your browser does not support the NLM PubReader view.<br />Go to <a href="/pmc/about/pr-browsers/">this page</a> to see a list of supported browsers<br />or return to the <br /><a href="/books/NBK143193/?report=classic">regular view</a>.</td></tr></table></div><div id="jr-ui" class="hidden"><nav id="jr-head"><div class="flexh tb"><div id="jr-tb1"><a id="jr-links-sw" class="hidden" title="Links"><svg xmlns="http://www.w3.org/2000/svg" version="1.1" x="0px" y="0px" viewBox="0 0 70.6 85.3" style="enable-background:new 0 0 70.6 85.3;vertical-align:middle" xml:space="preserve" width="24" height="24">
|
|
<style type="text/css">.st0{fill:#939598;}</style>
|
|
<g>
|
|
<path class="st0" d="M36,0C12.8,2.2-22.4,14.6,19.6,32.5C40.7,41.4-30.6,14,35.9,9.8"></path>
|
|
<path class="st0" d="M34.5,85.3c23.2-2.2,58.4-14.6,16.4-32.5c-21.1-8.9,50.2,18.5-16.3,22.7"></path>
|
|
<path class="st0" d="M34.7,37.1c66.5-4.2-4.8-31.6,16.3-22.7c42.1,17.9,6.9,30.3-16.4,32.5h1.7c-66.2,4.4,4.8,31.6-16.3,22.7 c-42.1-17.9-6.9-30.3,16.4-32.5"></path>
|
|
</g>
|
|
</svg> Books</a></div><div class="jr-rhead f1 flexh"><div class="head"><a href="/books/n/mlprobe/ml173/?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="body"><div class="t">Development of the First Highly Selective mAChR 5 (M5) Positive Allosteric Modulator (PAM)</div><div class="j">Probe Reports from the NIH Molecular Libraries Program [Internet]</div></div><div class="tail"><a href="/books/n/mlprobe/ml171/?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></div><div id="jr-tb2"><a id="jr-bkhelp-sw" class="btn wsprkl hidden" title="Help with NLM PubReader">?</a><a id="jr-help-sw" class="btn wsprkl hidden" title="Settings and typography in NLM PubReader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 512 512" preserveAspectRatio="none"><path d="M462,283.742v-55.485l-29.981-10.662c-11.431-4.065-20.628-12.794-25.274-24.001 c-0.002-0.004-0.004-0.009-0.006-0.013c-4.659-11.235-4.333-23.918,0.889-34.903l13.653-28.724l-39.234-39.234l-28.72,13.652 c-10.979,5.219-23.68,5.546-34.908,0.889c-0.005-0.002-0.01-0.003-0.014-0.005c-11.215-4.65-19.933-13.834-24-25.273L283.741,50 h-55.484l-10.662,29.981c-4.065,11.431-12.794,20.627-24.001,25.274c-0.005,0.002-0.009,0.004-0.014,0.005 c-11.235,4.66-23.919,4.333-34.905-0.889l-28.723-13.653l-39.234,39.234l13.653,28.721c5.219,10.979,5.545,23.681,0.889,34.91 c-0.002,0.004-0.004,0.009-0.006,0.013c-4.649,11.214-13.834,19.931-25.271,23.998L50,228.257v55.485l29.98,10.661 c11.431,4.065,20.627,12.794,25.274,24c0.002,0.005,0.003,0.01,0.005,0.014c4.66,11.236,4.334,23.921-0.888,34.906l-13.654,28.723 l39.234,39.234l28.721-13.652c10.979-5.219,23.681-5.546,34.909-0.889c0.005,0.002,0.01,0.004,0.014,0.006 c11.214,4.649,19.93,13.833,23.998,25.271L228.257,462h55.484l10.595-29.79c4.103-11.538,12.908-20.824,24.216-25.525 c0.005-0.002,0.009-0.004,0.014-0.006c11.127-4.628,23.694-4.311,34.578,0.863l28.902,13.738l39.234-39.234l-13.66-28.737 c-5.214-10.969-5.539-23.659-0.886-34.877c0.002-0.005,0.004-0.009,0.006-0.014c4.654-11.225,13.848-19.949,25.297-24.021 L462,283.742z M256,331.546c-41.724,0-75.548-33.823-75.548-75.546s33.824-75.547,75.548-75.547 c41.723,0,75.546,33.824,75.546,75.547S297.723,331.546,256,331.546z"></path></svg></a><a id="jr-fip-sw" class="btn wsprkl hidden" title="Find"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 550 600" preserveAspectRatio="none"><path fill="none" stroke="#000" stroke-width="36" stroke-linecap="round" style="fill:#FFF" d="m320,350a153,153 0 1,0-2,2l170,170m-91-117 110,110-26,26-110-110"></path></svg></a><a id="jr-rtoc-sw" class="btn wsprkl hidden" title="Table of Contents"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M20,20h10v8H20V20zM36,20h44v8H36V20zM20,37.33h10v8H20V37.33zM36,37.33h44v8H36V37.33zM20,54.66h10v8H20V54.66zM36,54.66h44v8H36V54.66zM20,72h10v8 H20V72zM36,72h44v8H36V72z"></path></svg></a></div></div></nav><nav id="jr-dash" class="noselect"><nav id="jr-dash" class="noselect"><div id="jr-pi" class="hidden"><a id="jr-pi-prev" class="hidden" title="Previous page"><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 class="pginfo">Page <i class="jr-pg-pn">0</i> of <i class="jr-pg-lp">0</i></div><a id="jr-pi-next" class="hidden" title="Next page"><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><div id="jr-is-tb"><a id="jr-is-sw" class="btn wsprkl hidden" title="Switch between Figures/Tables strip and Progress bar"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><rect x="10" y="40" width="20" height="20"></rect><rect x="40" y="40" width="20" height="20"></rect><rect x="70" y="40" width="20" height="20"></rect></svg></a></div><nav id="jr-istrip" class="istrip hidden"><a id="jr-is-prev" href="#" class="hidden" title="Previous"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M80,40 60,65 80,90 70,90 50,65 70,40z M50,40 30,65 50,90 40,90 20,65 40,40z"></path><text x="35" y="25" textLength="60" style="font-size:25px">Prev</text></svg></a><a id="jr-is-next" href="#" class="hidden" title="Next"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M20,40 40,65 20,90 30,90 50,65 30,40z M50,40 70,65 50,90 60,90 80,65 60,40z"></path><text x="15" y="25" textLength="60" style="font-size:25px">Next</text></svg></a></nav><nav id="jr-progress"></nav></nav></nav><aside id="jr-links-p" class="hidden flexv"><div class="tb sk-htbar flexh"><div><a class="jr-p-close btn wsprkl">Done</a></div><div class="title-text f1">NCBI Bookshelf</div></div><div class="cnt lol f1"><a href="/books/">Home</a><a href="/books/browse/">Browse All Titles</a><a class="btn share" target="_blank" rel="noopener noreferrer" href="https://www.facebook.com/sharer/sharer.php?u=https://www.ncbi.nlm.nih.gov/books/NBK143193/"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 33 33" style="vertical-align:middle" width="24" height="24" preserveAspectRatio="none"><g><path d="M 17.996,32L 12,32 L 12,16 l-4,0 l0-5.514 l 4-0.002l-0.006-3.248C 11.993,2.737, 13.213,0, 18.512,0l 4.412,0 l0,5.515 l-2.757,0 c-2.063,0-2.163,0.77-2.163,2.209l-0.008,2.76l 4.959,0 l-0.585,5.514L 18,16L 17.996,32z"></path></g></svg> Share on Facebook</a><a class="btn share" target="_blank" rel="noopener noreferrer" href="https://twitter.com/intent/tweet?url=https://www.ncbi.nlm.nih.gov/books/NBK143193/&text=Development%20of%20the%20First%20Highly%20Selective%20mAChR%205%20(M5)%20Positive%20Allosteric%20Modulator%20(PAM)"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 33 33" style="vertical-align:middle" width="24" height="24"><g><path d="M 32,6.076c-1.177,0.522-2.443,0.875-3.771,1.034c 1.355-0.813, 2.396-2.099, 2.887-3.632 c-1.269,0.752-2.674,1.299-4.169,1.593c-1.198-1.276-2.904-2.073-4.792-2.073c-3.626,0-6.565,2.939-6.565,6.565 c0,0.515, 0.058,1.016, 0.17,1.496c-5.456-0.274-10.294-2.888-13.532-6.86c-0.565,0.97-0.889,2.097-0.889,3.301 c0,2.278, 1.159,4.287, 2.921,5.465c-1.076-0.034-2.088-0.329-2.974-0.821c-0.001,0.027-0.001,0.055-0.001,0.083 c0,3.181, 2.263,5.834, 5.266,6.438c-0.551,0.15-1.131,0.23-1.73,0.23c-0.423,0-0.834-0.041-1.235-0.118 c 0.836,2.608, 3.26,4.506, 6.133,4.559c-2.247,1.761-5.078,2.81-8.154,2.81c-0.53,0-1.052-0.031-1.566-0.092 c 2.905,1.863, 6.356,2.95, 10.064,2.95c 12.076,0, 18.679-10.004, 18.679-18.68c0-0.285-0.006-0.568-0.019-0.849 C 30.007,8.548, 31.12,7.392, 32,6.076z"></path></g></svg> Share on Twitter</a></div></aside><aside id="jr-rtoc-p" class="hidden flexv"><div class="tb sk-htbar flexh"><div><a class="jr-p-close btn wsprkl">Done</a></div><div class="title-text f1">Table of Content</div></div><div class="cnt lol f1"><a href="/books/n/mlprobe/?report=reader">Title Information</a><a href="/books/n/mlprobe/toc/?report=reader">Table of Contents Page</a></div></aside><aside id="jr-help-p" class="hidden flexv"><div class="tb sk-htbar flexh"><div><a class="jr-p-close btn wsprkl">Done</a></div><div class="title-text f1">Settings</div></div><div class="cnt f1"><div id="jr-typo-p" class="typo"><div><a class="sf btn wsprkl">A-</a><a class="lf btn wsprkl">A+</a></div><div><a class="bcol-auto btn wsprkl"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 200 100" preserveAspectRatio="none"><text x="10" y="70" style="font-size:60px;font-family: Trebuchet MS, ArialMT, Arial, sans-serif" textLength="180">AUTO</text></svg></a><a class="bcol-1 btn wsprkl"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M15,25 85,25zM15,40 85,40zM15,55 85,55zM15,70 85,70z"></path></svg></a><a class="bcol-2 btn wsprkl"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M5,25 45,25z M55,25 95,25zM5,40 45,40z M55,40 95,40zM5,55 45,55z M55,55 95,55zM5,70 45,70z M55,70 95,70z"></path></svg></a></div></div><div class="lol"><a class="" href="/books/NBK143193/?report=classic">Switch to classic view</a><a href="/books/NBK143193/pdf/Bookshelf_NBK143193.pdf">PDF (877K)</a><a href="/books/NBK143193/?report=printable">Print View</a></div></div></aside><aside id="jr-bkhelp-p" class="hidden flexv"><div class="tb sk-htbar flexh"><div><a class="jr-p-close btn wsprkl">Done</a></div><div class="title-text f1">Help</div></div><div class="cnt f1 lol"><a id="jr-helpobj-sw" data-path="/corehtml/pmc/jatsreader/ptpmc_3.22/" data-href="/corehtml/pmc/jatsreader/ptpmc_3.22/img/bookshelf/help.xml" href="">Help</a><a href="mailto:info@ncbi.nlm.nih.gov?subject=PubReader%20feedback%20%2F%20NBK143193%20%2F%20sid%3ACE8B5AF87C7FFCB1_0191SID%20%2F%20phid%3ACE8B33C87D663EB10000000000760066.4">Send us feedback</a><a id="jr-about-sw" data-path="/corehtml/pmc/jatsreader/ptpmc_3.22/" data-href="/corehtml/pmc/jatsreader/ptpmc_3.22/img/bookshelf/about.xml" href="">About PubReader</a></div></aside><aside id="jr-objectbox" class="thidden hidden"><div class="jr-objectbox-close wsprkl">✘</div><div class="jr-objectbox-inner cnt"><div class="jr-objectbox-drawer"></div></div></aside><nav id="jr-pm-left" class="hidden"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 40 800" preserveAspectRatio="none"><text font-stretch="ultra-condensed" x="800" y="-15" text-anchor="end" transform="rotate(90)" font-size="18" letter-spacing=".1em">Previous Page</text></svg></nav><nav id="jr-pm-right" class="hidden"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 40 800" preserveAspectRatio="none"><text font-stretch="ultra-condensed" x="800" y="-15" text-anchor="end" transform="rotate(90)" font-size="18" letter-spacing=".1em">Next Page</text></svg></nav><nav id="jr-fip" class="hidden"><nav id="jr-fip-term-p"><input type="search" placeholder="search this page" id="jr-fip-term" autocorrect="off" autocomplete="off" /><a id="jr-fip-mg" class="wsprkl btn" title="Find"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 550 600" preserveAspectRatio="none"><path fill="none" stroke="#000" stroke-width="36" stroke-linecap="round" style="fill:#FFF" d="m320,350a153,153 0 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="_NBK143193_"><span class="title" itemprop="name">Development of the First Highly Selective mAChR 5 (M<sub>5</sub>) Positive Allosteric Modulator (PAM)</span></h1><p class="contribs">Bridges TM, Lewis LM, Weaver CD, et al.</p><p class="fm-aai"><a href="#_NBK143193_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 probe (<a href="/pcsubstance/?term=ML172[synonym]" ref="pagearea=abstract&targetsite=entrez&targetcat=term&targettype=pubchem">ML172</a>, CID 44602489), which possesses improved muscarinic selectivity over our previous M<sub>5</sub> positive allosteric modulator (PAM) probe (<a href="/pcsubstance/?term=ML129[synonym]" ref="pagearea=abstract&targetsite=entrez&targetcat=term&targettype=pubchem">ML129</a>, CID 42633508), can be used for <i>in vitro</i> molecular pharmacology and electrophysiology experiments to study the role of selective M<sub>5</sub> receptor activation. This probe possesses unprecedented selectivity versus M<sub>1</sub>, M<sub>2</sub>, M<sub>3</sub> and M<sub>4</sub>. The probe (<a href="/pcsubstance/?term=ML172[synonym]" ref="pagearea=abstract&targetsite=entrez&targetcat=term&targettype=pubchem">ML172</a>, CID 44602489) is not readily CNS penetrant, and so would need to be administered i.c.v. to study the role of central M<sub>5</sub> activation <i>in vivo</i>.</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> P. Jeffrey Conn, Vanderbilt University</p><p><b>PubChem Summary Bioassay Identifier (AID):</b>
|
|
