109 lines
136 KiB
Text
109 lines
136 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="NBK50704">
|
|
<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="/NBK50704/?report=reader">
|
|
<meta name="ncbi_pagename" content="Discovery and development of a second highly selective M1 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>Discovery and development of a second highly selective M1 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/ml170/?report=reader">
|
|
<meta name="jr-next-unit" content="/books/n/mlprobe/ml168/?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="Discovery and development of a second highly selective M1 Positive Allosteric Modulator (PAM)">
|
|
<meta name="citation_publisher" content="National Center for Biotechnology Information (US)">
|
|
<meta name="citation_date" content="2010/10/29">
|
|
<meta name="citation_author" content="Thomas M Bridges">
|
|
<meta name="citation_author" content="Paul R Reid">
|
|
<meta name="citation_author" content="L Michelle Lewis">
|
|
<meta name="citation_author" content="Eric S Dawson">
|
|
<meta name="citation_author" content="C David Weaver">
|
|
<meta name="citation_author" content="Michael R Wood">
|
|
<meta name="citation_author" content="Craig W Lindsley">
|
|
<meta name="citation_pmid" content="21433394">
|
|
<meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK50704/">
|
|
<link rel="schema.DC" href="http://purl.org/DC/elements/1.0/">
|
|
<meta name="DC.Title" content="Discovery and development of a second highly selective M1 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="Paul R Reid">
|
|
<meta name="DC.Contributor" content="L Michelle Lewis">
|
|
<meta name="DC.Contributor" content="Eric S Dawson">
|
|
<meta name="DC.Contributor" content="C David Weaver">
|
|
<meta name="DC.Contributor" content="Michael R Wood">
|
|
<meta name="DC.Contributor" content="Craig W Lindsley">
|
|
<meta name="DC.Date" content="2010/10/29">
|
|
<meta name="DC.Identifier" content="https://www.ncbi.nlm.nih.gov/books/NBK50704/">
|
|
<meta name="description" content="The specific aim of this project is to identify, via a functional high-throughput screening (HTS) approach, small molecule positive allosteric modulators (PAMs) and/or allosteric agonists of the M1 muscarinic acetylcholine receptor (mAChR) that are cell permeable, possess submicromolar potency, and show greater than 10-fold selectivity over the other mAChRs (M2-M5). The currently identified probe ML169 (CID-44475955) can be used for in vitro molecular pharmacology and electrophysiology experiments to study the receptor trafficking profile, and the role of selective M1 receptor activation by this unique M1 PAM chemotype. Use of this probe alongside the authors' initially identified M1 PAM probe, ML137 (CID-44251556) could improve understanding of the M1 signaling pathway and elucidate the difference, if any, between high and low ACh fold-shift compounds due to their different pharmacological characteristics. This probe possesses high selectivity versus M2-M5, as well as a large panel of GPCRs, ion channels and transporters. While in vivo studies are possible, it has not been investigated for such uses. Probes developed from these efforts will greatly advance the current state of the art by aiding in the understanding of M1's role in cell-based physiology, and may extend the clinical understanding of psychotic and cognitive symptoms associated with neurodegenerative disorders like Alzheimer's Disease and schizophrenia.">
|
|
<meta name="og:title" content="Discovery and development of a second highly selective M1 Positive Allosteric Modulator (PAM)">
|
|
<meta name="og:type" content="book">
|
|
<meta name="og:description" content="The specific aim of this project is to identify, via a functional high-throughput screening (HTS) approach, small molecule positive allosteric modulators (PAMs) and/or allosteric agonists of the M1 muscarinic acetylcholine receptor (mAChR) that are cell permeable, possess submicromolar potency, and show greater than 10-fold selectivity over the other mAChRs (M2-M5). The currently identified probe ML169 (CID-44475955) can be used for in vitro molecular pharmacology and electrophysiology experiments to study the receptor trafficking profile, and the role of selective M1 receptor activation by this unique M1 PAM chemotype. Use of this probe alongside the authors' initially identified M1 PAM probe, ML137 (CID-44251556) could improve understanding of the M1 signaling pathway and elucidate the difference, if any, between high and low ACh fold-shift compounds due to their different pharmacological characteristics. This probe possesses high selectivity versus M2-M5, as well as a large panel of GPCRs, ion channels and transporters. While in vivo studies are possible, it has not been investigated for such uses. Probes developed from these efforts will greatly advance the current state of the art by aiding in the understanding of M1's role in cell-based physiology, and may extend the clinical understanding of psychotic and cognitive symptoms associated with neurodegenerative disorders like Alzheimer's Disease and schizophrenia.">
|
|
<meta name="og:url" content="https://www.ncbi.nlm.nih.gov/books/NBK50704/">
|
|
<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/ml169/?report=reader">
|
|
<link rel="canonical" href="https://www.ncbi.nlm.nih.gov/books/NBK50704/">
|
|
<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="CE8E09DF7D65DA810000000000FD00D6.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/NBK50704/?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/ml170/?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">Discovery and development of a second highly selective M1 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/ml168/?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/NBK50704/"><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/NBK50704/&text=Discovery%20and%20development%20of%20a%20second%20highly%20selective%20M1%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/NBK50704/?report=classic">Switch to classic view</a><a href="/books/NBK50704/pdf/Bookshelf_NBK50704.pdf">PDF (2.0M)</a><a href="/books/NBK50704/?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%20NBK50704%20%2F%20sid%3ACE8B5AF87C7FFCB1_0191SID%20%2F%20phid%3ACE8E09DF7D65DA810000000000FD00D6.4">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="_NBK50704_"><span class="title" itemprop="name">Discovery and development of a second highly selective M<sub>1</sub> Positive Allosteric Modulator (PAM)</span></h1><p class="contribs">Bridges TM, Reid PR, Lewis LM, et al.</p><p class="fm-aai"><a href="#_NBK50704_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> The specific aim of this project is to identify, via a functional high-throughput screening (HTS) approach, small molecule positive allosteric modulators (PAMs) and/or allosteric agonists of the M1 muscarinic acetylcholine receptor (mAChR) that are cell permeable, possess submicromolar potency, and show greater than 10-fold selectivity over the other mAChRs (M2-M5). The currently identified probe <a href="/pcsubstance/?term=ML169[synonym]" ref="pagearea=abstract&targetsite=entrez&targetcat=term&targettype=pubchem">ML169</a> (CID-44475955) can be used for in vitro molecular pharmacology and electrophysiology experiments to study the receptor trafficking profile, and the role of selective M1 receptor activation by this unique M1 PAM chemotype. Use of this probe alongside the authors' initially identified M1 PAM probe, <a href="/pcsubstance/?term=ML137[synonym]" ref="pagearea=abstract&targetsite=entrez&targetcat=term&targettype=pubchem">ML137</a> (CID-44251556) could improve understanding of the M1 signaling pathway and elucidate the difference, if any, between high and low ACh fold-shift compounds due to their different pharmacological characteristics. This probe possesses high selectivity versus M2-M5, as well as a large panel of GPCRs, ion channels and transporters. While in vivo studies are possible, it has not been investigated for such uses. Probes developed from these efforts will greatly advance the current state of the art by aiding in the understanding of M1's role in cell-based physiology, and may extend the clinical understanding of psychotic and cognitive symptoms associated with neurodegenerative disorders like Alzheimer's Disease and schizophrenia.</p></div><div class="h2"></div><p><b>Assigned Assay Grant #:</b> MH077606-01</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/2543" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-2543</a></p><div id="ml169.s2"><h2 id="_ml169_s2_">Probe Structure & Characteristics</h2><p>2-((1-(5-bromo-2-fluorobenzyl)-1<i>H</i>-indol-3-yl)sulfonyl)- N-(5-methylisoxazol-3-yl)acetamide</p><p>MW = 506.4, logP = 3.9, TPSA = 94.2 Å<sup>2</sup></p><div id="ml169.fu1" class="figure"><div class="graphic"><img src="/books/NBK50704/bin/ml169fu1.jpg" alt="Image ml169fu1" /></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml169tu1"><a href="/books/NBK50704/table/ml169.tu1/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figml169tu1" rid-ob="figobml169tu1"><img class="small-thumb" src="/books/NBK50704/table/ml169.tu1/?report=thumb" src-large="/books/NBK50704/table/ml169.tu1/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ml169.tu1"><a href="/books/NBK50704/table/ml169.tu1/?report=objectonly" target="object" rid-ob="figobml169tu1">Table</a></h4></div></div></div><div id="ml169.s3"><h2 id="_ml169_s3_">Recommendations for the scientific use of this probe</h2><p>This probe (CID 44475955) can be used for <i>in vitro</i> molecular pharmacology and electrophysiology experiments to study the receptor trafficking profile and the role of selective M<sub>1</sub> receptor activation by this unique M<sub>1</sub> PAM chemotype. Use of this probe alongside our initial M<sub>1</sub> PAM probe (CID 44251556) could improve our understanding of the M<sub>1</sub> signaling pathway and elucidate the difference, if any, between high and low ACh fold-shift compounds, due to their different pharmacological characteristics. This probe possesses high selectivity versus M<sub>2</sub>–M<sub>5</sub>, as well as a large panel of GPCRs, ion channels and transporters. While <i>in vivo</i> studies are possible, it has not been investigated for such uses.</p><div id="ml169.s4"><h3>Specific AIM</h3><p>To identify small molecule positive allosteric modulators (PAMs) and/or allosteric agonists of the M<sub>1</sub> muscarinic acetylcholine receptor that are cell permeable, possess submicromolar potency and show greater than 10-fold selectivity over the other mAChRs (M<sub>2</sub>–M<sub>5</sub>) employing a functional HTS approach. Out of this effort aimed at M<sub>1</sub>, which afforded a highly selective M<sub>1</sub> antagonist (CID 24768606), a highly selective M<sub>1</sub> allosteric agonist (CID 25010775) and a highly selective M1 PAM (CID 44251556), we also identified and optimized the first M<sub>5</sub> ligand, an M<sub>5</sub> PAM (CID 42633508). Starting from an unrelated lead, belonging to a novel chemotype, we have now been able to develop a second highly selective M<sub>1</sub> PAM with a low-micromolar EC<sub>50</sub> and a greatly improved ACh fold-shift. Another MLSCN screening effort identified a highly selective M<sub>4</sub> PAM (CID 864492); thus, two MLSCN/MLPCN screens have provided a toolkit of highly selective mAChR ligands available from the MLPCN to study individual mAChR function both <i>in vitro</i> and <i>in vivo</i>.