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<meta name="ncbi_db" content="books" /><meta name="ncbi_pdid" content="book-part" /><meta name="ncbi_acc" content="NBK184496" /><meta name="ncbi_domain" content="mlprobe" /><meta name="ncbi_report" content="record" /><meta name="ncbi_type" content="fulltext" /><meta name="ncbi_objectid" content="" /><meta name="ncbi_pcid" content="/NBK184496/" /><meta name="ncbi_pagename" content="Small Molecule Agonists for the Neurotensin 1 Receptor (NTR1 Agonists) - Probe Reports from the NIH Molecular Libraries Program - NCBI Bookshelf" /><meta name="ncbi_bookparttype" content="chapter" /><meta name="ncbi_app" content="bookshelf" />
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<title>Small Molecule Agonists for the Neurotensin 1 Receptor (NTR1 Agonists) - Probe Reports from the NIH Molecular Libraries Program - NCBI Bookshelf</title>
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<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="Small Molecule Agonists for the Neurotensin 1 Receptor (NTR1 Agonists)" /><meta name="citation_publisher" content="National Center for Biotechnology Information (US)" /><meta name="citation_date" content="2013/03/07" /><meta name="citation_author" content="Paul Hershberger" /><meta name="citation_author" content="Michael Hedrick" /><meta name="citation_author" content="Satyamaheshwar Peddibhotla" /><meta name="citation_author" content="Patrick Maloney" /><meta name="citation_author" content="Yujie Li" /><meta name="citation_author" content="Monika Milewski" /><meta name="citation_author" content="Palak Gosalia" /><meta name="citation_author" content="Wilson Gray" /><meta name="citation_author" content="Alka Mehta" /><meta name="citation_author" content="Eliot Sugarman" /><meta name="citation_author" content="Becky Hood" /><meta name="citation_author" content="Eigo Suyama" /><meta name="citation_author" content="Kevin Nguyen" /><meta name="citation_author" content="Susanne Heynen-Genel" /><meta name="citation_author" content="Stefan Vasile" /><meta name="citation_author" content="Sumeet Salaniwal" /><meta name="citation_author" content="Derek Stonich" /><meta name="citation_author" content="Ying Su" /><meta name="citation_author" content="Arianna Mangravita-Novo" /><meta name="citation_author" content="Michael Vicchiarelli" /><meta name="citation_author" content="Layton H. Smith" /><meta name="citation_author" content="Gregory Roth" /><meta name="citation_author" content="Jena Diwan" /><meta name="citation_author" content="Thomas D.Y. Chung" /><meta name="citation_author" content="Marc G. Caron" /><meta name="citation_author" content="James B. Thomas" /><meta name="citation_author" content="Anthony B. Pinkerton" /><meta name="citation_author" content="Lawrence R. Barak" /><meta name="citation_pmid" content="24501783" /><meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK184496/" /><link rel="schema.DC" href="http://purl.org/DC/elements/1.0/" /><meta name="DC.Title" content="Small Molecule Agonists for the Neurotensin 1 Receptor (NTR1 Agonists)" /><meta name="DC.Type" content="Text" /><meta name="DC.Publisher" content="National Center for Biotechnology Information (US)" /><meta name="DC.Contributor" content="Paul Hershberger" /><meta name="DC.Contributor" content="Michael Hedrick" /><meta name="DC.Contributor" content="Satyamaheshwar Peddibhotla" /><meta name="DC.Contributor" content="Patrick Maloney" /><meta name="DC.Contributor" content="Yujie Li" /><meta name="DC.Contributor" content="Monika Milewski" /><meta name="DC.Contributor" content="Palak Gosalia" /><meta name="DC.Contributor" content="Wilson Gray" /><meta name="DC.Contributor" content="Alka Mehta" /><meta name="DC.Contributor" content="Eliot Sugarman" /><meta name="DC.Contributor" content="Becky Hood" /><meta name="DC.Contributor" content="Eigo Suyama" /><meta name="DC.Contributor" content="Kevin Nguyen" /><meta name="DC.Contributor" content="Susanne Heynen-Genel" /><meta name="DC.Contributor" content="Stefan Vasile" /><meta name="DC.Contributor" content="Sumeet Salaniwal" /><meta name="DC.Contributor" content="Derek Stonich" /><meta name="DC.Contributor" content="Ying Su" /><meta name="DC.Contributor" content="Arianna Mangravita-Novo" /><meta name="DC.Contributor" content="Michael Vicchiarelli" /><meta name="DC.Contributor" content="Layton H. Smith" /><meta name="DC.Contributor" content="Gregory Roth" /><meta name="DC.Contributor" content="Jena Diwan" /><meta name="DC.Contributor" content="Thomas D.Y. Chung" /><meta name="DC.Contributor" content="Marc G. Caron" /><meta name="DC.Contributor" content="James B. Thomas" /><meta name="DC.Contributor" content="Anthony B. Pinkerton" /><meta name="DC.Contributor" content="Lawrence R. Barak" /><meta name="DC.Date" content="2013/03/07" /><meta name="DC.Identifier" content="https://www.ncbi.nlm.nih.gov/books/NBK184496/" /><meta name="description" content="A non-high throughput screening (HTS) scaffold-hop program identified the probe candidate