<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2416" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2416</a></p><div id="ml172.s1"><h2 id="_ml172_s1_">Probe Structure & Characteristics</h2><p>1-(4-phenoxybenzyl)-5-(trifluoromethoxy)indoline-2,3-dione, MW = 413.4, logP = 5.8, tPSA = 107.0 Å<sup>2</sup></p><div id="ml172.fu1" class="figure bk_fig"><div class="graphic"><img src="/books/NBK143193/bin/ml172fu1.jpg" alt="ML172." /></div><h3><span class="title">ML172</span></h3></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml172tu1"><a href="/books/NBK143193/table/ml172.tu1/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figml172tu1" rid-ob="figobml172tu1"><img class="small-thumb" src="/books/NBK143193/table/ml172.tu1/?report=thumb" src-large="/books/NBK143193/table/ml172.tu1/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ml172.tu1"><a href="/books/NBK143193/table/ml172.tu1/?report=objectonly" target="object" rid-ob="figobml172tu1">Table</a></h4></div></div></div><div id="ml172.s2"><h2 id="_ml172_s2_">Recommendations for Scientific Use of the Probe</h2><p>This probe (<a href="/pcsubstance/?term=ML172[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML172</a>, CID 44602489), which possesses improved muscarinic selectivity over our previous M<sub>5</sub> PAM probe (<a href="/pcsubstance/?term=ML129[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML 129</a>, CID 42633508), can be used for <i>in vitro</i> molecular pharmacology and electrophysiology experiments to study the role of selective M<sub>5</sub> receptor activation. This probe possesses unprecedented selectivity versus M<sub>1</sub>, M<sub>2</sub>, M<sub>3</sub> and M<sub>4</sub>. The probe (<a href="/pcsubstance/?term=ML172[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML172</a>, CID 44602489) is not readily CNS penetrant, and so would need to be administered i.c.v. to study the role of central M<sub>5</sub> activation <i>in vivo</i>.</p></div><div id="ml172.s3"><h2 id="_ml172_s3_">1. Introduction</h2><p><b>Specific AIM:</b> To identify small molecule positive allosteric modulators (PAMs) and/or allosteric agonists of the M<sub>5</sub> muscarinic acetylcholine receptor that are cell permeable, possess low- to sub-micromolar potency and show greater than 10-fold selectivity over the other mAChRs (M<sub>1</sub>, M<sub>2</sub>, M<sub>3</sub> and M<sub>4</sub>) employing a functional HTS approach. Out of this effort primarily aimed at M<sub>1</sub>, which afforded a highly selective M<sub>1</sub> allosteric agonist (CID 25010775) and two highly selective M<sub>1</sub> PAM probes (CID 44251556, and CID 44475955), we also identified and optimized the first selective M<sub>5</sub> PAM (CID 42633508), and now report the next-generation M<sub>5</sub> PAM described herein. Another MLSCN screening effort identified a highly selective M<sub>4</sub> PAM (CID 864492) and a subsequent highly selective M<sub>4</sub> PAM endowed with improved human potency (<a href="/pcsubstance/?term=ML173[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML 173</a>, CID 45142486); thus, a toolkit containing highly selective, allosteric mAChR ligands are available from the MLPCN to study individual mAChR function.</p><p><b>Significance:</b> The five cloned muscarinic acetylcholine receptor subtypes (mAChR1-5
|
|
or M<sub>1–5</sub>) are known to play highly important and diverse roles in many basic physiological processes.<sup><a class="bibr" href="#ml172.r1" rid="ml172.r1">1</a>–<a class="bibr" href="#ml172.r3" rid="ml172.r3">3</a></sup> Correspondingly, muscarinic agonists and antagonists targeting one or more subtypes have been used preclinically and clinically for research and treatment of a wide range of pathologies.<sup><a class="bibr" href="#ml172.r3" rid="ml172.r3">3</a>,<a class="bibr" href="#ml172.r4" rid="ml172.r4">4</a></sup> Based on the high sequence homology of the mAChRs across subtypes, and particularly within the orthosteric acetylcholine (ACh) binding site, discovery of truly subtype-selective compounds has proven historically difficult. Due to the scarcity of selective compounds, a detailed understanding of the precise roles of each subtype in neurobiology and in various central nervous system (CNS) disorders has thus remained challenging.<sup><a class="bibr" href="#ml172.r3" rid="ml172.r3">3</a>,<a class="bibr" href="#ml172.r4" rid="ml172.r4">4</a></sup> A number of novel highly subtype-selective allosteric ligands for M<sub>1</sub> and M<sub>4</sub> have emerged from functional cell-based screening efforts.<sup><a class="bibr" href="#ml172.r5" rid="ml172.r5">5</a>,<a class="bibr" href="#ml172.r6" rid="ml172.r6">6</a></sup> Only recently have the first M<sub>5</sub> selective ligands been disclosed from these laboratories.<sup><a class="bibr" href="#ml172.r13" rid="ml172.r13">13</a></sup> Relative to the other mAChRs, little is known about M<sub>5</sub>, which is expressed at very low levels in the CNS and peripheral tissues.<sup><a class="bibr" href="#ml172.r2" rid="ml172.r2">2</a>–<a class="bibr" href="#ml172.r4" rid="ml172.r4">4</a></sup></p><p><b>Rationale:</b> Data from studies using mAChR5 knock-out (M<sub>5</sub>-KO) mice suggest that M<sub>5</sub> is the sole mediator of ACh-induced vasodilation in the cerebral vasculature and thereby may have therapeutic relevance for cerebrovascular diseases or acute ischemic stroke.<sup><a class="bibr" href="#ml172.r7" rid="ml172.r7">7</a>,<a class="bibr" href="#ml172.r8" rid="ml172.r8">8</a></sup> M<sub>5</sub>-KO mice have also been found to exhibit deficits in long-term potentiation (LTP) at the hippocampal mossy fiber-CA3 synapse and show deficits in hippocampal-dependent behavioral cognitive tests.<sup><a class="bibr" href="#ml172.r8" rid="ml172.r8">8</a></sup> In light of these and related findings, activation of M<sub>5</sub> has been suggested as a potential target for treatment of Alzheimer’s disease, perhaps in combination with M<sub>1</sub> activation.<sup><a class="bibr" href="#ml172.r9" rid="ml172.r9">9</a></sup> Consistent with the putative post-synaptic localization of M<sub>5</sub> in the ventral tegmental area (VTA), other M<sub>5</sub>-KO data suggest this subtype plays an important role in regulation of mesolimbic dopamine transmission.<sup><a class="bibr" href="#ml172.r3" rid="ml172.r3">3</a>,<a class="bibr" href="#ml172.r9" rid="ml172.r9">9</a></sup> Indeed, M<sub>5</sub>-KO mice exhibit decreased reward responses to morphine, decreased self-administration of cocaine, and less pronounced drug withdrawal symptoms, suggesting that M<sub>5</sub> antagonists or negative allosteric modulators may have therapeutic value in the treatment of illicit drug addiction.<sup><a class="bibr" href="#ml172.r9" rid="ml172.r9">9</a>–<a class="bibr" href="#ml172.r11" rid="ml172.r11">11</a></sup> Further pharmacological exploration of these and related hypotheses greatly depends on the discovery of novel M<sub>5</sub>-preferring or selective small molecule tools.</p></div><div id="ml172.s4"><h2 id="_ml172_s4_">2. Materials and Methods</h2><div id="ml172.s5"><h3>2.1. Assays</h3><p><b>PubChem Primary Assay Description:</b> Chinese hamster ovary (CHO K1) cells stably expressing rat (r)M<sub>1</sub> were purchased from the American Type Culture Collection (ATCC, Manassas, VA) and cultured according to their recommendations. CHO cells stably expressing human (h) M<sub>2</sub>, hM<sub>3</sub>, and hM<sub>5</sub> were generously provided by A. Levey (Emory University, Atlanta, GA); rM<sub>4</sub> 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 hM<sub>2</sub> and rM<sub>4</sub> cell lines for use in calcium mobilization assays, cell lines were cotransfected with a chimeric G protein (G<sub>qi5</sub>) using Lipofectamine 2000. rM<sub>2</sub>, hM<sub>3</sub>, and hM<sub>5</sub> 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. hM<sub>2</sub>-G<sub>qi5</sub> cells were grown in the same medium supplemented with 500 μg/mL hygromycin B. Stable rM<sub>4</sub> 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; rM<sub>4</sub>-G<sub>qi5</sub> cells were grown in the same medium supplemented with 500 μg/mL hygromycin B. CHO cells stably expressing rM<sub>1</sub>, hM<sub>3</sub>, or hM<sub>5</sub> were plated at a seeding density of 50,000 cells/100 μL/well. CHO cells stably coexpressing hM<sub>2</sub>/G<sub>qi5</sub> and rM<sub>4</sub>/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><p><b>Calcium Mobilization Assay:</b> 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 (1xHanks’ 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 2x 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 10x 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 (ACh). 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 id="ml172.s6"><h4>List of PubChem bioassay identifiers generated for this screening project</h4><p><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/2186" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2186</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2192" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2192</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2194" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2194</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2198" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2198</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2204" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2204</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2206" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2206</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2416" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2416</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2665" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2665</a></p></div></div><div id="ml172.s7"><h3>2.2. Probe Chemical Characterization</h3><div id="ml172.s8"><h4>Synthetic procedure (large scale) and spectral data for ML172 (CID 44602489)</h4><div id="ml172.fu2" class="figure"><div class="graphic"><img src="/books/NBK143193/bin/ml172fu2.jpg" alt="Image ml172fu2" /></div></div><p>Probe compound <a href="/pcsubstance/?term=ML172[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML172</a> (CID 44602489) was prepared according to the above scheme and provided the following characterization data: LCMS (>98%) <i>m/z</i> = 414 [M+H<sup>+</sup>] (1.65 min retention, 214 nm),<sup>1</sup>H NMR (>95%) (400 MHz, CDCl<sub>3</sub>) <i>δ</i> =7.52 (s, 1H), 7.36 (m, 6H), 7.15 (t, <i>J</i> = 7.2 Hz, 1H), 7.10 (t, <i>J</i> = 5.2 Hz, 2H), 6.86 (d, <i>J</i> = 8.8 Hz, 2H), 4.93 (s, 2H). <sup>13</sup>C-NMR (100MHz, <i>d</i><sub><i>6</i></sub> - DMSO) <i>δ</i> 182.2, 157.8, 157.6, 156.4, 145.3, 130.9, 129.8, 129.0, 128.3, 123.7, 121.6, 120.4, 119.2, 119.0, 118.5, 118.1, 111.9, 43.7, HRMS (Q-TOF): <i>m/z</i> calc for C<sub>22</sub>H<sub>15</sub>NO<sub>4</sub>F<sub>3</sub> [M + H]: 414.0953, found 414.0959.</p><p><b>Solubility.</b> Solubility in PBS (at pH = 7.4) was determined to be less than 0.10 μM although alternative formulations could potentially improve this number. For example, <a href="/pcsubstance/?term=ML172[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML172</a> shows good solubility in DMSO (>100 μM), but this is not a universally acceptable vehicle.</p><p><b>Stability.</b> Stability (at room temperature = 23 °C) for <a href="/pcsubstance/?term=ML172[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML172</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 134%, but the assay variability over the course of the experiment ranged from a low of 84% (at 24 hours) to a high of 167% (at 30 minutes). It is important to point out that <a href="/pcsubstance/?term=ML172[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML172</a> showed very poor LCMS sensitivity and exhibited high levels of non-specific binding. Given these caveats, it is difficult to draw any firm conclusions with respect to <a href="/pcsubstance/?term=ML172[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML172</a>’s stability from this experiment.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml172tu2"><a href="/books/NBK143193/table/ml172.tu2/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figml172tu2" rid-ob="figobml172tu2"><img class="small-thumb" src="/books/NBK143193/table/ml172.tu2/?report=thumb" src-large="/books/NBK143193/table/ml172.tu2/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ml172.tu2"><a href="/books/NBK143193/table/ml172.tu2/?report=objectonly" target="object" rid-ob="figobml172tu2">Table</a></h4></div></div><p><b>Reactivity.</b> 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=ML172[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML172</a> was found to not form any detectable GSH adducts.<sup><a class="bibr" href="#ml172.r21" rid="ml172.r21">21</a></sup></p><p><b>Compounds added to the SMR collection (MLS#s):</b> 003108019 (<a href="/pcsubstance/?term=ML172[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML172</a>, CID 44602489, 500 mg), 003108020, 003108021, 003108022, 003108023, 003108024.</p></div></div><div id="ml172.s9"><h3>2.3. Probe Preparation</h3><p><b>1-(4-phenoxybenzyl)-5-(trifluoromethoxy)indoline-2,3-dione (<a href="/pcsubstance/?term=ML172[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML172</a>, CID 44602489):</b> To a flask containing acetonitrile (20 mL) was added 5-trifluoromethoxyisatin (750 mg, 3.245 mmol), potassium carbonate (897 mg, 6.490 mmol), 4-phenoxybenzyl bromide (897 mg, 3.407 mmol), and potassium iodide (54 mg, 0.325 mmol). The reaction was stirred overnight at room temperature and then judged complete by LCMS analysis. The solution was partitioned between CH<sub>2</sub>Cl<sub>2</sub> and H<sub>2</sub>O, the organics were dried over MgSO<sub>4</sub>, and then the solution was filtered and concentrated <i>in vacuo</i> to afford the crude product. Purification by silica gel plug (1:3 EtOAc:Hexanes fixed solvent gradient) afforded the title compound as a bright red-orange sticky solid (1.340 g, 3.242 mmol, 99%)</p></div></div><div id="ml172.s10"><h2 id="_ml172_s10_">3. Results</h2><p><b>Center Summary of Screen:</b> This screen was performed in the pilot phase, the MLSCN,