</p></div><div id="ml169.s5"><h3>Significance</h3><p>The five cloned muscarinic acetylcholine receptor subtypes (mAChR1-5 or M<sub>1</sub>–M<sub>5</sub>) are known to play highly important and diverse roles in many basic physiological processes.<a class="bibr" href="#ml169.r1" rid="ml169.r1 ml169.r2 ml169.r3">1–3</a> 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.<a class="bibr" href="#ml169.r3" rid="ml169.r3">3</a>,<a class="bibr" href="#ml169.r4" rid="ml169.r4">4</a> 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 elusive.<a class="bibr" href="#ml169.r3" rid="ml169.r3">3</a>,<a class="bibr" href="#ml169.r4" rid="ml169.r4">4</a> In numerous Phase II and III clinical trials, pan-mAChR agonists were shown to improve cognitive performance in AD patients, but the GI-and/or cardiovascular side effects, resulting from activation of peripheral mAChRs, were deemed intolerable and the trials were discontinued.<a class="bibr" href="#ml169.r5" rid="ml169.r5">5</a>,<a class="bibr" href="#ml169.r6" rid="ml169.r6">6</a> Importantly, several pan-mAChR agonists demonstrated a decline in the concentration of Aβ42 in the cerebral spinal fluid of AD patients, suggesting that mAChR activation has the potential to be disease modifying as well as providing palliative cognitive therapy.<a class="bibr" href="#ml169.r7" rid="ml169.r7">7</a> More recent studies in 3xTg-AD mice further support a disease modifying role for mAChR activation, and several Ph III trials demonstrated that mAChR activation lowered Aβ42 in patients.<a class="bibr" href="#ml169.r8" rid="ml169.r8">8</a> Interestingly, the M<sub>1</sub>/M<sub>4</sub> preferring xanomeline, in addition to improving cognitive performance, had robust therapeutic effects on the psychotic symptoms and behavioral disturbances associated with AD and recently published clinical trial data indicates efficacy in schizophrenic patients.<a class="bibr" href="#ml169.r9" rid="ml169.r9">9</a>,<a class="bibr" href="#ml169.r10" rid="ml169.r10">10</a> Probes developed from these efforts will greatly advance the current state of the art by aiding in the understanding of M<sub>1</sub>’s role in cell-based physiology and may extend the clinical understanding of psychotic and cognitive symptoms associated with neurodegenerative disorders like Alzheimer’s Disease and schizophrenia.</p></div><div id="ml169.s6"><h3>Rationale</h3><p>In recent years, major advances have been made in the discovery of highly selective agonists of other G protein-coupled receptors (GPCRs) that act at an allosteric site rather than the orthosteric binding site.<a class="bibr" href="#ml169.r11" rid="ml169.r11">11</a>,<a class="bibr" href="#ml169.r12" rid="ml169.r12">12</a> By screening for compounds that act at an allosteric site on the receptor, it is anticipated that compounds that selectively activate M<sub>1</sub> versus the other muscarinic subtypes may be identified.<a class="bibr" href="#ml169.r13" rid="ml169.r13 ml169.r14 ml169.r15 ml169.r16 ml169.r17 ml169.r18">13–18</a> While allosteric M<sub>1</sub> agonists have been identified, AC-42 and TBPB, they both suffer from undesirable ancillary pharmacology, poor physicochemical properties, poor pharmacokinetics and/or limited CNS exposure.<a class="bibr" href="#ml169.r19" rid="ml169.r19">19</a>,<a class="bibr" href="#ml169.r20" rid="ml169.r20">20</a> Thus, to truly enable the biomedical community to dissect the relative contributions of selective M<sub>1</sub> activation in preclinical models of AD and schizophrenia and to understand the role of M<sub>1</sub> in the pronounced efficacy of the M<sub>1</sub>/M<sub>4</sub> preferring xanomeline, improved M<sub>1</sub> probes are required. Recently, 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 – several are MLPCN probes along with the prototypical M<sub>1</sub> PAM, BQCA.<a class="bibr" href="#ml169.r13" rid="ml169.r13 ml169.r14 ml169.r15 ml169.r16 ml169.r17 ml169.r18">13–18</a>,<a class="bibr" href="#ml169.r20" rid="ml169.r20 ml169.r21 ml169.r22">20–22</a> Although considerable interest was initially generated around BQCA, this level of interest appears to have waned and may point to a fatal flaw in its general chemotype (See <a class="figpopup" href="/books/NBK50704/figure/ml169.f2/?report=objectonly" target="object" rid-figpopup="figml169f2" rid-ob="figobml169f2">Figure 2</a>). Our initial report on the discovery of CID 3008304, a pan G<sub>q</sub> M<sub>1</sub>, M<sub>3</sub>, M<sub>5</sub> PAM, also described three other series of weak M<sub>1</sub> PAMs, and established that different M<sub>1</sub> PAM chemotypes displayed different modes of activity on downstream receptor signaling/trafficking despite similar profiles in Ca<sup>2+</sup> assays.<a class="bibr" href="#ml169.r13" rid="ml169.r13">13</a> Thus, all allosteric M<sub>1</sub> activation is not equivalent, and additional tool compounds representing diverse chemotypes are required to truly dissect and study M<sub>1</sub> function in the CNS. Subsequent to our development of an M<sub>5</sub> selective PAM from a pan G<sub>q</sub> M<sub>1</sub>, M<sub>3</sub>, M<sub>5</sub> PAM,<a class="bibr" href="#ml169.r21" rid="ml169.r21">21</a>,<a class="bibr" href="#ml169.r22" rid="ml169.r22">22</a> we next optimized CID 3008304 for M<sub>1</sub> PAM activity resulting in the first highly selective M<sub>1</sub> PAM MLCPN probe (CID 44251556). For the above reasons associated with downstream receptor signaling/trafficking, we were simultaneously pursuing alternative leads in an attempt to add unique chemotypes to our tool kit of selective M<sub>1</sub> activators.<a class="bibr" href="#ml169.r23" rid="ml169.r23">23</a></p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml169f2" co-legend-rid="figlgndml169f2"><a href="/books/NBK50704/figure/ml169.f2/?report=objectonly" target="object" title="Figure 2" class="img_link icnblk_img figpopup" rid-figpopup="figml169f2" rid-ob="figobml169f2"><img class="small-thumb" src="/books/NBK50704/bin/ml169f2.gif" src-large="/books/NBK50704/bin/ml169f2.jpg" alt="Figure 2. M1 PAMs, CID 44251556 and BQCA." /></a><div class="icnblk_cntnt" id="figlgndml169f2"><h4 id="ml169.f2"><a href="/books/NBK50704/figure/ml169.f2/?report=objectonly" target="object" rid-ob="figobml169f2">Figure 2</a></h4><p class="float-caption no_bottom_margin">M<sub>1</sub> PAMs, CID 44251556 and BQCA. </p></div></div></div></div><div id="ml169.s7"><h2 id="_ml169_s7_">Assay Implementation and Screening</h2><div id="ml169.s8"><h3>PubChem Bioassay Name</h3><p>Discovery of Novel Allosteric Modulators of the M<sub>1</sub> Muscarinic Receptor: Positive Allosteric Modulator (PAM)</p></div><div id="ml169.s9"><h3>List of PubChem bioassay identifiers generated for this screening project (AIDs)</h3><p><b><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2651" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-2651</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2425" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-2425</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2428" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-2428</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2430" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-2430</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2434" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-2434</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2433" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-2433</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2438" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-2438</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2626" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-2626</a>, and <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2543" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-2543</a>.</b></p></div><div id="ml169.s10"><h3>PubChem Primary Assay Description</h3><p>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. hM<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></div><div id="ml169.s11"><h3>Calcium Mobilization Assay</h3><p>Cells were loaded with calcium indicator dye [2 μM Fluo-4 acetoxymethyl ester (50 μL/well) prepared as a stock in DMSO and mixed in a 1:1 ratio with 10% Pluronic acid F-127 in assay buffer (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. Cells were then stimulated for 50 s with a submaximal concentration (EC<sub>20</sub>) or a full dose-response curve of acetylcholine. The signal amplitude was first normalized to baseline and then as a percentage of the maximal response to acetylcholine.</p></div><div id="ml169.s12"><h3>Summary of Screen</h3><p>This screen was performed in the pilot phase, the MLSCN, when the MLSMR compound collection at Vanderbilt only contained ~65,000 compounds. Results from the primary M<sub>1</sub> screen of these compounds identified ~12 putative M<sub>1</sub> PAMs with an average Z’ score of 0.70±0.09. The confirmation screen (singles at 10 μM) produced two lead compounds, one of which was optimized into our first M<sub>1</sub> PAM probe (CID 44251556). The other, CID 2157678, represented a viable lead structure already endowed with good receptor subtype selectivity across the M<sub>3</sub>/M<sub>5</sub> receptors (<a class="figpopup" href="/books/NBK50704/figure/ml169.f1/?report=objectonly" target="object" rid-figpopup="figml169f1" rid-ob="figobml169f1">Figure 1</a>). However, its potency upon reconfirmation from dry solid (M<sub>1</sub> EC<sub>50</sub> = 12.9 μM) was not particularly attractive and so a program was initiated to develop this lead into a pharmacologically more useful tool by improving its potency while maintaining its M<sub>2</sub>–M<sub>5</sub> receptor subtype selectivity. Ultimately, it was envisioned that an M<sub>1</sub> PAM not structurally related to the known M<sub>1</sub> PAMs (CID 44251556 and BQCA, <a class="figpopup" href="/books/NBK50704/figure/ml169.f2/?report=objectonly" target="object" rid-figpopup="figml169f2" rid-ob="figobml169f2">Figure 2</a>) may possess a distinct pharmacology at the M<sub>1</sub> receptor, thereby enabling an expanded understanding of the M<sub>1</sub> muscarinic receptor’s downstream signaling/trafficking.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml169f1" co-legend-rid="figlgndml169f1"><a href="/books/NBK50704/figure/ml169.f1/?report=objectonly" target="object" title="Figure 1" class="img_link icnblk_img figpopup" rid-figpopup="figml169f1" rid-ob="figobml169f1"><img class="small-thumb" src="/books/NBK50704/bin/ml169f1.gif" src-large="/books/NBK50704/bin/ml169f1.jpg" alt="Figure 1. CRCs at M1–M5 for HTS lead CID 2157678." /></a><div class="icnblk_cntnt" id="figlgndml169f1"><h4 id="ml169.f1"><a href="/books/NBK50704/figure/ml169.f1/?report=objectonly" target="object" rid-ob="figobml169f1">Figure 1</a></h4><p class="float-caption no_bottom_margin">CRCs at M<sub>1</sub>–M<sub>5</sub> for HTS lead CID 2157678. </p></div></div></div><div id="ml169.s13"><h3>Probe Chemical Lead Optimization Strategy</h3><p>Our initial optimization strategy is outlined in <a class="figpopup" href="/books/NBK50704/figure/ml169.f3/?report=objectonly" target="object" rid-figpopup="figml169f3" rid-ob="figobml169f3">Figure 3</a>, and as SAR with allosteric ligands is often shallow, we employed an iterative parallel synthesis approach, along with targeted syntheses for structures encompassing more speculative modifications. Attempted modifications of the Eastern oxazole-amide, although not extensive, met with no success, returning only compounds with undetectable activity (Such as CID 44129586, 44634499, 44634501 and 44634503). In a straightforward attempt to reduce molecular weight the benzyl group attached to the indole nitrogen was omitted, but met with a similar lack of success (CID 751482, EC<sub>50</sub> > 10 μM).