ML301 and associated analogs. ML301 met probe nomination criteria, exhibiting full agonist behavior (79 – 93%) with an half maximal effective concentration (EC50) of 2.0 – 4.1 μM against neurotensin 1 receptor (NTR1) in the primary assay. This probe satisfied our secondary assay requirements; namely, the Ca2+ mobilization Fluorescence Imaging Plate Reader (FLIPR) assay (93% efficacy at 298 nM) and good selectivity relative to NTR2 and G protein-coupled receptor (GPR)35. In further profiling, ML301 showed low potential for promiscuity and improved pharmacological data when compared to existing art. A scaffold hop program was initiated in parallel with the originally planned high throughput screening based approach. This approach identified new scaffolds of which the most promising was a quinazoline derivative represented by the singleton MLS-0233108. Medicinal chemistry optimization of MLS-0233108 led to ML314, the most potent molecule in this second series that exhibited full agonist behavior (100 %) on NTR1 (EC50 = 1.9 μM). ML314 showed good selectivity against NTR2 and GPR35, but did not stimulate Ca2+ mobilization. ML314 is potentially a biased agonist operating via the β-arrestin pathway rather than the traditional Gq coupled pathway. Signaling mediated by β-arrestin has distinct biochemical and functional consequences that may lead to physiological advantages as described below. This probe report describes the discovery and properties of ML301 and summarizes the HTS and follow-up campaign, which identified ML314." /><meta name="og:title" content="Small Molecule Agonists for the Neurotensin 1 Receptor (NTR1 Agonists)" /><meta name="og:type" content="book" /><meta name="og:description" content="A non-high throughput screening (HTS) scaffold-hop program identified the probe candidate ML301 and associated analogs. ML301 met probe nomination criteria, exhibiting full agonist behavior (79 – 93%) with an half maximal effective concentration (EC50) of 2.0 – 4.1 μM against neurotensin 1 receptor (NTR1) in the primary assay. This probe satisfied our secondary assay requirements; namely, the Ca2+ mobilization Fluorescence Imaging Plate Reader (FLIPR) assay (93% efficacy at 298 nM) and good selectivity relative to NTR2 and G protein-coupled receptor (GPR)35. In further profiling, ML301 showed low potential for promiscuity and improved pharmacological data when compared to existing art. A scaffold hop program was initiated in parallel with the originally planned high throughput screening based approach. This approach identified new scaffolds of which the most promising was a quinazoline derivative represented by the singleton MLS-0233108. Medicinal chemistry optimization of MLS-0233108 led to ML314, the most potent molecule in this second series that exhibited full agonist behavior (100 %) on NTR1 (EC50 = 1.9 μM). ML314 showed good selectivity against NTR2 and GPR35, but did not stimulate Ca2+ mobilization. ML314 is potentially a biased agonist operating via the β-arrestin pathway rather than the traditional Gq coupled pathway. Signaling mediated by β-arrestin has distinct biochemical and functional consequences that may lead to physiological advantages as described below. This probe report describes the discovery and properties of ML301 and summarizes the HTS and follow-up campaign, which identified ML314." /><meta name="og:url" content="https://www.ncbi.nlm.nih.gov/books/NBK184496/" /><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/ml314/" /><link rel="canonical" href="https://www.ncbi.nlm.nih.gov/books/NBK184496/" /><link rel="stylesheet" href="/corehtml/pmc/css/figpopup.css" type="text/css" media="screen" /><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" /><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><script type="text/javascript" src="/corehtml/pmc/js/jquery.hoverIntent.min.js"> </script><script type="text/javascript" src="/corehtml/pmc/js/common.min.js?_=3.18"> </script><script type="text/javascript" src="/corehtml/pmc/js/large-obj-scrollbars.min.js"> </script><script type="text/javascript">window.name="mainwindow";</script><script type="text/javascript" src="/corehtml/pmc/js/bookshelf/2.26/book-toc.min.js"> </script><script type="text/javascript" src="/corehtml/pmc/js/bookshelf/2.26/books.min.js"> </script><meta name="book-collection" content="NONE" />