|
|
when the MLSMR compound collection at Vanderbilt only contained 65K compounds. From the primary
|
|
M<sub>1</sub> screen of 65K compounds, ~12 putative M<sub>1</sub> PAMs were identified giving an
|
|
average Z’ score of 0.70±0.09. The confirmation screen (singles at 10 μM) produced two lead compounds, one of which was recently developed into a structurally novel M<sub>1</sub> PAM (CID 44475955). The other, CID 3008304, represented a unique, and never before seen, pharmacological profile (<a class="figpopup" href="/books/NBK143193/figure/ml172.f1/?report=objectonly" target="object" rid-figpopup="figml172f1" rid-ob="figobml172f1">Figure 1</a>) in that it was a PAM of all the G<sub>q</sub>-coupled mAChRs (M<sub>1</sub> EC<sub>50</sub> = 6.1 μM, M<sub>3</sub> EC<sub>50</sub> = 6.4 μM and M<sub>5</sub> EC<sub>50</sub> = 4.1 μM), but devoid of activity at the G<sub>i/o</sub>-coupled M<sub>2</sub> and M<sub>4</sub>.<sup><a class="bibr" href="#ml172.r12" rid="ml172.r12">12</a></sup> This led us to predict it would be possible to dial-in or dial-out different mAChR sub-types and potentially develop an M<sub>1</sub> selective PAM, an M<sub>3</sub> selective PAM and/or an M<sub>5</sub> selective PAM from this non-selective lead through chemical optimization.<sup><a class="bibr" href="#ml172.c13a" rid="ml172.c13a">13a</a></sup> As predicted, CID 3008304 served as the common starting point for the development of the two highly selective probe molecules shown in <a class="figpopup" href="/books/NBK143193/figure/ml172.f2/?report=objectonly" target="object" rid-figpopup="figml172f2" rid-ob="figobml172f2">Figure 2</a>: the M<sub>1</sub> PAM (CID 44251556) and the M<sub>5</sub> PAM (CID 42633508, EC<sub>50</sub> = 1.1 μM, 91% ACh Max). Although very selective for M<sub>5</sub>, CID 42633508 did retain a detectable amount of activity at the M<sub>1</sub> and M<sub>3</sub> receptors at concentrations of 30 μM and above. Therefore we chose to explore the possibility of further optimizing CID 42633508 as described next.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml172f1" co-legend-rid="figlgndml172f1"><a href="/books/NBK143193/figure/ml172.f1/?report=objectonly" target="object" title="Figure 1" class="img_link icnblk_img figpopup" rid-figpopup="figml172f1" rid-ob="figobml172f1"><img class="small-thumb" src="/books/NBK143193/bin/ml172f1.gif" src-large="/books/NBK143193/bin/ml172f1.jpg" alt="Figure 1. CRCs at M1–M5 for HTS lead CID 3008304." /></a><div class="icnblk_cntnt" id="figlgndml172f1"><h4 id="ml172.f1"><a href="/books/NBK143193/figure/ml172.f1/?report=objectonly" target="object" rid-ob="figobml172f1">Figure 1</a></h4><p class="float-caption no_bottom_margin">CRCs at M1–M5 for HTS lead CID 3008304. CID 3008304 is a pan G<sub>q</sub>-M1, M3, M5 PAM </p></div></div><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml172f2" co-legend-rid="figlgndml172f2"><a href="/books/NBK143193/figure/ml172.f2/?report=objectonly" target="object" title="Figure 2" class="img_link icnblk_img figpopup" rid-figpopup="figml172f2" rid-ob="figobml172f2"><img class="small-thumb" src="/books/NBK143193/bin/ml172f2.gif" src-large="/books/NBK143193/bin/ml172f2.jpg" alt="Figure 2. Two MLPCN probe molecules derived from CID 3008304." /></a><div class="icnblk_cntnt" id="figlgndml172f2"><h4 id="ml172.f2"><a href="/books/NBK143193/figure/ml172.f2/?report=objectonly" target="object" rid-ob="figobml172f2">Figure 2</a></h4><p class="float-caption no_bottom_margin">Two MLPCN probe molecules derived from CID 3008304. </p></div></div><p><b>Probe Optimization Strategy:</b> For the continued optimization of CID 42633508, we chose the strategy depicted in <a class="figpopup" href="/books/NBK143193/figure/ml172.f3/?report=objectonly" target="object" rid-figpopup="figml172f3" rid-ob="figobml172f3">Figure 3</a>, and as SAR with allosteric ligands is often shallow, we employed an iterative parallel synthesis approach. From the development of our initial M<sub>5</sub> probe, we were confident that the 5-OCF<sub>3</sub> group was essential for M<sub>5</sub>-preferring activity and selectivity, so this moiety was universally retained. Libraries were prepared according to <a class="figpopup" href="/books/NBK143193/figure/ml172.f7/?report=objectonly" target="object" rid-figpopup="figml172f7" rid-ob="figobml172f7">Scheme 1</a>, wherein the commercially available indoline-2,3-dione <b>1</b> was alkylated with 4-bromobenzylbromide to deliver intermediate <b>2</b>. An eleven-membered Suzuki library was then prepared to explore the biaryl and heterobiaryl replacements for the methyl ether of CID 42633508, thus providing analogs <b>3</b>. Concomitantly, <b>1</b> was alkylated with functionalized phenethyl bromides <b>4</b> to explore the effect of chain homologation present in analogs <b>5</b>. Compounds from these libraries were then triaged by a single point (10 μM) screen for their ability to potentiate an EC<sub>20</sub> of ACh in M<sub>5</sub>-CHO cells with those results appearing in <a class="figpopup" href="/books/NBK143193/figure/ml172.f4/?report=objectonly" target="object" rid-figpopup="figml172f4" rid-ob="figobml172f4">Figure 4</a>.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml172f3" co-legend-rid="figlgndml172f3"><a href="/books/NBK143193/figure/ml172.f3/?report=objectonly" target="object" title="Figure 3" class="img_link icnblk_img figpopup" rid-figpopup="figml172f3" rid-ob="figobml172f3"><img class="small-thumb" src="/books/NBK143193/bin/ml172f3.gif" src-large="/books/NBK143193/bin/ml172f3.jpg" alt="Figure 3. Optimization strategy for CID 42633508, a highly M5-preferring PAM." /></a><div class="icnblk_cntnt" id="figlgndml172f3"><h4 id="ml172.f3"><a href="/books/NBK143193/figure/ml172.f3/?report=objectonly" target="object" rid-ob="figobml172f3">Figure 3</a></h4><p class="float-caption no_bottom_margin">Optimization strategy for CID 42633508, a highly M<sub>5</sub>-preferring PAM. </p></div></div><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml172f7" co-legend-rid="figlgndml172f7"><a href="/books/NBK143193/figure/ml172.f7/?report=objectonly" target="object" title="Scheme 1" class="img_link icnblk_img figpopup" rid-figpopup="figml172f7" rid-ob="figobml172f7"><img class="small-thumb" src="/books/NBK143193/bin/ml172f7.gif" src-large="/books/NBK143193/bin/ml172f7.jpg" alt="Scheme 1. Reagents and conditions." /></a><div class="icnblk_cntnt" id="figlgndml172f7"><h4 id="ml172.f7"><a href="/books/NBK143193/figure/ml172.f7/?report=objectonly" target="object" rid-ob="figobml172f7">Scheme 1</a></h4><p class="float-caption no_bottom_margin">Reagents and conditions. (a) <i>p</i>-bromobenzylbromide, K<sub>2</sub>CO<sub>3</sub>, KI, CAN, rt, 16 h (99%); (b) R-B(OH)<sub>2</sub>, Pd(<i>t</i>-Bu<sub>3</sub>P)<sub>2</sub>, Cs<sub>2</sub>CO<sub>3</sub>, THF:H<sub>2</sub>O, mw, 120 °C, 20 min (10–90%); (c) K<sub>2</sub>CO<sub>3</sub>, KI, CAN, rt, 16 h (50–90%) </p></div></div><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml172f4" co-legend-rid="figlgndml172f4"><a href="/books/NBK143193/figure/ml172.f4/?report=objectonly" target="object" title="Figure 4" class="img_link icnblk_img figpopup" rid-figpopup="figml172f4" rid-ob="figobml172f4"><img class="small-thumb" src="/books/NBK143193/bin/ml172f4.gif" src-large="/books/NBK143193/bin/ml172f4.jpg" alt="Figure 4. Ca2+ mobilization screen with M5-CHO cells using 10 μM test compound in the presence of a submaximal concentration of Ach (~EC20) to triage libraries 3 and 5 for PAM activity." /></a><div class="icnblk_cntnt" id="figlgndml172f4"><h4 id="ml172.f4"><a href="/books/NBK143193/figure/ml172.f4/?report=objectonly" target="object" rid-ob="figobml172f4">Figure 4</a></h4><p class="float-caption no_bottom_margin">Ca2+ mobilization screen with M<sub>5</sub>-CHO cells using 10 μM test compound in the presence of a submaximal concentration of Ach (~EC<sub>20</sub>) to triage libraries 3 and 5 for PAM activity. Data represent means ± SEM from 3 independent determinations <a href="/books/NBK143193/figure/ml172.f4/?report=objectonly" target="object" rid-ob="figobml172f4">(more...)</a></p></div></div><p>In general, chain homologation in analogs <b>5</b> did not produce improved profiles relative to the benzyl analogs <b>3</b>. Although M<sub>5</sub> PAM efficacy was maintained it came at the cost of right-shifted EC<sub>50</sub> values. For example, CID 45281805, the direct phenethyl analog of CID 42633508 possessed an M<sub>5</sub> EC<sub>50</sub> of 4.9 and an 80% ACh maximum response (data not shown). Biaryl and heterobiaryl analogs <b>3</b> proved far more productive, affording a number of M<sub>5</sub> PAMs with high selectivity versus M<sub>1</sub> (M<sub>1</sub> EC<sub>50</sub>s >30 μM) and low micromolar M<sub>5</sub> EC<sub>50</sub>s (<a class="figpopup" href="/books/NBK143193/table/ml172.t1/?report=objectonly" target="object" rid-figpopup="figml172t1" rid-ob="figobml172t1">Table 1</a>). The remaining 5 analogs of <b>3</b> displayed M5 EC<sub>50</sub>s > 10 μM. A wide variety of R- groups could be tolerated, both five- (CIDs 45281797 and 45281803) and six-membered heterocycles (CIDs 45281798 and 45281801) provided active compounds, as did bare phenyl (CID 45281794) and substituted phenyl (CID 45281796). Potency was virtually identical for all of the active analogs <b>3</b> (M<sub>5</sub> EC<sub>50</sub>s 2.7 – 4.8 μM) with similar ACh Max values (70–85%). Shallow SAR was again noted for these allosteric ligands, with compounds either being active in the micromolar potency range or inactive as M<sub>5</sub> PAMs.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml172t1"><a href="/books/NBK143193/table/ml172.t1/?report=objectonly" target="object" title="Table 1" class="img_link icnblk_img figpopup" rid-figpopup="figml172t1" rid-ob="figobml172t1"><img class="small-thumb" src="/books/NBK143193/table/ml172.t1/?report=thumb" src-large="/books/NBK143193/table/ml172.t1/?report=previmg" alt="Table 1. Structures and activities of analogs 3." /></a><div class="icnblk_cntnt"><h4 id="ml172.t1"><a href="/books/NBK143193/table/ml172.t1/?report=objectonly" target="object" rid-ob="figobml172t1">Table 1</a></h4><p class="float-caption no_bottom_margin">Structures and activities of analogs 3. </p></div></div><p>The two most potent analogs from <a class="figpopup" href="/books/NBK143193/table/ml172.t1/?report=objectonly" target="object" rid-figpopup="figml172t1" rid-ob="figobml172t1">Table 1</a> (CIDs
|
|