</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml169f3" co-legend-rid="figlgndml169f3"><a href="/books/NBK50704/figure/ml169.f3/?report=objectonly" target="object" title="Figure 3" class="img_link icnblk_img figpopup" rid-figpopup="figml169f3" rid-ob="figobml169f3"><img class="small-thumb" src="/books/NBK50704/bin/ml169f3.gif" src-large="/books/NBK50704/bin/ml169f3.jpg" alt="Figure 3. Initial optimization strategy for CID 2157678." /></a><div class="icnblk_cntnt" id="figlgndml169f3"><h4 id="ml169.f3"><a href="/books/NBK50704/figure/ml169.f3/?report=objectonly" target="object" rid-ob="figobml169f3">Figure 3</a></h4><p class="float-caption no_bottom_margin">Initial optimization strategy for CID 2157678. </p></div></div><p>Accordingly, libraries were concomitantly prepared as shown in <a class="figpopup" href="/books/NBK50704/figure/ml169.f7/?report=objectonly" target="object" rid-figpopup="figml169f7" rid-ob="figobml169f7">Scheme 1</a> and predominately surveyed diversity on the Southern benzyl moiety. Methyl thioglycolate (<b>1</b>) was arylated with indole using iodine and potassium iodide, followed by saponification of the ester using lithium hydroxide to give acid <b>2</b>. This acid was then peptide coupled with 3-amino-5-methyl-isoxazole (<b>3</b>) employing PyClU (chlorodipyrrolidinocarbenium hexafluorophosphate), in DCE, with microwave heating to yield thioether <b>4</b>. The sulfur was then oxidized to the sulfone with Oxone, thereby allowing the benzylation of the indole nitrogen to be performed as the final step in the preparation of the initial library (Analogs <b>5</b>, <a class="figpopup" href="/books/NBK50704/table/ml169.t1/?report=objectonly" target="object" rid-figpopup="figml169t1" rid-ob="figobml169t1">Table 1</a>). As would be expected for this benzylation, bis-alkylation was observed to a small extent, and occasionally allowed for the isolation of analogs like CID 44129599 (<a class="figpopup" href="/books/NBK50704/figure/ml169.f4/?report=objectonly" target="object" rid-figpopup="figml169f4" rid-ob="figobml169f4">Figure 4</a>). While it was not terribly surprising that these analogs were devoid of M<sub>1</sub> PAM activity, it would eventually be ascertained that even the introduction of a solitary methyl group α to the amide abolished any measureable M<sub>1</sub> PAM activity (CID 44634500, M<sub>1</sub> EC<sub>50</sub> > 10 μM, is the μ-methylated analog of the probe compound). Alternatively, if the Oxone oxidation step is omitted or replaced with a milder oxidant (e.g. FeCl<sub>3</sub>/H<sub>5</sub>IO<sub>6</sub>) then thioethers (CID 3305286) or sulfoxides (CID 44247543) analogous to the lead structure were produced. However only the sulfoxide (CID 44247543) retained measureable activity (M<sub>1</sub> EC<sub>50</sub> = 5.23 μM), but did not represent a significant improvement over its sulfone analog (<b>5b</b>, CID 44129591, <a class="figpopup" href="/books/NBK50704/table/ml169.t1/?report=objectonly" target="object" rid-figpopup="figml169t1" rid-ob="figobml169t1">Table 1</a>).</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml169f7" co-legend-rid="figlgndml169f7"><a href="/books/NBK50704/figure/ml169.f7/?report=objectonly" target="object" title="Scheme 1" class="img_link icnblk_img figpopup" rid-figpopup="figml169f7" rid-ob="figobml169f7"><img class="small-thumb" src="/books/NBK50704/bin/ml169f7.gif" src-large="/books/NBK50704/bin/ml169f7.jpg" alt="Scheme 1. Synthesis of CID 2157678 and the route to its analogs." /></a><div class="icnblk_cntnt" id="figlgndml169f7"><h4 id="ml169.f7"><a href="/books/NBK50704/figure/ml169.f7/?report=objectonly" target="object" rid-ob="figobml169f7">Scheme 1</a></h4><p class="float-caption no_bottom_margin">Synthesis of CID 2157678 and the route to its analogs. </p></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml169t1"><a href="/books/NBK50704/table/ml169.t1/?report=objectonly" target="object" title="Table 1" class="img_link icnblk_img figpopup" rid-figpopup="figml169t1" rid-ob="figobml169t1"><img class="small-thumb" src="/books/NBK50704/table/ml169.t1/?report=thumb" src-large="/books/NBK50704/table/ml169.t1/?report=previmg" alt="Table 1. Structures and activities of analogs 5." /></a><div class="icnblk_cntnt"><h4 id="ml169.t1"><a href="/books/NBK50704/table/ml169.t1/?report=objectonly" target="object" rid-ob="figobml169t1">Table 1</a></h4><p class="float-caption no_bottom_margin">Structures and activities of analogs <i>5</i>. </p></div></div><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml169f4" co-legend-rid="figlgndml169f4"><a href="/books/NBK50704/figure/ml169.f4/?report=objectonly" target="object" title="Figure 4" class="img_link icnblk_img figpopup" rid-figpopup="figml169f4" rid-ob="figobml169f4"><img class="small-thumb" src="/books/NBK50704/bin/ml169f4.gif" src-large="/books/NBK50704/bin/ml169f4.jpg" alt="Figure 4. A representative over-alkylation product from Scheme 1." /></a><div class="icnblk_cntnt" id="figlgndml169f4"><h4 id="ml169.f4"><a href="/books/NBK50704/figure/ml169.f4/?report=objectonly" target="object" rid-ob="figobml169f4">Figure 4</a></h4><p class="float-caption no_bottom_margin">A representative over-alkylation product from Scheme 1. </p></div></div><p>Focusing on the library of analogs appearing in <a class="figpopup" href="/books/NBK50704/table/ml169.t1/?report=objectonly" target="object" rid-figpopup="figml169t1" rid-ob="figobml169t1">Table 1</a>, we quickly discovered that substitution in the 3-position of the phenyl ring was preferred. Moving the chlorine from the 2-position in the lead structure (<b>5a</b>) to the 3-position (<b>5b</b>) improved the M<sub>1</sub> EC<sub>50</sub> by about 50%. While, either a methoxy (<b>5e</b>) or a fluorine (<b>5f</b>) at this position afforded a small improvement in their EC<sub>50</sub> values, a 2-fold increase in potency could be obtained by introducing a bromine at the 3-position providing <b>5h</b>, which possessed an EC<sub>50</sub> = 3.79 μM. The remainder of <a class="figpopup" href="/books/NBK50704/table/ml169.t1/?report=objectonly" target="object" rid-figpopup="figml169t1" rid-ob="figobml169t1">Table 1</a>, servers to illustrated how steep the SAR was for this class of allosteric modulators. For example, the addition of a second halogen in examples <b>5k</b> and <b>5l</b> eliminated the measurable efficacy displayed by their mono-halogenated analogs (<b>5h</b> and <b>5b</b>, respectively). In general it could also be concluded that substitution at the 4-position on these aryl groups was uniformly detrimental. Having learned from the initial library that proper substitution at the 3-position of the benzyl group could be beneficial, and with the bromide <b>5h</b> in hand we sought to introduce various aryl rings at this location. The small library of analogs <b>6</b> appearing in <a class="figpopup" href="/books/NBK50704/table/ml169.t2/?report=objectonly" target="object" rid-figpopup="figml169t2" rid-ob="figobml169t2">Table 2</a> were prepared via microwave-assisted Suzuki couplings between <b>5h</b> and the requisite boronic acid. Impetus for the introduction of the pyrazole moiety found in <b>6a–c</b>, came from its successful incorporation into our previous M<sub>1</sub> PAM probe (CID 44251556) and BQCA analogs (<a class="figpopup" href="/books/NBK50704/figure/ml169.f2/?report=objectonly" target="object" rid-figpopup="figml169f2" rid-ob="figobml169f2">Figure 2</a>). Gratifyingly, the <i>N</i>-methyl pyrazole <b>6a</b> did have measureable activity but did not impart a significant improvement in potency over the corresponding bromide (<b>5h</b>). Divergent from the SAR established during the development of CID 44251556, the unalkylated pyrazole <b>6b</b> was now preferred, possessing an M<sub>1</sub> EC<sub>50</sub> = 2.19 μM. In contrast to the <i>N</i>-methyl pyrazole <b>6a</b>, the larger <i>sec</i>-butyl substituent of <b>6c</b> was not tolerated, and neither were the other heterocycles of the remaining analogs (<b>6d–h</b>).</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml169t2"><a href="/books/NBK50704/table/ml169.t2/?report=objectonly" target="object" title="Table 2" class="img_link icnblk_img figpopup" rid-figpopup="figml169t2" rid-ob="figobml169t2"><img class="small-thumb" src="/books/NBK50704/table/ml169.t2/?report=thumb" src-large="/books/NBK50704/table/ml169.t2/?report=previmg" alt="Table 2. Structures and activities of analogs 6." /></a><div class="icnblk_cntnt"><h4 id="ml169.t2"><a href="/books/NBK50704/table/ml169.t2/?report=objectonly" target="object" rid-ob="figobml169t2">Table 2</a></h4><p class="float-caption no_bottom_margin">Structures and activities of analogs <i>6</i>. </p></div></div><p>To further the development of this novel series of M<sub>1</sub> PAMs we focused on three of the more potent analogs (<b>5b</b>, <b>5h</b> and <b>6b</b>) and applied a fine-tuning process of introducing fluorine atoms at various locations to provide analogs <b>7</b> (<a class="figpopup" href="/books/NBK50704/table/ml169.t3/?report=objectonly" target="object" rid-figpopup="figml169t3" rid-ob="figobml169t3">Table 3</a>). Across the series, substitution at the 4-position was uniformly not tolerated (<b>7a–c</b>), consistent with the SAR appearing in <a class="figpopup" href="/books/NBK50704/table/ml169.t1/?report=objectonly" target="object" rid-figpopup="figml169t1" rid-ob="figobml169t1">Table 1</a>. Bis-fluorination of the indole ring eroded activity in the context of the bromine analog <b>7d</b> but conversely augmented the activity of the pyrazole congener <b>7e</b>. This type of subtle/confounding SAR was similarly observed with respect to fluorination at the R<sup>2</sup> position in analogs <b>7f–h</b>. While the presence of a fluorine at R<sup>2</sup> was neutral or slightly beneficial in the context of the chlorine analog (<b>7f</b>), its presence resulted in clearly decreased activity for both the bromine and pyrazole analogs, <b>7g</b> and <b>7h</b>. Lastly, the introduction of a single fluorine at the R<sup>6</sup> position could either be moderately detrimental in the context of pyrazole <b>7i</b> or decidedly beneficial with respect to bromine analog <b>7j</b>, where an almost 3-fold improvement in potency was observed. In this manner, both CID 44475955 (<b>7j</b>) and the related difluorindole analog CID 44475948 (<b>7e</b>) were developed and chosen for further evaluation (For clarity, these compounds are shown in <a class="figpopup" href="/books/NBK50704/figure/ml169.f5/?report=objectonly" target="object" rid-figpopup="figml169f5" rid-ob="figobml169f5">Figure 5</a>).