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<div class="pre-content"><div><div class="bk_prnt"><p class="small">NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.</p><p>Probe Reports from the NIH Molecular Libraries Program [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2010-. </p></div><div class="iconblock clearfix whole_rhythm no_top_margin bk_noprnt"><a class="img_link icnblk_img" title="Table of Contents Page" href="/books/n/mlprobe/"><img class="source-thumb" src="/corehtml/pmc/pmcgifs/bookshelf/thumbs/th-mlprobe-lrg.png" alt="Cover of Probe Reports from the NIH Molecular Libraries Program" height="100px" width="80px" /></a><div class="icnblk_cntnt eight_col"><h2>Probe Reports from the NIH Molecular Libraries Program [Internet].</h2><a data-jig="ncbitoggler" href="#__NBK184496_dtls__">Show details</a><div style="display:none" class="ui-widget" id="__NBK184496_dtls__"><div>Bethesda (MD): National Center for Biotechnology Information (US); 2010-.</div></div><div class="half_rhythm"><ul class="inline_list"><li style="margin-right:1em"><a class="bk_cntns" href="/books/n/mlprobe/">Contents</a></li></ul></div><div class="bk_noprnt"><form method="get" action="/books/n/mlprobe/" id="bk_srch"><div class="bk_search"><label for="bk_term" class="offscreen_noflow">Search term</label><input type="text" title="Search this book" id="bk_term" name="term" value="" data-jig="ncbiclearbutton" /> <input type="submit" class="jig-ncbibutton" value="Search this book" submit="false" style="padding: 0.1em 0.4em;" /></div></form></div></div><div class="icnblk_cntnt two_col"><div class="pagination bk_noprnt"><a class="active page_link prev" href="/books/n/mlprobe/ml315/" title="Previous page in this title">< Prev</a><a class="active page_link next" href="/books/n/mlprobe/ml312/" title="Next page in this title">Next ></a></div></div></div></div></div>
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<div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><h1 id="_NBK184496_"><span class="title" itemprop="name">Small Molecule Agonists for the Neurotensin 1 Receptor (NTR1 Agonists)</span></h1><p class="contrib-group"><span itemprop="author">Paul Hershberger</span>, <span itemprop="author">Michael Hedrick</span>, <span itemprop="author">Satyamaheshwar Peddibhotla</span>, <span itemprop="author">Patrick Maloney</span>, <span itemprop="author">Yujie Li</span>, <span itemprop="author">Monika Milewski</span>, <span itemprop="author">Palak Gosalia</span>, <span itemprop="author">Wilson Gray</span>, <span itemprop="author">Alka Mehta</span>, <span itemprop="author">Eliot Sugarman</span>, <span itemprop="author">Becky Hood</span>, <span itemprop="author">Eigo Suyama</span>, <span itemprop="author">Kevin Nguyen</span>, <span itemprop="author">Susanne Heynen-Genel</span>, <span itemprop="author">Stefan Vasile</span>, <span itemprop="author">Sumeet Salaniwal</span>, <span itemprop="author">Derek Stonich</span>, <span itemprop="author">Ying Su</span>, <span itemprop="author">Arianna Mangravita-Novo</span>, <span itemprop="author">Michael Vicchiarelli</span>, <span itemprop="author">Layton H. Smith</span>, <span itemprop="author">Gregory Roth</span>, <span itemprop="author">Jena Diwan</span>, <span itemprop="author">Thomas D.Y. Chung</span>, <span itemprop="author">Marc G. Caron</span>, <span itemprop="author">James B. Thomas</span>, <span itemprop="author">Anthony B. Pinkerton</span>, and <span itemprop="author">Lawrence R. Barak</span>.</p><a data-jig="ncbitoggler" href="#__NBK184496_ai__" style="border:0;text-decoration:none">Author Information and Affiliations</a><div style="display:none" class="ui-widget" id="__NBK184496_ai__"><p class="contrib-group"><h4>Authors</h4><span itemprop="author">Paul Hershberger</span>,<sup>1</sup><sup>,<a href="#ml314.fn1" class="bk_pop">*</a></sup> <span itemprop="author">Michael Hedrick</span>,<sup>2</sup> <span itemprop="author">Satyamaheshwar Peddibhotla</span>,<sup>1</sup><sup>,<a href="#ml314.fn1" class="bk_pop">*</a></sup> <span itemprop="author">Patrick Maloney</span>,<sup>1</sup> <span itemprop="author">Yujie Li</span>,<sup>2</sup> <span itemprop="author">Monika Milewski</span>,<sup>2</sup> <span itemprop="author">Palak Gosalia</span>,<sup>2</sup> <span itemprop="author">Wilson Gray</span>,<sup>2</sup> <span itemprop="author">Alka Mehta</span>,<sup>1</sup> <span itemprop="author">Eliot Sugarman</span>,<sup>1</sup> <span itemprop="author">Becky Hood</span>,<sup>1</sup> <span itemprop="author">Eigo Suyama</span>,<sup>1</sup> <span itemprop="author">Kevin Nguyen</span>,<sup>1</sup> <span itemprop="author">Susanne Heynen-Genel</span>,<sup>2</sup> <span itemprop="author">Stefan Vasile</span>,<sup>1</sup> <span itemprop="author">Sumeet Salaniwal</span>,<sup>2</sup> <span itemprop="author">Derek Stonich</span>,<sup>2</sup> <span itemprop="author">Ying Su</span>,<sup>2</sup> <span itemprop="author">Arianna Mangravita-Novo</span>,<sup>1</sup> <span itemprop="author">Michael Vicchiarelli</span>,<sup>1</sup> <span itemprop="author">Layton H. Smith</span>,<sup>1</sup> <span itemprop="author">Gregory Roth</span>,<sup>1</sup> <span itemprop="author">Jena Diwan</span>,<sup>2</sup> <span itemprop="author">Thomas D.Y. Chung</span>,<sup>2</sup> <span itemprop="author">Marc G. Caron</span>,<sup>3</sup> <span itemprop="author">James B. Thomas</span>,<sup>4</sup> <span itemprop="author">Anthony B. Pinkerton</span>,<sup>2</sup><sup>,5</sup> and <span itemprop="author">Lawrence R. Barak</span><sup>3</sup>.</p><h4>Affiliations</h4><div class="affiliation"><sup>1</sup>