45281794 and 45281797) were selected for additional follow-up. <a class="figpopup" href="/books/NBK143193/figure/ml172.f5/?report=objectonly" target="object" rid-figpopup="figml172f5" rid-ob="figobml172f5">Figure 5</a> depicts only the G<sub>q</sub> mAChR (M<sub>1</sub>, M<sub>3</sub> and M<sub>5</sub>) concentration response curves (CRCs) for CID 45281794 and CID 45281797. Note that CID 45281794 possesses improved M<sub>5</sub> selectivity versus our initial M<sub>5</sub> probe CID 42633508, with almost negligible activation of M<sub>3</sub> at 30 μM (<a class="figpopup" href="/books/NBK143193/figure/ml172.f5/?report=objectonly" target="object" rid-figpopup="figml172f5" rid-ob="figobml172f5">Figure 5A</a>). Both analogs CID 45281794 and CID 45281797 elicit significant leftward shifts (> 50-fold) of the ACh CRC at M5 (<a class="figpopup" href="/books/NBK143193/figure/ml172.f5/?report=objectonly" target="object" rid-figpopup="figml172f5" rid-ob="figobml172f5">Figure 5C</a>), as compared to the 14-fold shift of our initial M<sub>5</sub> probe CID 42633508. As seen with the M<sub>1</sub> PAM BQCA<sup><a class="bibr" href="#ml172.r14" rid="ml172.r14">14</a>–<a class="bibr" href="#ml172.r16" rid="ml172.r16">16</a></sup> and other ago-potentiators for class C GPCRs.<sup><a class="bibr" href="#ml172.r17" rid="ml172.r17">17</a>–<a class="bibr" href="#ml172.r19" rid="ml172.r19">19</a></sup>
|
|
<a class="figpopup" href="/books/NBK143193/figure/ml172.f5/?report=objectonly" target="object" rid-figpopup="figml172f5" rid-ob="figobml172f5">Figure 5C</a> indicates moderate intrinsic allosteric agonism at 30 μM for both analogs at the M<sub>5</sub> receptor.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml172f5" co-legend-rid="figlgndml172f5"><a href="/books/NBK143193/figure/ml172.f5/?report=objectonly" target="object" title="Figure 5" class="img_link icnblk_img figpopup" rid-figpopup="figml172f5" rid-ob="figobml172f5"><img class="small-thumb" src="/books/NBK143193/bin/ml172f5.gif" src-large="/books/NBK143193/bin/ml172f5.jpg" alt="Figure 5. Concentration-response curves in Ca2+ mobilization assays with M1-,M2Gqi5-, M3, M4/Gqi5-, and M5-CHO cells for (A) CID 45281794 (M5 EC50 = 2.7 μM) and (B) CID 45281797 (M5 EC50 = 2.8 μM). (C) Ach concentration-response fold-shift Ca2+ mobilization assay with M5-CHO cells for CID 45281794 and 45281797 (Both >50x shift versus vehicle control). Data represent means ± SEM from 3 independent determinations." /></a><div class="icnblk_cntnt" id="figlgndml172f5"><h4 id="ml172.f5"><a href="/books/NBK143193/figure/ml172.f5/?report=objectonly" target="object" rid-ob="figobml172f5">Figure 5</a></h4><p class="float-caption no_bottom_margin">Concentration-response curves in Ca<sup>2+</sup> mobilization assays with M<sub>1</sub>-,M<sub>2Gqi5</sub>-, M<sub>3</sub>, M<sub>4/Gqi5</sub>-, and M<sub>5</sub>-CHO cells for (A) CID 45281794 (M<sub>5</sub> EC<sub>50</sub> = 2.7 μM) and (B) CID 45281797 (M5 EC50 = 2.8 μM). (C) Ach concentration-response fold-shift Ca2+ <a href="/books/NBK143193/figure/ml172.f5/?report=objectonly" target="object" rid-ob="figobml172f5">(more...)</a></p></div></div><p>Encouraged by the potency and mAChR selectivity of the phenyl-containing CID 45281794 and the ether-containing CID 42633508 (<a class="figpopup" href="/books/NBK143193/figure/ml172.f2/?report=objectonly" target="object" rid-figpopup="figml172f2" rid-ob="figobml172f2">Figure 2</a>), a hydrid analog was prepared (<a class="figpopup" href="/books/NBK143193/figure/ml172.f8/?report=objectonly" target="object" rid-figpopup="figml172f8" rid-ob="figobml172f8">Scheme 2</a>) that possessed a biphenyl ether moiety, CID 44602489 (<a href="/pcsubstance/?term=ML172[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML 172</a>), and displayed an M<sub>5</sub> EC<sub>50</sub> of 1.9 μM with a 75% ACh Max. More Importantly, CID 44602489 (<a href="/pcsubstance/?term=ML172[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML 172</a>) was completely selective versus M<sub>1–4</sub>, affording no elevation of an ACh EC<sub>20</sub> at M<sub>1–4</sub> at concentrations as high as 30 μM (<a class="figpopup" href="/books/NBK143193/figure/ml172.f6/?report=objectonly" target="object" rid-figpopup="figml172f6" rid-ob="figobml172f6">Figure 6</a>). Notably, CID 44602489 (<a href="/pcsubstance/?term=ML172[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML 172</a>) represents the most selective M<sub>5</sub> PAM described to date; however, unlike CID 45281794 and CID 45281797, this hybrid analog only afforded a ~5-fold shift of the M<sub>5</sub> ACh CRC at 30 μM and did not display intrinsic allosteric agonism (graph not shown). While subsequent compounds were prepared in an effort to improve this fold shift, potency and fold shift do not always track in the same direction, and in this case our attempts were unfruitful. Therefore CID 44602489 (<a href="/pcsubstance/?term=ML172[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML172</a>), the most highly M<sub>5</sub> muscarinic selective PAM known to date, was chosen as our next-generation M<sub>5</sub> probe molecule.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml172f8" co-legend-rid="figlgndml172f8"><a href="/books/NBK143193/figure/ml172.f8/?report=objectonly" target="object" title="Scheme 2" class="img_link icnblk_img figpopup" rid-figpopup="figml172f8" rid-ob="figobml172f8"><img class="small-thumb" src="/books/NBK143193/bin/ml172f8.gif" src-large="/books/NBK143193/bin/ml172f8.jpg" alt="Scheme 2. Reagents and conditions: (a) K2CO3, KI, CAN, mw, 160 °C, 10 min (68%)." /></a><div class="icnblk_cntnt" id="figlgndml172f8"><h4 id="ml172.f8"><a href="/books/NBK143193/figure/ml172.f8/?report=objectonly" target="object" rid-ob="figobml172f8">Scheme 2</a></h4><p class="float-caption no_bottom_margin">Reagents and conditions: (a) K<sub>2</sub>CO<sub>3</sub>, KI, CAN, mw, 160 °C, 10 min (68%). </p></div></div><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml172f6" co-legend-rid="figlgndml172f6"><a href="/books/NBK143193/figure/ml172.f6/?report=objectonly" target="object" title="Figure 6" class="img_link icnblk_img figpopup" rid-figpopup="figml172f6" rid-ob="figobml172f6"><img class="small-thumb" src="/books/NBK143193/bin/ml172f6.gif" src-large="/books/NBK143193/bin/ml172f6.jpg" alt="Figure 6. Concentration-response curves in Ca2+ mobilization assays with M1-,M2Gqi5-, M3, M4/Gqi5-, and M5-CHO cells for CID 44602489 (M5 EC50 = 1.9 μM)." /></a><div class="icnblk_cntnt" id="figlgndml172f6"><h4 id="ml172.f6"><a href="/books/NBK143193/figure/ml172.f6/?report=objectonly" target="object" rid-ob="figobml172f6">Figure 6</a></h4><p class="float-caption no_bottom_margin">Concentration-response curves in Ca<sup>2+</sup> mobilization assays with M<sub>1</sub>-,M<sub>2Gqi5</sub>-, M<sub>3</sub>, M<sub>4/Gqi5</sub>-, and M<sub>5</sub>-CHO cells for CID 44602489 (M<sub>5</sub> EC<sub>50</sub> = 1.9 μM). Data represent means ± SEM from 3 independent determinations </p></div></div><p>Subsequent follow up demonstrated that many of these analogs displayed moderate to poor PK in rats with limited brain exposure (AUC<sub>Brain</sub>/AUC<sub>Plasma</sub> ~ 0.25), presumably due to the bis-carbonyl of the isatin moiety. However, these are important tools to study M<sub>5</sub> function in cells, in electrophysiology and by i.c.v. injection. We did not examine the brain exposure when a DMSO-containing vehicle was employed, but using a DMSO-containing vehicle has been shown to improve brain levels.<sup><a class="bibr" href="#ml172.r17" rid="ml172.r17">17</a>–<a class="bibr" href="#ml172.r18" rid="ml172.r18">18</a></sup></p><p>The calculated physical properties appearing in <a class="figpopup" href="/books/NBK143193/table/ml172.t2/?report=objectonly" target="object" rid-figpopup="figml172t2" rid-ob="figobml172t2">Table 2</a> for the in initial M<sub>5</sub> probe molecule (CID 42633508) and this current probe <a href="/pcsubstance/?term=ML172[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML172</a> (CID 44602489) were generated using TRIPOS software. Also included in <a class="figpopup" href="/books/NBK143193/table/ml172.t2/?report=objectonly" target="object" rid-figpopup="figml172t2" rid-ob="figobml172t2">Table 2</a> are the averages from the MDDR database of compounds both entering Phase I and launched drugs. These numbers indicate that both probes are within the average values for Phase I compounds and launched compounds with respect to MW, hydrogen bond donors/acceptors and number of rotatable bonds. However, both molecules have relatively high cLogP values, which may contribute to their moderate to poor PK, and is also supported by the calculated low LogS (Solubility) values of −4.94 and −6.67 (CID 42633508 and CID 44602489, respectively). Similarly, the greater than 100 square angstroms of polar surface area for each molecule, although not necessarily high enough to preclude entry into the CNS, might be contributing to their less than ideal CNS exposure.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml172t2"><a href="/books/NBK143193/table/ml172.t2/?report=objectonly" target="object" title="Table 2" class="img_link icnblk_img figpopup" rid-figpopup="figml172t2" rid-ob="figobml172t2"><img class="small-thumb" src="/books/NBK143193/table/ml172.t2/?report=thumb" src-large="/books/NBK143193/table/ml172.t2/?report=previmg" alt="Table 2. Calculated Property Comparison with MDDR Compounds." /></a><div class="icnblk_cntnt"><h4 id="ml172.t2"><a href="/books/NBK143193/table/ml172.t2/?report=objectonly" target="object" rid-ob="figobml172t2">Table 2</a></h4><p class="float-caption no_bottom_margin">Calculated Property Comparison with MDDR Compounds. </p></div></div><p>To more fully characterize this novel M<sub>5</sub> PAM probe molecule, <a href="/pcsubstance/?term=ML172[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML172</a> (CID 44602489) was tested at MDS Pharma’s (now Ricerca’s) Lead Profiling Screen (binding assay panel of 68 GPCRs, ion channels and transporters screened at 10 μM), and was found to not significantly interact with 36 out of the 68 assays conducted (no inhibition > 50% at 10 μM).<sup><a class="bibr" href="#ml172.r20" rid="ml172.r20">20</a></sup>
|
|
<a href="/pcsubstance/?term=ML172[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML172</a> (CID 44602489) did have activity at the following 32 targets (human targets at 10 μM, unless stated as rat): Adenosine A<sub>1</sub> (50%), Adenosine A<sub>3</sub> (97%), rat Adrenergic α<sub>1A</sub> (79%), Adrenergic α<sub>1D</sub> (66%), Adrenergic α<sub>2A</sub> (100%), Adrenergic β<sub>1</sub> (89%), NET (93%), Bradykinin B<sub>1</sub> (52%), rat Calcium Channel L-Type, Dihydropyridine (74%), CB<sub>1</sub> (109%), D<sub>1</sub> (99%), D<sub>2S</sub> (85%), D<sub>3</sub> (79%), DAT (90%), rat GABA transporter (56%), H<sub>1</sub> (99%), H<sub>2</sub> (101%), rat Imidazoline, central (50%), Leukotriene, Cysteinyl CysLT<sub>1</sub> (83%), MT<sub>1</sub> (60%), Muscarinic M<sub>1</sub> (98%), Muscarinic M<sub>2</sub> (96%), Neuropeptide Y Y<sub>1</sub> (83%), KOP (98%), MOP (99%), PAF (58%), hERG (81%), EP<sub>4</sub> (66%), 5-HT<sub>1A</sub> (69%), 5-HT<sub>2B</sub> (90%), SERT (80%) and rat Sodium Channel, site 2 (97%). However it should be pointed out that these are only single-point values and that functional selectivity may be significantly better than suggested by these “% activities.” This is best illustrated by the fact that we see no functional activity for <a href="/pcsubstance/?term=ML172[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML172</a> (CID 44602489) at either the M<sub>1</sub> or M<sub>2</sub> receptor at concentrations as high as 30 μM (<a class="figpopup" href="/books/NBK143193/figure/ml172.f6/?report=objectonly" target="object" rid-figpopup="figml172f6" rid-ob="figobml172f6">Figure 6</a>), while the lead profiling screen indicates 98% and 96% inhibition of radio ligand binding at M<sub>1</sub> and M<sub>2</sub>, respectively, at just 10 μM.</p><p>In summary, <a href="/pcsubstance/?term=ML172[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML172</a> (CID 44602489) represents a marked improvement over our initial M<sub>5</sub> probe with respect to muscarinic selectivity, however ancillary pharmacology, at the binding level, appears to have suffered. CNS penetration is poor, using DMSO-free vehicles, possibly restricting <a href="/pcsubstance/?term=ML172[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML172</a> (CID 44602489) to use as an <i>in vitro</i> or i.c.v. probe.</p><div id="ml172.s11"><h3>3.1. Summary of Screening Results</h3><div id="ml172.fu3" class="figure"><div class="graphic"><img src="/books/NBK143193/bin/ml172fu10.jpg" alt="Image ml172fu10" /></div></div></div><div id="ml172.s12"><h3>3.2. Dose Response Curves for Probe</h3><p>See <a class="figpopup" href="/books/NBK143193/figure/ml172.f6/?report=objectonly" target="object" rid-figpopup="figml172f6" rid-ob="figobml172f6">Figure 6</a> (<i>vide supra</i>) for M<sub>5</sub> PAM potency and selectivity against M<sub>1–4</sub>.