</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml169t3"><a href="/books/NBK50704/table/ml169.t3/?report=objectonly" target="object" title="Table 3" class="img_link icnblk_img figpopup" rid-figpopup="figml169t3" rid-ob="figobml169t3"><img class="small-thumb" src="/books/NBK50704/table/ml169.t3/?report=thumb" src-large="/books/NBK50704/table/ml169.t3/?report=previmg" alt="Table 3. Structures and activities of analogs 7." /></a><div class="icnblk_cntnt"><h4 id="ml169.t3"><a href="/books/NBK50704/table/ml169.t3/?report=objectonly" target="object" rid-ob="figobml169t3">Table 3</a></h4><p class="float-caption no_bottom_margin">Structures and activities of analogs <i>7</i>. </p></div></div><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml169f5" co-legend-rid="figlgndml169f5"><a href="/books/NBK50704/figure/ml169.f5/?report=objectonly" target="object" title="Figure 5" class="img_link icnblk_img figpopup" rid-figpopup="figml169f5" rid-ob="figobml169f5"><img class="small-thumb" src="/books/NBK50704/bin/ml169f5.gif" src-large="/books/NBK50704/bin/ml169f5.jpg" alt="Figure 5. The two most potent M1 PAMs developed from the lead CID 2157678." /></a><div class="icnblk_cntnt" id="figlgndml169f5"><h4 id="ml169.f5"><a href="/books/NBK50704/figure/ml169.f5/?report=objectonly" target="object" rid-ob="figobml169f5">Figure 5</a></h4><p class="float-caption no_bottom_margin">The two most potent M<sub>1</sub> PAMs developed from the lead CID 2157678. </p></div></div><p>Both CID 44475955 and CID 44475948 were highly selective PAMs for the M<sub>1</sub> receptor, displaying minimal/no potentiation of the M<sub>2</sub>–M<sub>5</sub> receptors up to 30 μM (<a class="figpopup" href="/books/NBK50704/figure/ml169.f6/?report=objectonly" target="object" rid-figpopup="figml169f6" rid-ob="figobml169f6">Figure 6A–B</a>). Similarly, both compounds demonstrated impressive left-ward shifts in the potency of ACh in M<sub>1</sub> ACh Concentration Response Curve (CRC) fold-shift experiments (<a class="figpopup" href="/books/NBK50704/figure/ml169.f6/?report=objectonly" target="object" rid-figpopup="figml169f6" rid-ob="figobml169f6">Figure 6C</a>). When tested at 30 μM, the bromine analog <b>7j</b> engendered a 45-fold increase in ACh activity, while the pyrazole analog <b>7e</b> increased ACh activity 98-fold. These levels of potentiation are very similar to those seen for BQCA<a class="bibr" href="#ml169.r14" rid="ml169.r14">14</a>,<a class="bibr" href="#ml169.r15" rid="ml169.r15">15</a> and represent a sizable improvement over the earlier M<sub>1</sub> PAM probe molecule CID 44251556 which produced only a 3-fold shift in an identical experiment. Still, these experiments did not reveal a definitive superiority for either molecule.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml169f6" co-legend-rid="figlgndml169f6"><a href="/books/NBK50704/figure/ml169.f6/?report=objectonly" target="object" title="Figure 6" class="img_link icnblk_img figpopup" rid-figpopup="figml169f6" rid-ob="figobml169f6"><img class="small-thumb" src="/books/NBK50704/bin/ml169f6.gif" src-large="/books/NBK50704/bin/ml169f6.jpg" alt="Figure 6. A) CRCs for CID 44475955 at M1–M5; B) CRCs for CID 44475948 at M1–M5; C) Fold-Shift for CID 44475955 and CID 44475948 at 30 μM." /></a><div class="icnblk_cntnt" id="figlgndml169f6"><h4 id="ml169.f6"><a href="/books/NBK50704/figure/ml169.f6/?report=objectonly" target="object" rid-ob="figobml169f6">Figure 6</a></h4><p class="float-caption no_bottom_margin">A) CRCs for CID 44475955 at M<sub>1</sub>–M<sub>5</sub>; B) CRCs for CID 44475948 at M<sub>1</sub>–M<sub>5</sub>; C) Fold-Shift for CID 44475955 and CID 44475948 at 30 μM. </p></div></div><p>An examination of calculated physical properties and practical considerations were more helpful in choosing the preferred probe. The <i>in silico</i> values for CID 44475955 and CID 44475948 appearing in <a class="figpopup" href="/books/NBK50704/table/ml169.t4/?report=objectonly" target="object" rid-figpopup="figml169t4" rid-ob="figobml169t4">Table 4</a> were calculated using TRIPOS software. Also included in <a class="figpopup" href="/books/NBK50704/table/ml169.t4/?report=objectonly" target="object" rid-figpopup="figml169t4" rid-ob="figobml169t4">Table 4</a> are the averages from the MDDR database of compounds both entering Phase I and launched drugs. Once again both compounds were very similar across a number of parameters. However, CID 44475955 possessed superior values for both total polar surface area (TPSA) and its number of hydrogen bond donors (Hdon). These two discrepancies both point to a lower probability of crossing the blood brain barrier for CID 44475948. Although not tested <i>in vivo</i>, this would lead to the prediction that CID 44475955 has a better chance of being a CNS penetrant molecule, and therefore a potentially superior MLPCN probe compound for the muscarinic receptors present in the CNS. Additionally, from a synthesis standpoint, the greater ease and lower cost for the acquisition of indole (<a class="figpopup" href="/books/NBK50704/figure/ml169.f7/?report=objectonly" target="object" rid-figpopup="figml169f7" rid-ob="figobml169f7">Scheme 1</a>) over 4,6-difluoroindole (the starting material for CID 44475948) makes CID 44475955 the more practical and cost-effective probe molecule.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml169t4"><a href="/books/NBK50704/table/ml169.t4/?report=objectonly" target="object" title="Table 4" class="img_link icnblk_img figpopup" rid-figpopup="figml169t4" rid-ob="figobml169t4"><img class="small-thumb" src="/books/NBK50704/table/ml169.t4/?report=thumb" src-large="/books/NBK50704/table/ml169.t4/?report=previmg" alt="Table 4. Calculated Property Comparison with MDDR Compounds." /></a><div class="icnblk_cntnt"><h4 id="ml169.t4"><a href="/books/NBK50704/table/ml169.t4/?report=objectonly" target="object" rid-ob="figobml169t4">Table 4</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>1</sub> PAM, CID 44475995 was tested at Ricerca’s (formerly MDS Pharma’s) Lead Profiling Screen (binding assay panel of 68 GPCRs, ion channels and transporters screened at 10 μM), and was, thus far, found to not significantly interact with 16 out of the 16 assays conducted (Remaining 52 pending).<a class="bibr" href="#ml169.r24" rid="ml169.r24">24</a> Thus, CID 44475955 is highly selective and can be used to dissect the role of M<sub>1</sub>
|
|
<i>in vitro</i>. Furthermore, when used in conjunction with our earlier M<sub>1</sub> PAM probe molecule, the potentially different effects caused by an ACh low fold-shift probe (CID 44251556, 3-fold) versus those of an ACh high fold-shift probe (CID 44475955, 45-fold) may reveal the importance of this parameter towards the treatment of different disease states.</p><p>In summary, from an initial MLSCN screening campaign of just 65,000 compounds a second, potent and highly selective M<sub>1</sub> PAM (CID 44475955) has been identified which is structurally distinct from our initial M<sub>1</sub> PAM probe (CID 44251556). CID 44475955, similar to our previous probe, possesses comparable potency to BQCA, but now in contrast to our first probe, also shares BQCA’s ability to produce a large left-ward shift in the activity of ACh at the M<sub>1</sub> receptor. CID 44475955 now represents the third known chemotype to provide potent and selective M<sub>1</sub> positive allosteric modulation. Further <i>in vitro</i> and <i>in vivo</i> characterization of CID 44475955 is in progress in the assay submitter’s lab, and data will be reported in due course.</p></div><div id="ml169.s14"><h3>Synthetic procedure and spectral data for CID 44475955</h3><div id="ml169.fu2" class="figure"><div class="graphic"><img src="/books/NBK50704/bin/ml169fu13.jpg" alt="Image ml169fu13" /></div></div><div id="ml169.s15"><h4>CID 44475955, 2-((1-(5-bromo-2-fluorobenzyl)-1<i>H</i>-indol-3-yl)sulfonyl)-<i>N</i>-(5-methylisoxazol-3-yl)acetamide [<a href="/pcsubstance/?term=ML169[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML169</a>]</h4><p>To a solution of indole (3.00 g, 25.6 mmol) and methyl thioglycolate (2.40 mL, 25.6 mmol) in methanol:water (80 mL : 20 mL) was added iodine (6.50 g, 25.6 mmol) and potassium iodide (4.25 g, 25.6 mmol). The reaction mixture was stirred at ambient temperature for 60 hours. Methanol was removed <i>in vacuo</i> and the aqueous layer diluted with a saturated solution of sodium bicarbonate and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, evaporated <i>in vacuo</i> and the resulting residue was purified on a silica gel column (0–100% ethyl acetate:hexanes over 33 min) to afford compound <b>8</b> as an oil (LCMS >98%). Compound <b>8</b> was dissolved in a mixture of tetrahydrofuran (20 mL) and 2.0M aqueous LiOH (15 mL), then stirred vigorously at ambient temperature for 30 minutes. Tetrahydrofuran was removed <i>in vacuo</i>, the aqueous layer neutralized with 1.2 N HCl and extracted with CH<sub>2</sub>Cl<sub>2</sub>. The organic layer was dried over magnesium sulfate and removed <i>in vacuo</i> to produce an oily residue. Upon diluting the residue in dichloromethane a reddish-brown solid formed which was filtered and dried to yield compound <b>9</b> (2.00 grams, 9.65 mmol, 38% yield over 2 steps, LCMS >98%).</p><p>Compound <b>9</b> (650 mg, 3.14 mmol), 3-amino-5-methyl-isoxazole (616 mg, 6.28 mmol), PyClU (2.00 g, 6.28 mmol), and DIEA (1.36 mL, 7.85 mmol) were added to dichloroethane (25 mL) and microwave irradiated at 110 °C for 20 minutes. After cooling, the solvent was removed <i>in vacuo</i> and the remaining residue purified on a silica gel column (0–70% ethyl acetate:hexanes over 33 min) to yield compound <b>10</b> (642 mg, 2.23 mmol, 71% yield, LCMS >98%). Compound <b>10</b> (502 mg, 1.77 mmol) was dissolved in 25 mL (9:1, methanol:water) and Oxone (10.0 g, 17.7 mmol) was added. Stirring at ambient temperature continued overnight. Water (20 mL) was added and the mixture extracted with ethyl acetate (3x20 mL). The organics were combined, dried over magnesium sulfate, and concentrated <i>in vacuo</i> to give an oily residue which was purified on silica gel (0–50% ethyl acetate:hexanes over 19 min) to yield compound <b>11</b> (500 mg, 1.57 mmol, 88% yield, LCMS >98%). In a 5 mL microwave vial, compound <b>11</b> (55.0 mg, 0.174 mmol) was dissolved in DMF (3 mL) and cooled to 0 °C. Sodium hydride (60% by weight, 14.0 mg, 0.348 mmol) was then added in one portion and the reaction mixture vigorously stirred at 0 °C for 15 minutes. 4-bromo-2-bromomethyl-1-flouro-benzene (51.0 mg, 0.191 mmol) was added in one portion and the reaction mixture was stirred while being allowed to warm to ambient temperature over 3 hours. The reaction mixture was quenched with water (2 mL) and the solution was extracted with ethyl acetate (3x4 mL). The combined organics were dried over magnesium sulfate, concentrated <i>in vacuo</i> to give an oily residue which was purified on silica gel (0–70% ethyl acetate:hexanes over 19 min) to yield <b>CID 44475955</b> (45 mg, 0.088 mmol, 51% yield). LCMS >98% 214 nm, R<sub>T</sub> = 1.34 min, m/z = 506 ([<sup>79</sup>Br]m+1), 508 ([<sup>81</sup>Br]m+1). <sup>1</sup>H NMR (400 MHz, DMSO-<i>d</i><i><sub>6</sub></i>) 11.27 (s, 1H), 8.23 (s, 1H), 7.82 (d, <i>J</i> = 8.0 Hz, 1H), 7.63 (d, <i>J</i> = 8.0 Hz, 1H), 7.56–7.58 (m, 1H), 7.47 (dd, <i>J</i> = 2.4 Hz, 6.4 Hz, 1H), 7.35–7.23 (m, 3H), 6.54 (s, 1H), 5.62 (s, 2H), 4.43 (s, 2H), 2.37 (s, 3H), HRMS found: 506.0184; calculated for C<sub>21</sub>H<sub>17</sub>BrFN<sub>3</sub>O<sub>4</sub>S: 506.0185.</p></div></div><div id="ml169.s16"><h3>MLS#s</h3><p>002700179 (Probe, 500 mg), 002700180, 002700181, 002700182, 002700183, 002700184</p></div></div><div id="ml169.rl1"><h2 id="_ml169_rl1_">Bibliography</h2><dl class="temp-labeled-list"><dl class="bkr_refwrap"><dt>1.</dt><dd><div class="bk_ref" id="ml169.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="ml169.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="ml169.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="ml169.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="ml169.r5">Eglen RM, Choppin A, Dillon MP, Hedge S. <span><span class="ref-journal">Curr. Opin. Chem. Biol. </span>1999;<span class="ref-vol">3</span>:426–432.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/10419852" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10419852</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>6.</dt><dd><div class="bk_ref" id="ml169.r6">Felder CC, Bymaster FP, Ward J, DeLapp N. <span><span class="ref-journal">J.Med. Chem. </span>2000;<span class="ref-vol">43</span>:4333–4353.