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Sanford-Burnham Center for Chemical Genomics at Sanford-Burnham Medical Research Institute, Orlando, Florida 32827, USA.</div><div class="affiliation"><sup>2</sup>
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Sanford-Burnham Center for Chemical Genomics at Sanford-Burnham Medical Research Institute, La Jolla, California 92037, USA.</div><div class="affiliation"><sup>3</sup>
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Duke University Medical Center, Durham, NC 27710, USA.</div><div class="affiliation"><sup>4</sup>
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RTI International, 3040 E Cornwallis Road, Durham, NC 27709, USA.</div><div class="affiliation"><sup>5</sup> Corresponding author: Anthony B. Pinkerton, Ph.D.<span class="before-email-separator"></span><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="gro.mahnrubdrofnas@notreknipa" class="oemail">gro.mahnrubdrofnas@notreknipa</a></div></div><p class="small">Received: <span itemprop="datePublished">April 8, 2012</span>; Last Update: <span itemprop="dateModified">March 7, 2013</span>.</p></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="_abs_rndgid_" itemprop="description"><p>A non-high throughput screening (HTS) scaffold-hop program identified the probe candidate <a href="/pcsubstance/?term=ML301[synonym]" ref="pagearea=abstract&targetsite=entrez&targetcat=term&targettype=pubchem">ML301</a> and associated analogs. <a href="/pcsubstance/?term=ML301[synonym]" ref="pagearea=abstract&targetsite=entrez&targetcat=term&targettype=pubchem">ML301</a> met probe nomination criteria, exhibiting full agonist behavior (79 – 93%) with an half maximal effective concentration (EC<sub>50)</sub> of 2.0 – 4.1 μM against neurotensin 1 receptor (NTR1) in the primary assay. This probe satisfied our secondary assay requirements; namely, the Ca<sup>2+</sup> mobilization Fluorescence Imaging Plate Reader (FLIPR) assay (93% efficacy at 298 nM) and good selectivity relative to NTR2 and G protein-coupled receptor (GPR)35. In further profiling, <a href="/pcsubstance/?term=ML301[synonym]" ref="pagearea=abstract&targetsite=entrez&targetcat=term&targettype=pubchem">ML301</a> showed low potential for promiscuity and improved pharmacological data when compared to existing art. A scaffold hop program was initiated in parallel with the originally planned high throughput screening based approach. This approach identified new scaffolds of which the most promising was a quinazoline derivative represented by the singleton MLS-0233108. Medicinal chemistry optimization of MLS-0233108 led to <a href="/pcsubstance/?term=ML314[synonym]" ref="pagearea=abstract&targetsite=entrez&targetcat=term&targettype=pubchem">ML314</a>, the most potent molecule in this second series that exhibited full agonist behavior (100 %) on NTR1 (EC<sub>50</sub> = 1.9 μM). <a href="/pcsubstance/?term=ML314[synonym]" ref="pagearea=abstract&targetsite=entrez&targetcat=term&targettype=pubchem">ML314</a> showed good selectivity against NTR2 and GPR35, but did not stimulate Ca<sup>2+</sup> mobilization. <a href="/pcsubstance/?term=ML314[synonym]" ref="pagearea=abstract&targetsite=entrez&targetcat=term&targettype=pubchem">ML314</a> is potentially a biased agonist operating via the β-arrestin pathway rather than the traditional G<sub>q</sub> coupled pathway. Signaling mediated by β-arrestin has distinct biochemical and functional consequences that may lead to physiological advantages as described below. This probe report describes the discovery and properties of <a href="/pcsubstance/?term=ML301[synonym]" ref="pagearea=abstract&targetsite=entrez&targetcat=term&targettype=pubchem">ML301</a> and summarizes the HTS and follow-up campaign, which identified <a href="/pcsubstance/?term=ML314[synonym]" ref="pagearea=abstract&targetsite=entrez&targetcat=term&targettype=pubchem">ML314</a>.</p></div><div class="h2"></div><p><b>Assigned Assay Grant #:</b> 1 R03 MH089653-01</p><p><b>Screening Center Name & PI:</b> Sanford Burnham Center for Chemical Genomics (SBCCG) & John C. Reed (PI)</p><p><b>Chemistry Center Name & PI:</b> Sanford Burnham Center for Chemical Genomics (SBCCG) & John C. Reed (PI)</p><p><b>Assay Submitter & Institution:</b> Lawrence R. Barak, Duke University Medical Center, Durham NC</p><p><b>Co-Assay Submitter & Institution:</b> James B. Thomas, RTI International</p><p><b>PubChem Summary Bioassay Identifier (AID):</b>