</p></div><div id="ml172.s13"><h3>3.3. Scaffold/Moiety Chemical Liabilities</h3><p>No chemical liabilities for the probe molecule have been identified at the present time; however its high lipophilicity may be contributing to a less than ideal profile in the Lead Profiling Screen (Ricerca).<sup><a class="bibr" href="#ml172.r20" rid="ml172.r20">20</a></sup> Additionally, the isatin core could be viewed as a liability given historical data. To address this potential issue one could envision various isatin replacements, but given the steep SAR generally associated with allosteric modulators it would be a significant undertaking to embark on such an effort. As such, the replacement of the isatin core might be more adequately undertaken as part of an extended probe characterization proposal.</p></div><div id="ml172.s14"><h3>3.4. SAR Table</h3><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml172t3"><a href="/books/NBK143193/table/ml172.t3/?report=objectonly" target="object" title="Table 3" class="img_link icnblk_img figpopup" rid-figpopup="figml172t3" rid-ob="figobml172t3"><img class="small-thumb" src="/books/NBK143193/table/ml172.t3/?report=thumb" src-large="/books/NBK143193/table/ml172.t3/?report=previmg" alt="Table 3. SAR Analysis for M1 Positive Allosteric Modulators." /></a><div class="icnblk_cntnt"><h4 id="ml172.t3"><a href="/books/NBK143193/table/ml172.t3/?report=objectonly" target="object" rid-ob="figobml172t3">Table 3</a></h4><p class="float-caption no_bottom_margin">SAR Analysis for M<sub>1</sub> Positive Allosteric Modulators. </p></div></div></div><div id="ml172.s15"><h3>3.5. Cellular Activity</h3><p>This series of positive allosteric modulators displayed functional activity (Ca<sup>+2</sup> mobilzation) in CHO cells stably expressing M<sub>1–5</sub> receptors [<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2416" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2416</a> and <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2204" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2204</a>]. Many of these analogs were tested in rat PK, but were found to give moderate to poor exposure (low absolute levels detected) and limited brain exposure (AUC<sub>Brain</sub>/AUC<sub>Plasma</sub> ~ 0.25) demonstrating that at least some level of CNS exposure was obtained.</p></div></div><div id="ml172.s16"><h2 id="_ml172_s16_">4. Discussion</h2><div id="ml172.s17"><h3>4.1. Comparison to existing art and how the new probe is an improvement</h3><p>Presently there are no known selective M<sub>5</sub> PAMs with the exception of those disclosed from our labs, which include the two MLPCN probe molecules (<a href="/pcsubstance/?term=ML129[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML 129</a> and <a href="/pcsubstance/?term=ML172[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML172</a>). Relative to our initial M<sub>5</sub> PAM probe (<a href="/pcsubstance/?term=ML129[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML 129</a>, CID 42633508) this second generation probe (<a href="/pcsubstance/?term=ML172[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML172</a>, CID 44602489) possesses dramatically improved selectivity relative to the other M<sub>1–4</sub> receptors. The previous probe, although very selective, did begin to show a trend towards off-target receptor activation at the highest doses, <a href="/pcsubstance/?term=ML172[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML172</a> (CID 44602489) is clearly improved in this context (<a class="figpopup" href="/books/NBK143193/figure/ml172.f6/?report=objectonly" target="object" rid-figpopup="figml172f6" rid-ob="figobml172f6">Figure 6</a>). Lastly, this probe (<a href="/pcsubstance/?term=ML172[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML172</a>, CID 44602489), along with our initial M<sub>5</sub> probe (<a href="/pcsubstance/?term=ML129[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML 129</a>, CID 42633508), is not encumbered with patent restrictions and rests firmly in the public domain.</p></div><div id="ml172.s18"><h3>4.2. Mechanism of Action Studies</h3><p>It is believed that this probe (<a href="/pcsubstance/?term=ML172[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML172</a>, CID 44602489) is functioning by positive allosteric modulation of the muscarinic acetylcholine M<sub>5</sub> receptor given its lack of activity on the other muscarinic receptor subtypes (M<sub>1–4</sub>) and its dependence on the presence of ACh to elicit functional activity.</p></div><div id="ml172.s19"><h3>4.3. Planned Future Studies</h3><p>Future work will focus on developing a more centrally penetrant M<sub>5</sub> PAM with improved physical properties, which maintains this unprecedented level of muscarinic selectivity and possesses an improved ancillary pharmacology profile. Ultimately it would be highly desirable to develop such a selective M<sub>5</sub> PAM for use as an <i>in vivo</i> tool to better understand the biological processes associated with the M<sub>5</sub> receptor.</p></div></div><div id="ml172.s20"><h2 id="_ml172_s20_">5. References</h2><dl class="temp-labeled-list"><dl class="bkr_refwrap"><dt>1.</dt><dd><div class="bk_ref" id="ml172.r1">Bonner TI, Buckley NJ, Young AC, Brann MR. <span><span class="ref-journal">Science. </span>1987;<span class="ref-vol">237</span>:527–532.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/3037705" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 3037705</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>2.</dt><dd><div class="bk_ref" id="ml172.r2">Bonner TI, Young AC, Brann MR, Buckley NJ. <span><span class="ref-journal">Neuron. </span>1988;<span class="ref-vol">1</span>:403–410.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/3272174" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 3272174</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>3.</dt><dd><div class="bk_ref" id="ml172.r3">Wess J. <span><span class="ref-journal">Annu Rev Pharmacol Toxicol. </span>2004;<span class="ref-vol">44</span>:423–450.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/14744253" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 14744253</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>4.</dt><dd><div class="bk_ref" id="ml172.r4">Langmead CJ, Watson J, Reavill C. <span><span class="ref-journal">Pharmacol Ther. </span>2008;<span class="ref-vol">117</span>:232–243.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/18082893" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18082893</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>5.</dt><dd><div class="bk_ref" id="ml172.r5">Birdsall NJM, Lazareno S. <span><span class="ref-journal">Mini Rev Med Chem. </span>2005;<span class="ref-vol">5</span>:523–543.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15974931" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15974931</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>6.</dt><dd><div class="bk_ref" id="ml172.r6">Conn PJ, Christopoulos A, Lindsley CW. <span><span class="ref-journal">Nat Rev Durg Disc. </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>7.</dt><dd><div class="bk_ref" id="ml172.r7">Yamada M, Lamping KG, Duttaroy A, Zhang W, Cui Y, Bymaster FP, McKinzie DL, Felder CC, Deng C, Faraci FM, Wess J. <span><span class="ref-journal">Proc Natl Acad Sci. </span>2001;<span class="ref-vol">98</span>:14096–14101.</span> [<a href="/pmc/articles/PMC61174/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC61174</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/11707605" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11707605</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>8.</dt><dd><div class="bk_ref" id="ml172.r8">Araya R, Noguchi T, Yuhki M, Kitamura N, Higuchi M, Saido TC, Seki K, Itohara S, Kawano M, Tanemura K, Takashima A, Yamada K, Kondoh Y, Kanno I, Wess J, Yamada M. <span><span class="ref-journal">Neurobiol Dis. </span>2006;<span class="ref-vol">24</span>:334–344.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16956767" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16956767</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>9.</dt><dd><div class="bk_ref" id="ml172.r9">Wess J, Eglen RM, Gautam D. <span><span class="ref-journal">Nat Rev Drug Discov. </span>2007;<span class="ref-vol">6</span>:721–733.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17762886" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17762886</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>10.</dt><dd><div class="bk_ref" id="ml172.r10">Basile AS, Fedorova I, Zapata A, Liu X, Shippenberg T, Duttaroy A, Yamada M, Wess J. <span><span class="ref-journal">Proc Natl Acad Sci. </span>2002;<span class="ref-vol">99</span>:11452–11457.</span> [<a href="/pmc/articles/PMC123277/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC123277</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/12154229" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12154229</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>11.</dt><dd><div class="bk_ref" id="ml172.r11">Thomsen M, Woldbye DPD, Wortwein G, Fink-Jensen A, Wess J, Caine SB. <span><span class="ref-journal">J Neurosci. </span>2005;<span class="ref-vol">25</span>:8141–8149.</span> [<a href="/pmc/articles/PMC6725551/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6725551</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/16148222" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16148222</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>12.</dt><dd><div class="bk_ref" id="ml172.r12">Marlo JE, Niswender CM, Days EL, Bridges TM, Xiang Y, Rodriguez AL, Shirey JK, Brady AE, Nalywajko T, Luo Q, Austin CA, Williams MB, Kim K, Williams R, Orton D, Brown HA, Lindsley CW, Weaver CD, Conn PJ. <span><span class="ref-journal">Mol Pharmacol. </span>2009;<span class="ref-vol">75</span>:577–588.</span> [<a href="/pmc/articles/PMC2684909/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2684909</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19047481" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19047481</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>13.</dt><dd><div class="bk_ref" id="ml172.r13"><a id="ml172.c13a"></a><strong>a. </strong>Bridges TM, Marlo JE, Niswender CM, Jones JK, Jadhav SB, Gentry PR, Weaver CD, Conn PJ, Lindsley CW. <span><span class="ref-journal">J Med Chem. </span>2009;<span class="ref-vol">52</span>:3445–3448.</span> [<a href="/pmc/articles/PMC3875304/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3875304</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19438238" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19438238</span></a>]<br /><strong>b. </strong>Bridges TM, Kennedy JP, Cho HP, Breinginger ML, Gentry PR, Hopkins CR, Conn PJ, Lindsley CW. <span><span class="ref-journal">Bioorg Med Chem Lett. </span>2010;<span class="ref-vol">20</span>:558–562.</span> [<a href="/pmc/articles/PMC3177601/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3177601</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/20004578" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20004578</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>14.</dt><dd><div class="bk_ref" id="ml172.r14">Ma L, Seager M, Wittman M, Bickel N, Burno M, Jones K, Graufelds VK, Xu G, Pearson M, McCampbell A, Gaspar R, Shughrue P, Danzinger A, Regan C, Garson S, Doran S, Kreatsoulas C, Veng L, Lindsley CW, Shipe W, Kuduk S, Jacobson M, Sur C, Kinney G, Seabrook GR, Ray WJ. <span><span class="ref-journal">Proc Natl Acad Sci USA. </span>2009;<span class="ref-vol">106</span>:15950–15955.</span> [<a href="/pmc/articles/PMC2732705/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2732705</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19717450" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19717450</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>15.</dt><dd><div class="bk_ref" id="ml172.r15">Shirey JK, Brady AE, Jones PJ, Davis AA, Bridges TM, Jadhav SB, Menon U, Christain EP, Doherty JJ, Quirk MC, Snyder DH, Levey AI, Watson ML, Nicolle MM, Lindsley CW, Conn PJ. <span><span class="ref-journal">J Neurosci. </span>2009;<span class="ref-vol">29</span>:14271–14286.</span> [<a href="/pmc/articles/PMC2811323/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2811323</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19906975" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19906975</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>16.