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/11087557" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11087557</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>7.</dt><dd><div class="bk_ref" id="ml169.r7">Bodick NC, Ofen WW, Levey AI, Cutler NR, Gauthier SG, Satlin A, Shannon HE, Tollefson GD, Rasmussen K, Bymster FP, Hurley DJ, Potter WZ, Paul SM. <span><span class="ref-journal">Arch. Neurol. </span>1997;<span class="ref-vol">54</span>:465–473.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/9109749" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9109749</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>8.</dt><dd><div class="bk_ref" id="ml169.r8">Caccamo A, Oddo S, Billings LM, Green KN, Martinez-Coria H, Fisher A, LaFerla FM. <span><span class="ref-journal">Neuron. </span>2006;<span class="ref-vol">49</span>:671–682.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16504943" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16504943</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>9.</dt><dd><div class="bk_ref" id="ml169.r9">Fisher A. <span><span class="ref-journal">Neurodegener. Dis. </span>2008;<span class="ref-vol">5</span>:237–240.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/18322400" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18322400</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>10.</dt><dd><div class="bk_ref" id="ml169.r10">Shekhar A, Potter WZ, Lightfoot J, Lienemann J, Dube S, Mallinckrodt C, Bymaster FP, McKinzie DL, Felder CC. <span><span class="ref-journal">Am. J. Psychiatry. </span>2008;<span class="ref-vol">165</span>:1033–1039.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/18593778" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18593778</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>11.</dt><dd><div class="bk_ref" id="ml169.r11">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>12.</dt><dd><div class="bk_ref" id="ml169.r12">Bridges TM, Lindsley CW. <span><span class="ref-journal">ACS Chem. Biol. </span>2008;<span class="ref-vol">3</span>:530–542.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/18652471" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18652471</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>13.</dt><dd><div class="bk_ref" id="ml169.r13">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>14.</dt><dd><div class="bk_ref" id="ml169.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="ml169.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="ml169.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="ml169.r17">Lebois EP, Bridges TM, Dawson ES, Kennedy Jp, Xiang Z, Jadhav SB, Yin H, Meiler J, Jones CK, Conn PJ, Weaver CD, Lindsley CW. <span><span class="ref-journal">ACS Chemical Neurosci. </span>2010;<span class="ref-vol">1</span>:104–121.</span> [<a href="/pmc/articles/PMC3180826/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3180826</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21961051" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21961051</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>18.</dt><dd><div class="bk_ref" id="ml169.r18">Spalding TA, Trotter C, Skajaerbaek N, Messier TL, Currier EA, Burstein ES, Li D, Hacksell U, Brann MR. <span><span class="ref-journal">Mol. Pharm. </span>2002;<span class="ref-vol">61</span>:1297–1302.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12021390" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12021390</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>19.</dt><dd><div class="bk_ref" id="ml169.r19">Jones CK, Brady AE, Davis AA, Xiang Z, Bubser M, Tantawy MN, Kane AS, Bridges TM, Kennedy JP, Bradley SR, Peterson TE, Ansari MW, Baldwin RM, Kessler RM, Deutch AY, Lah JJ, Levey AI, Lindsley CW, Conn PJ. <span><span class="ref-journal">J. Neurosci. </span>2008;<span class="ref-vol">28</span>:10422–10433.</span> [<a href="/pmc/articles/PMC2577155/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2577155</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/18842902" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18842902</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>20.</dt><dd><div class="bk_ref" id="ml169.r20">Brady A, Jones CK, Bridges TM, Kennedy PJ, Thompson AD, Breininger ML, Gentry PR, Yin H, Jadhav SB, Shirey J, Conn PJ, Lindsley CW. <span><span class="ref-journal">J. Pharm. & Exp. Ther. </span>2008;<span class="ref-vol">327</span>:941–953.</span> [<a href="/pmc/articles/PMC2745822/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2745822</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/18772318" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18772318</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>21.</dt><dd><div class="bk_ref" id="ml169.r21">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>]</div></dd></dl><dl class="bkr_refwrap"><dt>22.</dt><dd><div class="bk_ref" id="ml169.r22">Bridges TM, Kennedy JP, Cho HP, 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>23.</dt><dd><div class="bk_ref" id="ml169.r23">Bridges TM, Kennedy JP, Cho HP, Conn PJ, Lindsley CW. <span><span class="ref-journal">Bioorg Med Chem Lett. </span></span> in press.</div></dd></dl><dl class="bkr_refwrap"><dt>24.</dt><dd><div class="bk_ref" id="ml169.r24">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></div><div id="ml169.app1"><h2 id="_ml169_app1_">Appendix I. Solubility, Stability and Reactivity data as determined by Absorption Systems</h2><div id="ml169.s17"><h3>Solubility</h3><p>Solubility in PBS (at pH = 7.4) for <a href="/pcsubstance/?term=ML169[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML169</a> was 0.08 μM.</p></div><div id="ml169.s18"><h3>Stability</h3><p>Stability (at room temperature = 23 °C) for <a href="/pcsubstance/?term=ML169[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML169</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 not reported, but the assay variability over the course of the experiment ranged from a low of 89% (at 15 minutes) to a high of 142% (at 1 hour).</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml169tu2"><a href="/books/NBK50704/table/ml169.tu2/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figml169tu2" rid-ob="figobml169tu2"><img class="small-thumb" src="/books/NBK50704/table/ml169.tu2/?report=thumb" src-large="/books/NBK50704/table/ml169.tu2/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ml169.tu2"><a href="/books/NBK50704/table/ml169.tu2/?report=objectonly" target="object" rid-ob="figobml169tu2">Table</a></h4></div></div></div><div id="ml169.s19"><h3>Reactivity</h3><p>As assessed through a glutathione (GSH) trapping experiment in phosphate buffered saline (with a substrate concentration of typically 5–50 μM and a GSH concentration of 5 mM, at t = 60 minutes) <a href="/pcsubstance/?term=ML169[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML169</a> was found to not form any detectable GSH adducts.<sup><a href="#ml169.fn1">*</a></sup></p></div></div><div id="ml169.app2"><h2 id="_ml169_app2_">Appendix II. Liquid Chromatography-Mass Spectrometry (LCMS) and Nuclear Magnetic Resonance (NMR) as prepared by Vanderbilt Specialized Chemistry Center</h2><div id="ml169.fu3" class="figure"><div class="graphic"><img src="/books/NBK50704/bin/ml169fu14.jpg" alt="Image ml169fu14" /></div></div><div id="ml169.fu4" class="figure"><div class="graphic"><img src="/books/NBK50704/bin/ml169fu15.jpg" alt="Image ml169fu15" /></div></div><div id="ml169.fu5" class="figure"><div class="graphic"><img src="/books/NBK50704/bin/ml169fu16.jpg" alt="Image ml169fu16" /></div></div><div id="ml169.fu6" class="figure bk_fig"><div class="graphic"><img src="/books/NBK50704/bin/ml169fu17.jpg" alt="Element Composition Report." /></div><h3><span class="title">Element Composition Report</span></h3></div><div id="ml169.fu7" class="figure"><div class="graphic"><img src="/books/NBK50704/bin/ml169fu18.jpg" alt="Image ml169fu18" /></div></div><div id="ml169.fu8" class="figure"><div class="graphic"><img src="/books/NBK50704/bin/ml169fu19.jpg" alt="Image ml169fu19" /></div></div></div><h2 id="NBK50704_footnotes">Footnotes</h2><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>*</dt><dd><div id="ml169.fn1"><p class="no_top_margin">Solubility (PBS at pH = 7.4), Stability and Reactivity experiments were conducted at Absorption Systems. For additional information see: <a href="https://www.absorption.com/site" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">https://www<wbr style="display:inline-block"></wbr>​.absorption.com/site</a></p></div></dd></dl></dl><div id="bk_toc_contnr"></div></div></div><div class="fm-sec"><h2 id="_NBK50704_pubdet_">Publication Details</h2><h3>Author Information and Affiliations</h3><p class="contrib-group"><h4>Authors</h4><span itemprop="author">Thomas M Bridges</span>, <span itemprop="author">Paul R Reid</span>, <span itemprop="author">L Michelle Lewis</span>, <span itemprop="author">Eric S Dawson</span>, <span itemprop="author">C David Weaver</span>, <span itemprop="author">Michael R Wood</span>, and <span itemprop="author">Craig W Lindsley</span><sup>1</sup>.</p><h4>Contact</h4><div class="affiliation"><sup>1</sup> <span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ude.tlibrednav@yelsdnil.giarc" class="oemail">ude.tlibrednav@yelsdnil.giarc</a></div><h3>Publication History</h3><p class="small">Received: <span itemprop="datePublished">March 31, 2010</span>; Last Update: <span itemprop="dateModified">October 29, 2010</span>.</p><h3>Copyright</h3><div><div class="half_rhythm"><a href="/books/about/copyright/">Copyright Notice</a></div></div><h3>Publisher</h3><p>National Center for Biotechnology Information (US), Bethesda (MD)</p><h3>NLM Citation</h3><p>Bridges TM, Reid PR, Lewis LM, et al. Discovery and development of a second highly selective M1 Positive Allosteric Modulator (PAM) 2010 Mar 31 [Updated 2010 Oct 29]. 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/ml170/?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/ml168/?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="figobml169fu1"><div id="ml169.fu1" class="figure"><div class="graphic"><img data-src="/books/NBK50704/bin/ml169fu1.jpg" alt="Image ml169fu1" /></div></div></article><article data-type="table-wrap" id="figobml169tu1"><div id="ml169.tu1" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK50704/table/ml169.tu1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml169.tu1_lrgtbl__"><table><thead><tr><th id="hd_h_ml169.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">CID/ML#</th><th id="hd_h_ml169.tu1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Target Name</th><th id="hd_h_ml169.tu1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">IC<sub>50</sub>/EC<sub>50</sub> (nM) [SID, AID]</th><th id="hd_h_ml169.tu1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Anti-target Name(s)</th><th id="hd_h_ml169.tu1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">IC<sub>50</sub>/EC<sub>50</sub> (μM) [SID, AID]</th><th id="hd_h_ml169.tu1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Selectivity</th><th id="hd_h_ml169.tu1_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;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_ml169.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">CID-44475955<br /><a href="/pcsubstance/?term=ML169[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML169</a></td><td headers="hd_h_ml169.tu1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">M<sub>1</sub></td><td headers="hd_h_ml169.tu1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">1380 [<a href="https://pubchem.ncbi.nlm.nih.gov/substance/85756541" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID-85756541</a>,<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2651" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-2651</a>]</td><td headers="hd_h_ml169.tu1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">M<sub>2</sub>, M<sub>3</sub>, M<sub>4</sub>, M<sub>5</sub><br /><br />Ricerca Lead Profiling</td><td headers="hd_h_ml169.tu1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">> 30 μM [<a href="https://pubchem.ncbi.nlm.nih.gov/substance/85756541" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID-85756541</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2430" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-2430</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2428" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-2428</a>,