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<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/493055" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">493055</a></p><div id="ml314.rp"><h2 id="_ml314_rp_">Resulting Publications</h2><dl class="temp-labeled-list"><dt>1.</dt><dd><div class="bk_ref" id="ml314.rp1">Peddibhotla S., Hedrick M. P. et al. Discovery of ML314, a Brain Penetrant Nonpeptidic β-Arrestin Biased Agonist of the Neurotensin NTR1 Receptor. <span><span class="ref-journal">ACS Medicinal Chemistry Letters. </span>2013;<span class="ref-vol">4</span>(9):846–851.</span> [<a href="/pmc/articles/PMC3940307/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3940307</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24611085" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24611085</span></a>]</div></dd></dl></div><div id="ml314.s1"><h2 id="_ml314_s1_">Probe Structure & Characteristics</h2><p>This Center Probe Report describes two selective agonists of the neurotensin 1 receptor, <a href="/pcsubstance/?term=ML301[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML301</a>, which displays full agonist behavior in a β-arrestin pathway based assay as well as a calcium flux assay, and <a href="/pcsubstance/?term=ML314[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML314</a>, which displays full agonist behavior in a β-arrestin pathway based assay, but no activity in a calcium mobilization assay. Potency and selectivity characteristics for <a href="/pcsubstance/?term=ML301[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML301</a> and <a href="/pcsubstance/?term=ML314[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML314</a> are described in the summary table (<a class="figpopup" href="/books/NBK184496/table/ml314.t1/?report=objectonly" target="object" rid-figpopup="figml314t1" rid-ob="figobml314t1">Table 1</a>).</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml314t1"><a href="/books/NBK184496/table/ml314.t1/?report=objectonly" target="object" title="Table 1" class="img_link icnblk_img figpopup" rid-figpopup="figml314t1" rid-ob="figobml314t1"><img class="small-thumb" src="/books/NBK184496/table/ml314.t1/?report=thumb" src-large="/books/NBK184496/table/ml314.t1/?report=previmg" alt="Table 1. Summary of Probe activities." /></a><div class="icnblk_cntnt"><h4 id="ml314.t1"><a href="/books/NBK184496/table/ml314.t1/?report=objectonly" target="object" rid-ob="figobml314t1">Table 1</a></h4><p class="float-caption no_bottom_margin">Summary of Probe activities. </p></div></div><div id="ml314.fu1" class="figure"><div class="graphic"><img src="/books/NBK184496/bin/ml314fu1.jpg" alt="Image ml314fu1" /></div></div></div><div id="ml314.s2"><h2 id="_ml314_s2_">1. Recommendations for Scientific Use of the Probe</h2><p>Despite the fact that this receptor system was identified many years ago, very few non-peptide ligands have been described for the neurotensin 1 receptor (NTR1), particularly small molecule agonists with CNS activity. As discussed in the original grant application, there is evidence from neurotensin peptide research that strongly supports the use of neurotensin agonists in the pharmacologic intervention of addictive behavior. Therefore, a <i>non-peptide</i> agonist exhibiting <i>in vivo</i> properties, either residing in these probes or in analogs designed subsequently, will be of great value to the addiction research community.</p><p>Moreover, the presence of neurotensin receptors on dopaminergic neurons in the CNS suggests investigators studying the modulation of dopamine signaling will also utilize these probes. Ultimately, these probes or further successors will be quickly advanced to animal model testing for evaluation and modeling because of the potential they may have in the treatment of methamphetamine addiction. There is growing evidence in the field that agonism of several CNS receptors may lead to more efficacy against addiction. Both probes have some cross-activity to dopamine receptors and the dopamine transporter assays, though <a href="/pcsubstance/?term=ML314[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML314</a> is less selective against additional GPCRs in a panel competitive binding assays than <a href="/pcsubstance/?term=ML304[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML304</a>, so together they may provide tools for use in future comparative pharmacological studies to test this hypothesis of increased efficacy with less selective agonists.</p></div><div id="ml314.s3"><h2 id="_ml314_s3_">2. Materials and Methods</h2><p>The details of the primary HTS and additional assays can be found in the “Assay Description” section in the PubChem BioAssay view under the AIDs as listed in <a class="figpopup" href="/books/NBK184496/table/ml314.t2/?report=objectonly" target="object" rid-figpopup="figml314t2" rid-ob="figobml314t2">Table 2</a>.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml314t2"><a href="/books/NBK184496/table/ml314.t2/?report=objectonly" target="object" title="Table 2" class="img_link icnblk_img figpopup" rid-figpopup="figml314t2" rid-ob="figobml314t2"><img class="small-thumb" src="/books/NBK184496/table/ml314.t2/?report=thumb" src-large="/books/NBK184496/table/ml314.t2/?report=previmg" alt="Table 2. Summary of Assays and AIDs." /></a><div class="icnblk_cntnt"><h4 id="ml314.t2"><a href="/books/NBK184496/table/ml314.t2/?report=objectonly" target="object" rid-ob="figobml314t2">Table 2</a></h4><p class="float-caption no_bottom_margin">Summary of Assays and AIDs. </p></div></div><div id="ml314.s4"><h3>2.1. Assays</h3><p><a class="figpopup" href="/books/NBK184496/table/ml314.t2/?report=objectonly" target="object" rid-figpopup="figml314t2" rid-ob="figobml314t2">Table 2</a> summarizes the details for the assays that drove this probe project.