</dt><dd><div class="bk_ref" id="ml172.r16">Yang FV, Shipe WD, Bunda JL, Nolt MB, Wisnoski DD, Zhao Z, Barrow JC, Ray WJ, Ma L, Wittman M, Seager M, Koeplinger K, Hartman GD, Lindsley CW. <span><span class="ref-journal">Bioorg Med Chem Lett. </span>2010;<span class="ref-vol">20</span>:531–536.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/20004574" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20004574</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>17.</dt><dd><div class="bk_ref" id="ml172.r17">Lindsley CW, Wisnoski DD, Leister WH, O’Brien JA, Lemiare W, Williams DL Jr, Burno M, Sur C, Kinney GG, Pettibone DJ, Tiller PR, Smith S, Duggan ME, Hartman GD, Conn PJ, Huff JR. <span><span class="ref-journal">J Med Chem. </span>2004;<span class="ref-vol">47</span>:5825–5828.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15537338" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15537338</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>18.</dt><dd><div class="bk_ref" id="ml172.r18">Kinney GG, O’Brien JA, Lemaire W, Burno M, Bickel DJ, Clements MK, Wisnoski DD, Lindsley CW, Tiller PR, Smith S, Jacobson MA, Sur C, Duggan ME, Pettibone DJ, Williams DW Jr. <span><span class="ref-journal">J Pharmacol Exp Ther. </span>2005;<span class="ref-vol">313</span>:199–206.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15608073" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15608073</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>19.</dt><dd><div class="bk_ref" id="ml172.r19">Engers DW, Rodriguez AL, Oluwatola O, Hammond AS, Venable DF, Williams R, Sulikowski GA, Conn PJ, Lindsley CW. <span><span class="ref-journal">ChemMedChem. </span>2009;<span class="ref-vol">4</span>:505–511.</span> [<a href="/pmc/articles/PMC2865690/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2865690</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19197923" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19197923</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>20.</dt><dd><div class="bk_ref" id="ml172.r20">For information on the Ricerca (formerly MDS Pharma) Lead Profiling Screen see: <a href="https://pharmacology.ricerca.com/Catalog/" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">https:<wbr style="display:inline-block"></wbr>​//pharmacology<wbr style="display:inline-block"></wbr>​.ricerca.com/Catalog/</a></div></dd></dl><dl class="bkr_refwrap"><dt>21.</dt><dd><div class="bk_ref" id="ml172.r21">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=cite-ref&targetsite=external&targetcat=link&targettype=uri">https://www<wbr style="display:inline-block"></wbr>​.absorption.com/site</a></div></dd></dl></dl></div><div id="bk_toc_contnr"></div></div></div><div class="fm-sec"><h2 id="_NBK143193_pubdet_">Publication Details</h2><h3>Author Information and Affiliations</h3><p class="contrib-group"><h4>Authors</h4><span itemprop="author">Thomas M. Bridges</span>,<sup>1</sup> <span itemprop="author">L. Michelle Lewis</span>,<sup>2</sup> <span itemprop="author">C. David Weaver</span>,<sup>2</sup> <span itemprop="author">Michael R. Wood</span>,<sup>1</sup> <span itemprop="author">J. Scott Daniels</span>,<sup>3</sup> <span itemprop="author">P. Jeffrey Conn</span>,<sup>3</sup> and <span itemprop="author">Craig W. Lindsley</span><sup>1</sup><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 for Accelerated Probe Development, Nashville, TN</div><div class="affiliation"><sup>2</sup>
|
|
Vanderbilt Screening Center for GPCRs, Ion Channels and Transporters (MLPCN), Nashville, TN</div><div class="affiliation"><sup>3</sup>
|
|
Vanderbilt University, Vanderbilt Center for Neuroscience Drug Discovery, Nashville, TN</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@yelsdnil.giarc" class="oemail">ude.tlibrednav@yelsdnil.giarc</a></div><h3>Publication History</h3><p class="small">Received: <span itemprop="datePublished">August 31, 2010</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>Bridges TM, Lewis LM, Weaver CD, et al. Development of the First Highly Selective mAChR 5 (M5) Positive Allosteric Modulator (PAM) 2010 Aug 31 [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/ml173/?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/ml171/?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="figobml172fu1"><div id="ml172.fu1" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK143193/bin/ml172fu1.jpg" alt="ML172." /></div><h3><span class="title">ML172</span></h3></div></article><article data-type="table-wrap" id="figobml172tu1"><div id="ml172.tu1" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK143193/table/ml172.tu1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml172.tu1_lrgtbl__"><table><thead><tr><th id="hd_h_ml172.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CID/ML#</th><th id="hd_h_ml172.tu1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Target Name</th><th id="hd_h_ml172.tu1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">IC<sub>50</sub>/EC<sub>50</sub> (nM) [SID, AID]</th><th id="hd_h_ml172.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_ml172.tu1_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">IC<sub>50</sub>/EC<sub>50</sub> (μM) [SID, AID]</th><th id="hd_h_ml172.tu1_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Fold Selective</th><th id="hd_h_ml172.tu1_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Secondary Assay(s) Name: IC<sub>50</sub>/EC<sub>50</sub> (nM) [SID, AID]§</th></tr></thead><tbody><tr><td headers="hd_h_ml172.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CID 44602489/<a href="/pcsubstance/?term=ML172[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML172</a></td><td headers="hd_h_ml172.tu1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">M<sub>5</sub></td><td headers="hd_h_ml172.tu1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1900 [<a href="https://pubchem.ncbi.nlm.nih.gov/substance/87352032" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 87352032</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2416" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2416</a>]</td><td headers="hd_h_ml172.tu1_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">M<sub>1</sub>, M<sub>2</sub>, M<sub>3</sub>, M<sub>4</sub></td><td headers="hd_h_ml172.tu1_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">> 30 μM [<a href="https://pubchem.ncbi.nlm.nih.gov/substance/87352032" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 87352032</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2204" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2204</a>]</td><td headers="hd_h_ml172.tu1_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">> 30</td><td headers="hd_h_ml172.tu1_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">ACh Fold-Shift (5-fold) [<a href="https://pubchem.ncbi.nlm.nih.gov/substance/87352032" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 87352032</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2186" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2186</a>]</td></tr></tbody></table></div></div></article><article data-type="fig" id="figobml172fu2"><div id="ml172.fu2" class="figure"><div class="graphic"><img data-src="/books/NBK143193/bin/ml172fu2.jpg" alt="Image ml172fu2" /></div></div></article><article data-type="table-wrap" id="figobml172tu2"><div id="ml172.tu2" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK143193/table/ml172.tu2/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml172.tu2_lrgtbl__"><table><thead><tr><th id="hd_h_ml172.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></th><th id="hd_h_ml172.tu2_1_1_1_2" colspan="7" rowspan="1" style="text-align:center;vertical-align:top;">Percent Remaining (%)</th></tr><tr><th headers="hd_h_ml172.tu2_1_1_1_1" id="hd_h_ml172.tu2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Compound</th><th headers="hd_h_ml172.tu2_1_1_1_2" id="hd_h_ml172.tu2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0 Min</th><th headers="hd_h_ml172.tu2_1_1_1_2" id="hd_h_ml172.tu2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">15 Min</th><th headers="hd_h_ml172.tu2_1_1_1_2" id="hd_h_ml172.tu2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">30 Min</th><th headers="hd_h_ml172.tu2_1_1_1_2" id="hd_h_ml172.tu2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">1 Hour</th><th headers="hd_h_ml172.tu2_1_1_1_2" id="hd_h_ml172.tu2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2 Hour</th><th headers="hd_h_ml172.tu2_1_1_1_2" id="hd_h_ml172.tu2_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">24 Hour</th><th headers="hd_h_ml172.tu2_1_1_1_2" id="hd_h_ml172.tu2_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">48 Hour</th></tr></thead><tbody><tr><td headers="hd_h_ml172.tu2_1_1_1_1 hd_h_ml172.tu2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="/pcsubstance/?term=ML172[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML172</a></td><td headers="hd_h_ml172.tu2_1_1_1_2 hd_h_ml172.tu2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">100</td><td headers="hd_h_ml172.tu2_1_1_1_2 hd_h_ml172.tu2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">164</td><td headers="hd_h_ml172.tu2_1_1_1_2 hd_h_ml172.tu2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">167</td><td headers="hd_h_ml172.tu2_1_1_1_2 hd_h_ml172.tu2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">154</td><td headers="hd_h_ml172.tu2_1_1_1_2 hd_h_ml172.tu2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">114</td><td headers="hd_h_ml172.tu2_1_1_1_2 hd_h_ml172.tu2_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">84</td><td headers="hd_h_ml172.tu2_1_1_1_2 hd_h_ml172.tu2_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">134</td></tr></tbody></table></div></div></article><article data-type="fig" id="figobml172f1"><div id="ml172.f1" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK143193/bin/ml172f1.jpg" alt="Figure 1. CRCs at M1–M5 for HTS lead CID 3008304." /></div><h3><span class="label">Figure 1</span><span class="title">CRCs at M1–M5 for HTS lead CID 3008304</span></h3><div class="caption"><p>CID 3008304 is a pan G<sub>q</sub>-M1, M3, M5 PAM</p></div></div></article><article data-type="fig" id="figobml172f2"><div id="ml172.f2" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK143193/bin/ml172f2.jpg" alt="Figure 2. Two MLPCN probe molecules derived from CID 3008304." /></div><h3><span class="label">Figure 2</span><span class="title">Two MLPCN probe molecules derived from CID 3008304</span></h3></div></article><article data-type="fig" id="figobml172f3"><div id="ml172.f3" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK143193/bin/ml172f3.jpg" alt="Figure 3. Optimization strategy for CID 42633508, a highly M5-preferring PAM." /></div><h3><span class="label">Figure 3</span><span class="title">Optimization strategy for CID 42633508, a highly M<sub>5</sub>-preferring PAM</span></h3></div></article><article data-type="fig" id="figobml172f7"><div id="ml172.f7" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK143193/bin/ml172f7.jpg" alt="Scheme 1. Reagents and conditions." /></div><h3><span class="label">Scheme 1</span><span class="title">Reagents and conditions</span></h3><div class="caption"><p>(a) <i>p</i>-bromobenzylbromide, K<sub>2</sub>CO<sub>3</sub>, KI, CAN, rt, 16 h (99%); (b) R-B(OH)<sub>2</sub>, Pd(<i>t</i>-Bu<sub>3</sub>P)<sub>2</sub>, Cs<sub>2</sub>CO<sub>3</sub>, THF:H<sub>2</sub>O, mw, 120 °C, 20 min (10–90%); (c) K<sub>2</sub>CO<sub>3</sub>, KI, CAN, rt, 16 h (50–90%)</p></div></div></article><article data-type="fig" id="figobml172f4"><div id="ml172.f4" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%204.%20Ca2%2B%20mobilization%20screen%20with%20M5-CHO%20cells%20using%2010%20%003BCM%20test%20compound%20in%20the%20presence%20of%20a%20submaximal%20concentration%20of%20Ach%20(~EC20)%20to%20triage%20libraries%203%20and%205%20for%20PAM%20activity.&p=BOOKS&id=143193_ml172f4.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/NBK143193/bin/ml172f4.jpg" alt="Figure 4. Ca2+ mobilization screen with M5-CHO cells using 10 μM test compound in the presence of a submaximal concentration of Ach (~EC20) to triage libraries 3 and 5 for PAM activity." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 4</span><span class="title">Ca2+ mobilization screen with M<sub>5</sub>-CHO cells using 10 μM test compound in the presence of a submaximal concentration of Ach (~EC<sub>20</sub>) to triage libraries 3 and 5 for PAM activity</span></h3><div class="caption"><p>Data represent means ± SEM from 3 independent determinations</p></div></div></article><article data-type="table-wrap" id="figobml172t1"><div id="ml172.t1" class="table"><h3><span class="label">Table 1</span><span class="title">Structures and activities of analogs 3</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK143193/table/ml172.t1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml172.t1_lrgtbl__"><table class="no_margin"><thead><tr><th id="hd_h_ml172.t1_1_1_1_1" colspan="4" rowspan="1" style="text-align:center;vertical-align:top;">