|
|
<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2438" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-2438</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2433" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-2433</a>]</td><td headers="hd_h_ml169.tu1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">>30</td><td headers="hd_h_ml169.tu1_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><br />ACh Fold-shift
|
|
(45-fold)<br /><br />[<a href="https://pubchem.ncbi.nlm.nih.gov/substance/85756541" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID-85756541</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2434" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-2434</a>]</td></tr></tbody></table></div></div></article><article data-type="fig" id="figobml169f2"><div id="ml169.f2" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK50704/bin/ml169f2.jpg" alt="Figure 2. M1 PAMs, CID 44251556 and BQCA." /></div><h3><span class="label">Figure 2</span><span class="title">M<sub>1</sub> PAMs, CID 44251556 and BQCA</span></h3></div></article><article data-type="fig" id="figobml169f1"><div id="ml169.f1" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK50704/bin/ml169f1.jpg" alt="Figure 1. CRCs at M1–M5 for HTS lead CID 2157678." /></div><h3><span class="label">Figure 1</span><span class="title">CRCs at M<sub>1</sub>–M<sub>5</sub> for HTS lead CID 2157678</span></h3></div></article><article data-type="fig" id="figobml169f3"><div id="ml169.f3" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK50704/bin/ml169f3.jpg" alt="Figure 3. Initial optimization strategy for CID 2157678." /></div><h3><span class="label">Figure 3</span><span class="title">Initial optimization strategy for CID 2157678</span></h3></div></article><article data-type="fig" id="figobml169f7"><div id="ml169.f7" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK50704/bin/ml169f7.jpg" alt="Scheme 1. Synthesis of CID 2157678 and the route to its analogs." /></div><h3><span class="label">Scheme 1</span><span class="title">Synthesis of CID 2157678 and the route to its analogs</span></h3></div></article><article data-type="table-wrap" id="figobml169t1"><div id="ml169.t1" class="table"><h3><span class="label">Table 1</span><span class="title">Structures and activities of analogs <b>5</b></span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK50704/table/ml169.t1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml169.t1_lrgtbl__"><table class="no_top_margin"><thead><tr><th id="hd_h_ml169.t1_1_1_1_1" colspan="5" rowspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50704/bin/ml169fu2.jpg" alt="Image ml169fu2.jpg" /></div><span class="hr"></span></th></tr><tr><th headers="hd_h_ml169.t1_1_1_1_1" id="hd_h_ml169.t1_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Cmpd</th><th headers="hd_h_ml169.t1_1_1_1_1" id="hd_h_ml169.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID</th><th headers="hd_h_ml169.t1_1_1_1_1" id="hd_h_ml169.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">R</th><th headers="hd_h_ml169.t1_1_1_1_1" id="hd_h_ml169.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">M<sub>1</sub> EC<sub>50</sub> (μM)</th><th headers="hd_h_ml169.t1_1_1_1_1" id="hd_h_ml169.t1_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">%ACh Max</th></tr></thead><tbody><tr><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>5a</b></td><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">2157678</td><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">2-Cl phenyl</td><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">9.71</td><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_5" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">83</td></tr><tr><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>5b</b></td><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">44129591</td><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">3-Cl phenyl</td><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">5.82</td><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_5" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">96</td></tr><tr><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>5c</b></td><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">2157657</td><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">4-Cl phenyl</td><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">> 10</td><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_5" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">-</td></tr><tr><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>5d</b></td><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">44129592</td><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">2-OMe phenyl</td><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">> 10</td><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_5" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">-</td></tr><tr><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>5e</b></td><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">44129593</td><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">3-OMe phenyl</td><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">6.54</td><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_5" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">79</td></tr><tr><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>5f</b></td><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">44129594</td><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">4-OMe phenyl</td><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">> 10</td><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_5" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">-</td></tr><tr><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>5g</b></td><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">2157612</td><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">3-F phenyl</td><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">5.22</td><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_5" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">96</td></tr><tr><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>5h</b></td><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">44247542</td><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">3-Br phenyl</td><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">3.79</td><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_5" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">91</td></tr><tr><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>5i</b></td><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">44241483</td><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">3-CF<sub>3</sub> phenyl</td><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">> 10</td><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_5" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">-</td></tr><tr><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>5j</b></td><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">44241487</td><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">3-CN phenyl</td><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">> 10</td><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_5" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">-</td></tr><tr><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>5k</b></td><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">44634502</td><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">3,5-diBr phenyl</td><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">> 10</td><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_5" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">-</td></tr><tr><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>5l</b></td><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">44241486</td><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">3,4-diCl phenyl</td><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">> 10</td><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_5" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">-</td></tr><tr><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>5m</b></td><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">44129587</td><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">4-CF<sub>3</sub> phenyl</td><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">> 10</td><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_5" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">-</td></tr><tr><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>5n</b></td><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">44129588</td><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">4-OCF<sub>3</sub> phenyl</td><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">> 10</td><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_5" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">-</td></tr><tr><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>5o</b></td><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">44129590</td><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">2-F phenyl</td><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">> 10</td><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_5" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">-</td></tr><tr><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>5p</b></td><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">44129589</td><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">2,4-diF phenyl</td><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">> 10</td><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_5" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">-</td></tr><tr><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>5q</b></td><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">44129585</td><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">2-Br-4-F phenyl</td><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">> 10</td><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_5" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">-</td></tr><tr><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>5r</b></td><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">44216760</td><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">6-F pyridin-3-yl</td><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">> 10</td><td headers="hd_h_ml169.t1_1_1_1_1 hd_h_ml169.t1_1_1_2_5" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">-</td></tr></tbody></table></div></div></article><article data-type="fig" id="figobml169f4"><div id="ml169.f4" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK50704/bin/ml169f4.jpg" alt="Figure 4. A representative over-alkylation product from Scheme 1." /></div><h3><span class="label">Figure 4</span><span class="title">A representative over-alkylation product from <a class="figpopup" href="/books/NBK50704/figure/ml169.f7/?report=objectonly" target="object" rid-figpopup="figml169f7" rid-ob="figobml169f7">Scheme 1</a></span></h3></div></article><article data-type="table-wrap" id="figobml169t2"><div id="ml169.t2" class="table"><h3><span class="label">Table 2</span><span class="title">Structures and activities of analogs <b>6</b></span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK50704/table/ml169.t2/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml169.t2_lrgtbl__"><table class="no_top_margin"><thead><tr><th id="hd_h_ml169.t2_1_1_1_1" colspan="5" rowspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50704/bin/ml169fu3.jpg" alt="Image ml169fu3.jpg" /></div><span class="hr"></span></th></tr><tr><th headers="hd_h_ml169.t2_1_1_1_1" id="hd_h_ml169.