</p></div><div id="ml314.s5"><h3>2.2. Probe Chemical Characterization</h3><div id="ml314.s6"><h4>Chemical name of probe compound & structure including stereochemistry</h4><p>The IUPAC name of the probe is (2<i>S</i>)-2-{[2-(2,6-dimethoxyphenyl)-1-(7-chloro(4-quinolyl))imidazol-4-yl]carbonylamino}-4-methylpentanoic acid (<a href="/pcsubstance/?term=ML301[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML301</a>). The IUPAC name of <a href="/pcsubstance/?term=ML314[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML314</a> is 2-cyclopropyl-6,7-dimethoxy-4-(4-(2-methoxyphenyl)- piperazin-1-yl)quinazoline.</p><p>The specific batches prepared, tested and submitted to the MLSMR are archived as <a href="https://pubchem.ncbi.nlm.nih.gov/substance/126723249" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 126723249</a> corresponding to CID 49837912 (<a href="/pcsubstance/?term=ML301[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML301</a>) and <a href="https://pubchem.ncbi.nlm.nih.gov/substance/134225039" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 134225039</a> corresponding to CID 53245590 (<a href="/pcsubstance/?term=ML314[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML314</a>) and their structures are shown in <a class="figpopup" href="/books/NBK184496/figure/ml314.f1/?report=objectonly" target="object" rid-figpopup="figml314f1" rid-ob="figobml314f1">Figure 1</a>.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml314f1" co-legend-rid="figlgndml314f1"><a href="/books/NBK184496/figure/ml314.f1/?report=objectonly" target="object" title="Figure 1" class="img_link icnblk_img figpopup" rid-figpopup="figml314f1" rid-ob="figobml314f1"><img class="small-thumb" src="/books/NBK184496/bin/ml314f1.gif" src-large="/books/NBK184496/bin/ml314f1.jpg" alt="Figure 1. Structures of ML301 and ML314." /></a><div class="icnblk_cntnt" id="figlgndml314f1"><h4 id="ml314.f1"><a href="/books/NBK184496/figure/ml314.f1/?report=objectonly" target="object" rid-ob="figobml314f1">Figure 1</a></h4><p class="float-caption no_bottom_margin">Structures of ML301 and ML314. </p></div></div><p>These probes are not commercially available. 25 mg samples of <a href="/pcsubstance/?term=ML301[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML301</a> and <a href="/pcsubstance/?term=ML314[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML314</a> synthesized at SBCCG, along with five analogs of each, have been deposited in the MLSMR (Evotec) (See Probe Submission <a class="figpopup" href="/books/NBK184496/table/ml314.t4/?report=objectonly" target="object" rid-figpopup="figml314t4" rid-ob="figobml314t4">Tables 4a</a> and <a class="figpopup" href="/books/NBK184496/table/ml314.t5/?report=objectonly" target="object" rid-figpopup="figml314t5" rid-ob="figobml314t5">4b</a>.)</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml314t4"><a href="/books/NBK184496/table/ml314.t4/?report=objectonly" target="object" title="Table 4a" class="img_link icnblk_img figpopup" rid-figpopup="figml314t4" rid-ob="figobml314t4"><img class="small-thumb" src="/books/NBK184496/table/ml314.t4/?report=thumb" src-large="/books/NBK184496/table/ml314.t4/?report=previmg" alt="Table 4a. Probe and Analog Submissions to MLSMR (Evotec) for NTR1 Agonists." /></a><div class="icnblk_cntnt"><h4 id="ml314.t4"><a href="/books/NBK184496/table/ml314.t4/?report=objectonly" target="object" rid-ob="figobml314t4">Table 4a</a></h4><p class="float-caption no_bottom_margin">Probe and Analog Submissions to MLSMR (Evotec) for NTR1 Agonists. </p></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml314t5"><a href="/books/NBK184496/table/ml314.t5/?report=objectonly" target="object" title="Table 4b" class="img_link icnblk_img figpopup" rid-figpopup="figml314t5" rid-ob="figobml314t5"><img class="small-thumb" src="/books/NBK184496/table/ml314.t5/?report=thumb" src-large="/books/NBK184496/table/ml314.t5/?report=previmg" alt="Table 4b. Analog Submissions to MLSMR (Evotec) for NTR1 Agonists." /></a><div class="icnblk_cntnt"><h4 id="ml314.t5"><a href="/books/NBK184496/table/ml314.t5/?report=objectonly" target="object" rid-ob="figobml314t5">Table 4b</a></h4><p class="float-caption no_bottom_margin">Analog Submissions to MLSMR (Evotec) for NTR1 Agonists. </p></div></div><p><b>Synthetic Routes:</b> Two potential synthetic routes are outlined for the synthesis of <a href="/pcsubstance/?term=ML301[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML301</a> in <a class="figpopup" href="/books/NBK184496/figure/ml314.f8/?report=objectonly" target="object" rid-figpopup="figml314f8" rid-ob="figobml314f8">Scheme 1</a> (preferred and alternate). Although the alternate method was fewer steps, its low yields and the high cost of 4-aminoquinoline building blocks made the longer method more preferred and practical for most cases of interest.