|
|
<div class="graphic"><img src="/books/NBK143193/bin/ml172fu3.jpg" alt="Image ml172fu3.jpg" /></div></th></tr><tr><th headers="hd_h_ml172.t1_1_1_1_1" id="hd_h_ml172.t1_1_1_2_1" colspan="4" rowspan="1" style="text-align:left;vertical-align:top;">
|
|
<span class="hr"></span></th></tr><tr><th headers="hd_h_ml172.t1_1_1_1_1 hd_h_ml172.t1_1_1_2_1" id="hd_h_ml172.t1_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">CID</th><th headers="hd_h_ml172.t1_1_1_1_1 hd_h_ml172.t1_1_1_2_1" id="hd_h_ml172.t1_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">R</th><th headers="hd_h_ml172.t1_1_1_1_1 hd_h_ml172.t1_1_1_2_1" id="hd_h_ml172.t1_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">M<sub>5</sub> EC<sub>50</sub><sup>a</sup> (μM)</th><th headers="hd_h_ml172.t1_1_1_1_1 hd_h_ml172.t1_1_1_2_1" id="hd_h_ml172.t1_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">%ACh Max<sup>a</sup></th></tr></thead><tbody><tr><td headers="hd_h_ml172.t1_1_1_1_1 hd_h_ml172.t1_1_1_2_1 hd_h_ml172.t1_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">45281794</td><td headers="hd_h_ml172.t1_1_1_1_1 hd_h_ml172.t1_1_1_2_1 hd_h_ml172.t1_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
|
|
<div class="graphic"><img src="/books/NBK143193/bin/ml172fu4.jpg" alt="Image ml172fu4.jpg" /></div></td><td headers="hd_h_ml172.t1_1_1_1_1 hd_h_ml172.t1_1_1_2_1 hd_h_ml172.t1_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2.7</td><td headers="hd_h_ml172.t1_1_1_1_1 hd_h_ml172.t1_1_1_2_1 hd_h_ml172.t1_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">85</td></tr><tr><td headers="hd_h_ml172.t1_1_1_1_1 hd_h_ml172.t1_1_1_2_1 hd_h_ml172.t1_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">45281797</td><td headers="hd_h_ml172.t1_1_1_1_1 hd_h_ml172.t1_1_1_2_1 hd_h_ml172.t1_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
|
|
<div class="graphic"><img src="/books/NBK143193/bin/ml172fu5.jpg" alt="Image ml172fu5.jpg" /></div></td><td headers="hd_h_ml172.t1_1_1_1_1 hd_h_ml172.t1_1_1_2_1 hd_h_ml172.t1_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2.8</td><td headers="hd_h_ml172.t1_1_1_1_1 hd_h_ml172.t1_1_1_2_1 hd_h_ml172.t1_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">85</td></tr><tr><td headers="hd_h_ml172.t1_1_1_1_1 hd_h_ml172.t1_1_1_2_1 hd_h_ml172.t1_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">45281798</td><td headers="hd_h_ml172.t1_1_1_1_1 hd_h_ml172.t1_1_1_2_1 hd_h_ml172.t1_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
|
|
<div class="graphic"><img src="/books/NBK143193/bin/ml172fu6.jpg" alt="Image ml172fu6.jpg" /></div></td><td headers="hd_h_ml172.t1_1_1_1_1 hd_h_ml172.t1_1_1_2_1 hd_h_ml172.t1_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4.8</td><td headers="hd_h_ml172.t1_1_1_1_1 hd_h_ml172.t1_1_1_2_1 hd_h_ml172.t1_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">85</td></tr><tr><td headers="hd_h_ml172.t1_1_1_1_1 hd_h_ml172.t1_1_1_2_1 hd_h_ml172.t1_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">45281801</td><td headers="hd_h_ml172.t1_1_1_1_1 hd_h_ml172.t1_1_1_2_1 hd_h_ml172.t1_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
|
|
<div class="graphic"><img src="/books/NBK143193/bin/ml172fu7.jpg" alt="Image ml172fu7.jpg" /></div></td><td headers="hd_h_ml172.t1_1_1_1_1 hd_h_ml172.t1_1_1_2_1 hd_h_ml172.t1_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3.6</td><td headers="hd_h_ml172.t1_1_1_1_1 hd_h_ml172.t1_1_1_2_1 hd_h_ml172.t1_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">80</td></tr><tr><td headers="hd_h_ml172.t1_1_1_1_1 hd_h_ml172.t1_1_1_2_1 hd_h_ml172.t1_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">45281803</td><td headers="hd_h_ml172.t1_1_1_1_1 hd_h_ml172.t1_1_1_2_1 hd_h_ml172.t1_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
|
|
<div class="graphic"><img src="/books/NBK143193/bin/ml172fu8.jpg" alt="Image ml172fu8.jpg" /></div></td><td headers="hd_h_ml172.t1_1_1_1_1 hd_h_ml172.t1_1_1_2_1 hd_h_ml172.t1_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3.3</td><td headers="hd_h_ml172.t1_1_1_1_1 hd_h_ml172.t1_1_1_2_1 hd_h_ml172.t1_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">85</td></tr><tr><td headers="hd_h_ml172.t1_1_1_1_1 hd_h_ml172.t1_1_1_2_1 hd_h_ml172.t1_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">45281796</td><td headers="hd_h_ml172.t1_1_1_1_1 hd_h_ml172.t1_1_1_2_1 hd_h_ml172.t1_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
|
|
<div class="graphic"><img src="/books/NBK143193/bin/ml172fu9.jpg" alt="Image ml172fu9.jpg" /></div></td><td headers="hd_h_ml172.t1_1_1_1_1 hd_h_ml172.t1_1_1_2_1 hd_h_ml172.t1_1_1_3_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3.9</td><td headers="hd_h_ml172.t1_1_1_1_1 hd_h_ml172.t1_1_1_2_1 hd_h_ml172.t1_1_1_3_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">70</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="ml172.tfn1"><p class="no_margin">Average of at least 3 independent determinations. All compounds displayed M<sub>1</sub> EC<sub>50</sub> > 30 μm.</p></div></dd></dl></dl></div></div></div></article><article data-type="fig" id="figobml172f5"><div id="ml172.f5" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK143193/bin/ml172f5.jpg" alt="Figure 5. Concentration-response curves in Ca2+ mobilization assays with M1-,M2Gqi5-, M3, M4/Gqi5-, and M5-CHO cells for (A) CID 45281794 (M5 EC50 = 2.7 μM) and (B) CID 45281797 (M5 EC50 = 2.8 μM). (C) Ach concentration-response fold-shift Ca2+ mobilization assay with M5-CHO cells for CID 45281794 and 45281797 (Both >50x shift versus vehicle control). Data represent means ± SEM from 3 independent determinations." /></div><h3><span class="label">Figure 5</span><span class="title">Concentration-response curves in Ca<sup>2+</sup> mobilization assays with M<sub>1</sub>-,M<sub>2Gqi5</sub>-, M<sub>3</sub>, M<sub>4/Gqi5</sub>-, and M<sub>5</sub>-CHO cells for (A) CID 45281794 (M<sub>5</sub> EC<sub>50</sub> = 2.7 μM) and (B) CID 45281797 (M5 EC50 = 2.8 μM). (C) Ach concentration-response fold-shift Ca2+ mobilization assay with M5-CHO cells for CID 45281794 and 45281797 (Both >50x shift versus vehicle control). Data represent means ± SEM from 3 independent determinations</span></h3></div></article><article data-type="fig" id="figobml172f8"><div id="ml172.f8" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK143193/bin/ml172f8.jpg" alt="Scheme 2. Reagents and conditions: (a) K2CO3, KI, CAN, mw, 160 °C, 10 min (68%)." /></div><h3><span class="label">Scheme 2</span><span class="title">Reagents and conditions: (a) K<sub>2</sub>CO<sub>3</sub>, KI, CAN, mw, 160 °C, 10 min (68%)</span></h3></div></article><article data-type="fig" id="figobml172f6"><div id="ml172.f6" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK143193/bin/ml172f6.jpg" alt="Figure 6. Concentration-response curves in Ca2+ mobilization assays with M1-,M2Gqi5-, M3, M4/Gqi5-, and M5-CHO cells for CID 44602489 (M5 EC50 = 1.9 μM)." /></div><h3><span class="label">Figure 6</span><span class="title">Concentration-response curves in Ca<sup>2+</sup> mobilization assays with M<sub>1</sub>-,M<sub>2Gqi5</sub>-, M<sub>3</sub>, M<sub>4/Gqi5</sub>-, and M<sub>5</sub>-CHO cells for CID 44602489 (M<sub>5</sub> EC<sub>50</sub> = 1.9 μM)</span></h3><div class="caption"><p>Data represent means ± SEM from 3 independent determinations</p></div></div></article><article data-type="table-wrap" id="figobml172t2"><div id="ml172.t2" class="table"><h3><span class="label">Table 2</span><span class="title">Calculated Property Comparison with MDDR Compounds</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK143193/table/ml172.t2/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml172.t2_lrgtbl__"><table class="no_top_margin"><thead><tr><th id="hd_h_ml172.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Property</th><th id="hd_h_ml172.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">CID 42633508</th><th id="hd_h_ml172.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">CID 44602489 (<a href="/pcsubstance/?term=ML172[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML172</a>)</th><th id="hd_h_ml172.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">MDDR Phase I</th><th id="hd_h_ml172.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">MDDR Launched</th></tr></thead><tbody><tr><td headers="hd_h_ml172.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MW</td><td headers="hd_h_ml172.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">351.3</td><td headers="hd_h_ml172.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">413.4</td><td headers="hd_h_ml172.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">438.98</td><td headers="hd_h_ml172.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">415.20</td></tr><tr><td headers="hd_h_ml172.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">cLogP</td><td headers="hd_h_ml172.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">3.64</td><td headers="hd_h_ml172.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">5.82</td><td headers="hd_h_ml172.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">3.21</td><td headers="hd_h_ml172.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2.21</td></tr><tr><td headers="hd_h_ml172.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">TPSA</td><td headers="hd_h_ml172.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">103.9</td><td headers="hd_h_ml172.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">107.0</td><td headers="hd_h_ml172.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">97.06</td><td headers="hd_h_ml172.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">91.78</td></tr><tr><td headers="hd_h_ml172.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Hdon</td><td headers="hd_h_ml172.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0</td><td headers="hd_h_ml172.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0</td><td headers="hd_h_ml172.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2.12</td><td headers="hd_h_ml172.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2.13</td></tr><tr><td headers="hd_h_ml172.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Hacc</td><td headers="hd_h_ml172.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">5</td><td headers="hd_h_ml172.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">5</td><td headers="hd_h_ml172.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">7.06</td><td headers="hd_h_ml172.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">6.47</td></tr><tr><td headers="hd_h_ml172.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">LogS</td><td headers="hd_h_ml172.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">−4.94</td><td headers="hd_h_ml172.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">−6.67</td><td headers="hd_h_ml172.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">−4.96</td><td headers="hd_h_ml172.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">−3.73</td></tr><tr><td headers="hd_h_ml172.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">NrotB</td><td headers="hd_h_ml172.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">5</td><td headers="hd_h_ml172.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">6</td><td headers="hd_h_ml172.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">7.08</td><td headers="hd_h_ml172.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">5.71</td></tr></tbody></table></div></div></article><article data-type="fig" id="figobml172fu3"><div id="ml172.fu3" class="figure"><div class="graphic"><img data-src="/books/NBK143193/bin/ml172fu10.jpg" alt="Image ml172fu10" /></div></div></article><article data-type="table-wrap" id="figobml172t3"><div id="ml172.t3" class="table"><h3><span class="label">Table 3</span><span class="title">SAR Analysis for M<sub>1</sub> Positive Allosteric Modulators</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK143193/table/ml172.t3/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml172.t3_lrgtbl__"><table class="no_margin"><thead><tr><th id="hd_h_ml172.t3_1_1_1_1" colspan="10" rowspan="1" style="text-align:center;vertical-align:top;">
|
|