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Cmpd</th><th headers="hd_h_ml169.t2_1_1_1_1" id="hd_h_ml169.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID</th><th headers="hd_h_ml169.t2_1_1_1_1" id="hd_h_ml169.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">R</th><th headers="hd_h_ml169.t2_1_1_1_1" id="hd_h_ml169.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">M<sub>1</sub> EC<sub>50</sub> (μM)</th><th headers="hd_h_ml169.t2_1_1_1_1" id="hd_h_ml169.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">%ACh Max</th></tr></thead><tbody><tr><td headers="hd_h_ml169.t2_1_1_1_1 hd_h_ml169.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>6a</b></td><td headers="hd_h_ml169.t2_1_1_1_1 hd_h_ml169.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">44247543</td><td headers="hd_h_ml169.t2_1_1_1_1 hd_h_ml169.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50704/bin/ml169fu4.jpg" alt="Image ml169fu4.jpg" /></div></td><td headers="hd_h_ml169.t2_1_1_1_1 hd_h_ml169.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3.21</td><td headers="hd_h_ml169.t2_1_1_1_1 hd_h_ml169.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">102</td></tr><tr><td headers="hd_h_ml169.t2_1_1_1_1 hd_h_ml169.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>6b</b></td><td headers="hd_h_ml169.t2_1_1_1_1 hd_h_ml169.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">44216758</td><td headers="hd_h_ml169.t2_1_1_1_1 hd_h_ml169.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50704/bin/ml169fu5.jpg" alt="Image ml169fu5.jpg" /></div></td><td headers="hd_h_ml169.t2_1_1_1_1 hd_h_ml169.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2.19</td><td headers="hd_h_ml169.t2_1_1_1_1 hd_h_ml169.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">90</td></tr><tr><td headers="hd_h_ml169.t2_1_1_1_1 hd_h_ml169.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>6c</b></td><td headers="hd_h_ml169.t2_1_1_1_1 hd_h_ml169.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">44475951</td><td headers="hd_h_ml169.t2_1_1_1_1 hd_h_ml169.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50704/bin/ml169fu6.jpg" alt="Image ml169fu6.jpg" /></div></td><td headers="hd_h_ml169.t2_1_1_1_1 hd_h_ml169.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">> 10</td><td headers="hd_h_ml169.t2_1_1_1_1 hd_h_ml169.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">-</td></tr><tr><td headers="hd_h_ml169.t2_1_1_1_1 hd_h_ml169.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>6d</b></td><td headers="hd_h_ml169.t2_1_1_1_1 hd_h_ml169.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">44241482</td><td headers="hd_h_ml169.t2_1_1_1_1 hd_h_ml169.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50704/bin/ml169fu7.jpg" alt="Image ml169fu7.jpg" /></div></td><td headers="hd_h_ml169.t2_1_1_1_1 hd_h_ml169.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">> 10</td><td headers="hd_h_ml169.t2_1_1_1_1 hd_h_ml169.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">-</td></tr><tr><td headers="hd_h_ml169.t2_1_1_1_1 hd_h_ml169.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>6e</b></td><td headers="hd_h_ml169.t2_1_1_1_1 hd_h_ml169.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">44216757</td><td headers="hd_h_ml169.t2_1_1_1_1 hd_h_ml169.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50704/bin/ml169fu8.jpg" alt="Image ml169fu8.jpg" /></div></td><td headers="hd_h_ml169.t2_1_1_1_1 hd_h_ml169.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">> 10</td><td headers="hd_h_ml169.t2_1_1_1_1 hd_h_ml169.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">-</td></tr><tr><td headers="hd_h_ml169.t2_1_1_1_1 hd_h_ml169.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>6f</b></td><td headers="hd_h_ml169.t2_1_1_1_1 hd_h_ml169.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">44475953</td><td headers="hd_h_ml169.t2_1_1_1_1 hd_h_ml169.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50704/bin/ml169fu9.jpg" alt="Image ml169fu9.jpg" /></div></td><td headers="hd_h_ml169.t2_1_1_1_1 hd_h_ml169.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">> 10</td><td headers="hd_h_ml169.t2_1_1_1_1 hd_h_ml169.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">-</td></tr><tr><td headers="hd_h_ml169.t2_1_1_1_1 hd_h_ml169.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>6g</b></td><td headers="hd_h_ml169.t2_1_1_1_1 hd_h_ml169.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">44475954</td><td headers="hd_h_ml169.t2_1_1_1_1 hd_h_ml169.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50704/bin/ml169fu10.jpg" alt="Image ml169fu10.jpg" /></div></td><td headers="hd_h_ml169.t2_1_1_1_1 hd_h_ml169.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">NH > 10</td><td headers="hd_h_ml169.t2_1_1_1_1 hd_h_ml169.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">-</td></tr><tr><td headers="hd_h_ml169.t2_1_1_1_1 hd_h_ml169.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>6h</b></td><td headers="hd_h_ml169.t2_1_1_1_1 hd_h_ml169.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">44475952</td><td headers="hd_h_ml169.t2_1_1_1_1 hd_h_ml169.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50704/bin/ml169fu11.jpg" alt="Image ml169fu11.jpg" /></div></td><td headers="hd_h_ml169.t2_1_1_1_1 hd_h_ml169.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">> 10</td><td headers="hd_h_ml169.t2_1_1_1_1 hd_h_ml169.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">-</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobml169t3"><div id="ml169.t3" class="table"><h3><span class="label">Table 3</span><span class="title">Structures and activities of analogs <b>7</b></span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK50704/table/ml169.t3/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml169.t3_lrgtbl__"><table class="no_top_margin"><thead><tr><th id="hd_h_ml169.t3_1_1_1_1" colspan="9" rowspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50704/bin/ml169fu12.jpg" alt="Image ml169fu12.jpg" /></div><span class="hr"></span></th></tr><tr><th headers="hd_h_ml169.t3_1_1_1_1" id="hd_h_ml169.t3_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Cmpd</th><th headers="hd_h_ml169.t3_1_1_1_1" id="hd_h_ml169.t3_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID</th><th headers="hd_h_ml169.t3_1_1_1_1" id="hd_h_ml169.t3_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">G</th><th headers="hd_h_ml169.t3_1_1_1_1" id="hd_h_ml169.t3_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">R<sup>1</sup></th><th headers="hd_h_ml169.t3_1_1_1_1" id="hd_h_ml169.t3_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">R<sup>2</sup></th><th headers="hd_h_ml169.t3_1_1_1_1" id="hd_h_ml169.t3_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">R<sup>4</sup></th><th headers="hd_h_ml169.t3_1_1_1_1" id="hd_h_ml169.t3_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">R<sup>6</sup></th><th headers="hd_h_ml169.t3_1_1_1_1" id="hd_h_ml169.t3_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">M <sub>1</sub> EC<sub>50</sub> (μM)</th><th headers="hd_h_ml169.t3_1_1_1_1" id="hd_h_ml169.t3_1_1_2_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">%ACh Max</th></tr></thead><tbody><tr><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>7a</b></td><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">44475949</td><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">A</td><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">H</td><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">H</td><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">F</td><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">H</td><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">> 10</td><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_9" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">-</td></tr><tr><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>7b</b></td><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">44216756</td><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Br</td><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">H</td><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">H</td><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">F</td><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">H</td><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">> 10</td><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_9" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">-</td></tr><tr><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>7c</b></td><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">44241484</td><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Cl</td><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">H</td><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">H</td><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">F</td><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">H</td><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">> 10</td><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_9" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">-</td></tr><tr><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>7d</b></td><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">44475946</td><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Br</td><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">F</td><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">H</td><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">H</td><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">H</td><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">5.37</td><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_9" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">103</td></tr><tr><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>7e</b></td><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">44475948</td><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">A</td><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">F</td><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">H</td><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">H</td><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">H</td><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">1.85</td><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_9" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">102</td></tr><tr><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>7f</b></td><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">44241485</td><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Cl</td><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">H</td><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">F</td><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">H</td><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">H</td><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">5.10</td><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_9" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">56</td></tr><tr><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>7g</b></td><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">44475947</td><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Br</td><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">H</td><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">F</td><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">H</td><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">H</td><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">> 