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml314f8" co-legend-rid="figlgndml314f8"><a href="/books/NBK184496/figure/ml314.f8/?report=objectonly" target="object" title="Scheme 1" class="img_link icnblk_img figpopup" rid-figpopup="figml314f8" rid-ob="figobml314f8"><img class="small-thumb" src="/books/NBK184496/bin/ml314f8.gif" src-large="/books/NBK184496/bin/ml314f8.jpg" alt="Scheme 1. Synthesis of ML301." /></a><div class="icnblk_cntnt" id="figlgndml314f8"><h4 id="ml314.f8"><a href="/books/NBK184496/figure/ml314.f8/?report=objectonly" target="object" rid-ob="figobml314f8">Scheme 1</a></h4><p class="float-caption no_bottom_margin">Synthesis of ML301. Preferred route: Synthesis of ML301, conditions: a.<sup></sup> 1. NaOAc, water, 1,1-dibromo-3,3,3-trifluoroacetone, 100 °C, 30 min. 2. 2,6-dimethoxybenzaldehyde, ammonium hydroxide, water, methanol, 52%; b.<sup></sup> NaOH, water, 100 °C, <a href="/books/NBK184496/figure/ml314.f8/?report=objectonly" target="object" rid-ob="figobml314f8">(more...)</a></p></div></div><p>In contrast, one route for <a href="/pcsubstance/?term=ML314[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML314</a> is shown in <a class="figpopup" href="/books/NBK184496/figure/ml314.f9/?report=objectonly" target="object" rid-figpopup="figml314f9" rid-ob="figobml314f9">Scheme 2</a>, (following <a class="figpopup" href="/books/NBK184496/figure/ml314.f8/?report=objectonly" target="object" rid-figpopup="figml314f8" rid-ob="figobml314f8">Scheme 1</a>).</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml314f9" co-legend-rid="figlgndml314f9"><a href="/books/NBK184496/figure/ml314.f9/?report=objectonly" target="object" title="Scheme 2" class="img_link icnblk_img figpopup" rid-figpopup="figml314f9" rid-ob="figobml314f9"><img class="small-thumb" src="/books/NBK184496/bin/ml314f9.gif" src-large="/books/NBK184496/bin/ml314f9.jpg" alt="Scheme 2. Synthesis of ML314." /></a><div class="icnblk_cntnt" id="figlgndml314f9"><h4 id="ml314.f9"><a href="/books/NBK184496/figure/ml314.f9/?report=objectonly" target="object" rid-ob="figobml314f9">Scheme 2</a></h4><p class="float-caption no_bottom_margin">Synthesis of ML314. Conditions<sup></sup>: a): 4M HCl (1,4-dioxane), 100 °C, 15h, 65%; POCl<sub>3</sub>, reflux, 15 h, 84%; c) 1-(2-methoxyphenyl)piperazine hydrochloride (1.5 equiv.), K<sub>2</sub>CO<sub>3</sub> (3 equiv.), 1,4-dioxane, microwave, 80 °C, 1 h, 25%. </p></div></div><div id="ml314.f2" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%202.%201H%20NMR%2C%20and%20LC-MS%20spectra%20of%20ML301.&p=BOOKS&id=184496_ml314f2a.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK184496/bin/ml314f2a.jpg" alt="Figure 2. 1H NMR, and LC-MS spectra of ML301." class="tileshop" title="Click on image to zoom" /></a></div><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%202.%201H%20NMR%2C%20and%20LC-MS%20spectra%20of%20ML301.&p=BOOKS&id=184496_ml314f2b.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK184496/bin/ml314f2b.jpg" alt="Figure 2. 1H NMR, and LC-MS spectra of ML301." class="tileshop" title="Click on image to zoom" /></a></div><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%202.%201H%20NMR%2C%20and%20LC-MS%20spectra%20of%20ML301.&p=BOOKS&id=184496_ml314f2c.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK184496/bin/ml314f2c.jpg" alt="Figure 2. 1H NMR, and LC-MS spectra of ML301." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 2</span><span class="title">1H NMR, and LC-MS spectra of ML301</span></h3><div class="caption"><p>A. <sup>1</sup>H NMR Spectrum of <a href="/pcsubstance/?term=ML301[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML301</a> (500 MHz, CDCl<sub>3</sub>). B. LC of LC-MS spectra of <a href="/pcsubstance/?term=ML301[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML301</a>. C. MS of LC-MS spectra</p></div></div><div id="ml314.f3" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%203.%201H%20NMR%2C%2013C%20NMR%2C%20and%20LC-MS%20spectra%20of%20ML314.&p=BOOKS&id=184496_ml314f3a.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK184496/bin/ml314f3a.jpg" alt="Figure 3. 1H NMR, 13C NMR, and LC-MS spectra of ML314." class="tileshop" title="Click on image to zoom" /></a></div><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%203.%201H%20NMR%2C%2013C%20NMR%2C%20and%20LC-MS%20spectra%20of%20ML314.&p=BOOKS&id=184496_ml314f3b.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK184496/bin/ml314f3b.jpg" alt="Figure 3. 1H NMR, 13C NMR, and LC-MS spectra of ML314." class="tileshop" title="Click on image to zoom" /></a></div><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%203.%201H%20NMR%2C%2013C%20NMR%2C%20and%20LC-MS%20spectra%20of%20ML314.&p=BOOKS&id=184496_ml314f3c.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK184496/bin/ml314f3c.jpg" alt="Figure 3. 1H NMR, 13C NMR, and LC-MS spectra of ML314." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 3</span><span class="title">1H NMR, 13C NMR, and LC-MS spectra of ML314</span></h3><div class="caption"><p>A. <sup>1</sup>H NMR Spectrum (500 MHz, CDCl<sub>3</sub>). B. LC of LC-MS.(Reverse phase C18 column: isocratic). C. MS of LC-MS spectra.</p></div></div></div><div id="ml314.s7"><h4>Solubility and Stability of ML301 and ML314 in PBS at room temperature</h4><p>The solubility of <a href="/pcsubstance/?term=ML301[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML301</a> and <a href="/pcsubstance/?term=ML314[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML314</a> were investigated in aqueous buffers at room temperature. As noted in the <i>Summary of in vitro ADME/T properties,</i>