<div class="graphic"><img src="/books/NBK143193/bin/ml172fu11.jpg" alt="Image ml172fu11.jpg" /></div></th></tr><tr><th headers="hd_h_ml172.t3_1_1_1_1" id="hd_h_ml172.t3_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Entry</th><th headers="hd_h_ml172.t3_1_1_1_1" id="hd_h_ml172.t3_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">CID</th><th headers="hd_h_ml172.t3_1_1_1_1" id="hd_h_ml172.t3_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">SID</th><th headers="hd_h_ml172.t3_1_1_1_1" id="hd_h_ml172.t3_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">VU Number</th><th headers="hd_h_ml172.t3_1_1_1_1" id="hd_h_ml172.t3_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><sup>*</sup></th><th headers="hd_h_ml172.t3_1_1_1_1" id="hd_h_ml172.t3_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">X</th><th headers="hd_h_ml172.t3_1_1_1_1" id="hd_h_ml172.t3_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Y</th><th headers="hd_h_ml172.t3_1_1_1_1" id="hd_h_ml172.t3_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Z</th><th headers="hd_h_ml172.t3_1_1_1_1" id="hd_h_ml172.t3_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">M1 PAM EC50 (μM)<sup>**</sup></th><th headers="hd_h_ml172.t3_1_1_1_1" id="hd_h_ml172.t3_1_1_2_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">M1 ACh fold-shift<sup>***</sup></th></tr></thead><tbody><tr><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">1</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">45281794</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/92845376" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">92845376</a></td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">VU0365114-1</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">S</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">methylene</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">phenyl</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">-</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2.7</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">> 50</td></tr><tr><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">45281795</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/92845377" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">92845377</a></td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">VU0365115-1</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">S</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">methylene</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">3,5-dichlorophenyl</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">-</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">~ 10</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">ND</td></tr><tr><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">3</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">45281796</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/92845378" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">92845378</a></td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">VU0365116-1</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">S</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">methylene</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">phenyl</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2-methoxy</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">3.9</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">ND</td></tr><tr><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">4</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">45281797</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/92845379" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">92845379</a></td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">VU0365117-1</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">S</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">methylene</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">thiophen-3-yl</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">-</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2.8</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">> 50</td></tr><tr><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">5</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">45281798</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/92845380" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">92845380</a></td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">VU0365118-1</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">S</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">methylene</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">pyridin-3-yl</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">6-chloro</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">4.8</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">ND</td></tr><tr><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">6</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">45281799</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/92845381" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">92845381</a></td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">VU0365119-1</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">S</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">methylene</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">phenyl</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">4-chloro</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">~ 10</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">ND</td></tr><tr><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">7</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">45281800</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/92845382" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">92845382</a></td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">VU0365120-1</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">S</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">methylene</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2,5-difluorophenyl</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">-</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">~ 10</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">ND</td></tr><tr><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">8</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">45281801</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/92845383" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">92845383</a></td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">VU0365121-1</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">S</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">methylene</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">pyridin-3-yl</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">6-fluoro</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">3.6</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">ND</td></tr><tr><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">9</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">45281802</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/92845384" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">92845384</a></td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">VU0365122-1</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">S</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">methylene</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">phenyl</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">4-methoxy</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">~ 10</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">ND</td></tr><tr><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">45281803</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/92845385" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">92845385</a></td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">VU0365123-1</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">S</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">methylene</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">1H-pyrazol-4-yl</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">1-methyl</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">3.3</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">ND</td></tr><tr><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">11</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">45281804</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/92845386" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">92845386</a></td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">VU0365138-1</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">S</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">methylene</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">phenyl</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">4-propoxy</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">> 10</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">ND</td></tr><tr><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">12</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">45281805</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/92845387" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">92845387</a></td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">VU0365124-1</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">S</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">ethyl</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">4-methoxy</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">-</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">4.9</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">ND</td></tr><tr><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">13</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">45281806</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/92845388" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">92845388</a></td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">VU0365125-1</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">S</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">ethyl</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">4-bromo</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">-</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">~10</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">ND</td></tr><tr><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">14</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">44602489</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/87352032" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">87352032</a></td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">VU0400265-1</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">S</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">methylene</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">O</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">phenyl</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">1.9</td><td headers="hd_h_ml172.t3_1_1_1_1 hd_h_ml172.t3_1_1_2_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">5</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>*</dt><dd><div id="ml172.tfn2"><p class="no_margin">S = synthesized, P = purchased.</p></div></dd></dl><dl class="bkr_refwrap"><dt>**</dt><dd><div id="ml172.tfn3"><p class="no_margin">Data represent the mean values from at least 3 experiments with similar results [<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2416" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2416</a>].</p></div></dd></dl><dl class="bkr_refwrap"><dt>***</dt><dd><div id="ml172.tfn4"><p class="no_margin">Leftward shift of an ACh CRC in the presence of 30 μM compound relative to ACh CRC control [<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2186" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2186</a>].</p></div></dd></dl></dl></div></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>
|
|
|
|
|
|
|
|
|
|
<!-- Book content -->
|
|
|
|
<script type="text/javascript" src="/portal/portal3rc.fcgi/rlib/js/InstrumentNCBIBaseJS/InstrumentPageStarterJS.js"> </script>
|
|
|
|
|
|
<!-- CE8B5AF87C7FFCB1_0191SID /projects/books/PBooks@9.11 portal104 v4.1.r689238 Tue, Oct 22 2024 16:10:51 -->
|
|
<span id="portal-csrf-token" style="display:none" data-token="CE8B5AF87C7FFCB1_0191SID"></span>
|
|
|
|
<script type="text/javascript" src="//static.pubmed.gov/portal/portal3rc.fcgi/4216699/js/3968615.js" snapshot="books"></script></body>
|
|
</html>
|