10</td><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_9" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">-</td></tr><tr><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>7h</b></td><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">44475450</td><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">A</td><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">H</td><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">F</td><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">H</td><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">H</td><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">4.40</td><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_9" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">103</td></tr><tr><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>7i</b></td><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">44475956</td><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">A</td><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">H</td><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">H</td><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">H</td><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">F</td><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">3.07</td><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_9" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">96</td></tr><tr><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>7j</b></td><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">44475955</td><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Br</td><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">H</td><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">H</td><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">H</td><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">F</td><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">1.38</td><td headers="hd_h_ml169.t3_1_1_1_1 hd_h_ml169.t3_1_1_2_9" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">84</td></tr></tbody></table></div></div></article><article data-type="fig" id="figobml169f5"><div id="ml169.f5" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK50704/bin/ml169f5.jpg" alt="Figure 5. The two most potent M1 PAMs developed from the lead CID 2157678." /></div><h3><span class="label">Figure 5</span><span class="title">The two most potent M<sub>1</sub> PAMs developed from the lead CID 2157678</span></h3></div></article><article data-type="fig" id="figobml169f6"><div id="ml169.f6" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK50704/bin/ml169f6.jpg" alt="Figure 6. A) CRCs for CID 44475955 at M1–M5; B) CRCs for CID 44475948 at M1–M5; C) Fold-Shift for CID 44475955 and CID 44475948 at 30 μM." /></div><h3><span class="label">Figure 6</span><span class="title">A) CRCs for CID 44475955 at M<sub>1</sub>–M<sub>5</sub>; B) CRCs for CID 44475948 at M<sub>1</sub>–M<sub>5</sub>; C) Fold-Shift for CID 44475955 and CID 44475948 at 30 μM.</span></h3></div></article><article data-type="table-wrap" id="figobml169t4"><div id="ml169.t4" class="table"><h3><span class="label">Table 4</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/NBK50704/table/ml169.t4/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml169.t4_lrgtbl__"><table class="no_top_margin"><thead><tr><th id="hd_h_ml169.t4_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Property</th><th id="hd_h_ml169.t4_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CID 44475955</th><th id="hd_h_ml169.t4_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CID 44475948</th><th id="hd_h_ml169.t4_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MDDR Phase I</th><th id="hd_h_ml169.t4_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MDDR Launched</th></tr></thead><tbody><tr><td headers="hd_h_ml169.t4_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MW</td><td headers="hd_h_ml169.t4_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">506.3</td><td headers="hd_h_ml169.t4_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">511.5</td><td headers="hd_h_ml169.t4_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">438.98</td><td headers="hd_h_ml169.t4_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">415.20</td></tr><tr><td headers="hd_h_ml169.t4_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">cLogP</td><td headers="hd_h_ml169.t4_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">3.92</td><td headers="hd_h_ml169.t4_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">3.24</td><td headers="hd_h_ml169.t4_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">3.21</td><td headers="hd_h_ml169.t4_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2.21</td></tr><tr><td headers="hd_h_ml169.t4_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">TPSA</td><td headers="hd_h_ml169.t4_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">94.20</td><td headers="hd_h_ml169.t4_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">122.88</td><td headers="hd_h_ml169.t4_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">97.06</td><td headers="hd_h_ml169.t4_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">91.78</td></tr><tr><td headers="hd_h_ml169.t4_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Hdon</td><td headers="hd_h_ml169.t4_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1</td><td headers="hd_h_ml169.t4_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2</td><td headers="hd_h_ml169.t4_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2.12</td><td headers="hd_h_ml169.t4_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2.13</td></tr><tr><td headers="hd_h_ml169.t4_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Hacc</td><td headers="hd_h_ml169.t4_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">7</td><td headers="hd_h_ml169.t4_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">9</td><td headers="hd_h_ml169.t4_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">7.06</td><td headers="hd_h_ml169.t4_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">6.47</td></tr><tr><td headers="hd_h_ml169.t4_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">LogS</td><td headers="hd_h_ml169.t4_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">−7.18</td><td headers="hd_h_ml169.t4_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">−8.00</td><td headers="hd_h_ml169.t4_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">−4.96</td><td headers="hd_h_ml169.t4_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">−3.73</td></tr><tr><td headers="hd_h_ml169.t4_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">NrotB</td><td headers="hd_h_ml169.t4_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">5</td><td headers="hd_h_ml169.t4_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">6</td><td headers="hd_h_ml169.t4_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">7.08</td><td headers="hd_h_ml169.t4_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="figobml169fu2"><div id="ml169.fu2" class="figure"><div class="graphic"><img data-src="/books/NBK50704/bin/ml169fu13.jpg" alt="Image ml169fu13" /></div></div></article><article data-type="table-wrap" id="figobml169tu2"><div id="ml169.tu2" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK50704/table/ml169.tu2/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml169.tu2_lrgtbl__"><table><thead><tr><th id="hd_h_ml169.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></th><th id="hd_h_ml169.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_ml169.tu2_1_1_1_1" id="hd_h_ml169.tu2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Compound</th><th headers="hd_h_ml169.tu2_1_1_1_2" id="hd_h_ml169.tu2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0 Min</th><th headers="hd_h_ml169.tu2_1_1_1_2" id="hd_h_ml169.tu2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">15 Min</th><th headers="hd_h_ml169.tu2_1_1_1_2" id="hd_h_ml169.tu2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">30 Min</th><th headers="hd_h_ml169.tu2_1_1_1_2" id="hd_h_ml169.tu2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">1 Hour</th><th headers="hd_h_ml169.tu2_1_1_1_2" id="hd_h_ml169.tu2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2 Hour</th><th headers="hd_h_ml169.tu2_1_1_1_2" id="hd_h_ml169.tu2_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">24 Hour</th><th headers="hd_h_ml169.tu2_1_1_1_2" id="hd_h_ml169.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_ml169.tu2_1_1_1_1 hd_h_ml169.tu2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="/pcsubstance/?term=ML169[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML169</a></td><td headers="hd_h_ml169.tu2_1_1_1_2 hd_h_ml169.tu2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">100</td><td headers="hd_h_ml169.tu2_1_1_1_2 hd_h_ml169.tu2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">89</td><td headers="hd_h_ml169.tu2_1_1_1_2 hd_h_ml169.tu2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">99</td><td headers="hd_h_ml169.tu2_1_1_1_2 hd_h_ml169.tu2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">142</td><td headers="hd_h_ml169.tu2_1_1_1_2 hd_h_ml169.tu2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">91</td><td headers="hd_h_ml169.tu2_1_1_1_2 hd_h_ml169.tu2_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">103</td><td headers="hd_h_ml169.tu2_1_1_1_2 hd_h_ml169.tu2_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">---</td></tr></tbody></table></div></div></article><article data-type="fig" id="figobml169fu3"><div id="ml169.fu3" class="figure"><div class="graphic"><img data-src="/books/NBK50704/bin/ml169fu14.jpg" alt="Image ml169fu14" /></div></div></article><article data-type="fig" id="figobml169fu4"><div id="ml169.fu4" class="figure"><div class="graphic"><img data-src="/books/NBK50704/bin/ml169fu15.jpg" alt="Image ml169fu15" /></div></div></article><article data-type="fig" id="figobml169fu5"><div id="ml169.fu5" class="figure"><div class="graphic"><img data-src="/books/NBK50704/bin/ml169fu16.jpg" alt="Image ml169fu16" /></div></div></article><article data-type="fig" id="figobml169fu6"><div id="ml169.fu6" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK50704/bin/ml169fu17.jpg" alt="Element Composition Report." /></div><h3><span class="title">Element Composition Report</span></h3></div></article><article data-type="fig" id="figobml169fu7"><div id="ml169.fu7" class="figure"><div class="graphic"><img data-src="/books/NBK50704/bin/ml169fu18.jpg" alt="Image ml169fu18" /></div></div></article><article data-type="fig" id="figobml169fu8"><div id="ml169.fu8" class="figure"><div class="graphic"><img data-src="/books/NBK50704/bin/ml169fu19.jpg" alt="Image ml169fu19" /></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 portal107 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>
|