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<a href="/pcsubstance/?term=ML301[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML301</a> has good solubility, while <a href="/pcsubstance/?term=ML314[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML314</a> has good to moderate solubility, relative to their respective potency for NTR1 in aqueous buffer at pH 5, 6.2 and 7.4. To evaluate their potential hydrolytic instability 1 μM solutions of <a href="/pcsubstance/?term=ML301[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML301</a> and <a href="/pcsubstance/?term=ML314[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML314</a> were prepared in acetonitrile:PBS (1:1) and incubated at room temperature, and the amount of the parent compounds remaining at various times were analyzed by LC/MS (<a class="figpopup" href="/books/NBK184496/figure/ml314.f4/?report=objectonly" target="object" rid-figpopup="figml314f4" rid-ob="figobml314f4">Figure 4</a> time course and <a class="figpopup" href="/books/NBK184496/table/ml314.t3/?report=objectonly" target="object" rid-figpopup="figml314t3" rid-ob="figobml314t3">Table 3</a> data). The results indicate that at pH 7.4, both <a href="/pcsubstance/?term=ML301[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML301</a> and <a href="/pcsubstance/?term=ML314[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML314</a> are very stable in acetonitrile:PBS (1:1) with no appreciable loss up to 48 h.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml314f4" co-legend-rid="figlgndml314f4"><a href="/books/NBK184496/figure/ml314.f4/?report=objectonly" target="object" title="Figure 4" class="img_link icnblk_img figpopup" rid-figpopup="figml314f4" rid-ob="figobml314f4"><img class="small-thumb" src="/books/NBK184496/bin/ml314f4.gif" src-large="/books/NBK184496/bin/ml314f4.jpg" alt="Figure 4. Stability of ML301 and ML314." /></a><div class="icnblk_cntnt" id="figlgndml314f4"><h4 id="ml314.f4"><a href="/books/NBK184496/figure/ml314.f4/?report=objectonly" target="object" rid-ob="figobml314f4">Figure 4</a></h4><p class="float-caption no_bottom_margin">Stability of ML301 and ML314. Time course. </p></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml314t3"><a href="/books/NBK184496/table/ml314.t3/?report=objectonly" target="object" title="Table 3" class="img_link icnblk_img figpopup" rid-figpopup="figml314t3" rid-ob="figobml314t3"><img class="small-thumb" src="/books/NBK184496/table/ml314.t3/?report=thumb" src-large="/books/NBK184496/table/ml314.t3/?report=previmg" alt="Table 3. Stability of ML301 and ML314 in 1:1 PBS:acetonitrile at pH 7.4 ambient temperature." /></a><div class="icnblk_cntnt"><h4 id="ml314.t3"><a href="/books/NBK184496/table/ml314.t3/?report=objectonly" target="object" rid-ob="figobml314t3">Table 3</a></h4><p class="float-caption no_bottom_margin">Stability of ML301 and ML314 in 1:1 PBS:acetonitrile at pH 7.4 ambient temperature. </p></div></div></div><div id="ml314.s8"><h4>MLS#’s of probe molecule and five related samples that were submitted to the SMR collection</h4><p>Samples of the probe <a href="/pcsubstance/?term=ML301[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML301</a> and <a href="/pcsubstance/?term=ML314[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML314</a> (>25 mg), and five analogs of each (>20 mg), synthesized at SBCCG were submitted to MLSMR (<a class="figpopup" href="/books/NBK184496/table/ml314.t4/?report=objectonly" target="object" rid-figpopup="figml314t4" rid-ob="figobml314t4">Tables 4a</a> and <a class="figpopup" href="/books/NBK184496/table/ml314.t5/?report=objectonly" target="object" rid-figpopup="figml314t5" rid-ob="figobml314t5">4b</a>), and 5 mg of the probes were provided to the Assay Provider.</p></div></div><div id="ml314.s9"><h3>2.3. Probe Preparation</h3><p>(Compound lettering as per <a class="figpopup" href="/books/NBK184496/figure/ml314.f8/?report=objectonly" target="object" rid-figpopup="figml314f8" rid-ob="figobml314f8">Scheme 1</a> & <a class="figpopup" href="/books/NBK184496/figure/ml314.f9/?report=objectonly" target="object" rid-figpopup="figml314f9" rid-ob="figobml314f9">Scheme 2</a>)</p><p><b><a href="/pcsubstance/?term=ML301[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML301</a> Preparation</b>: Two potential synthetic routes are
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outlined for the synthesis of <a href="/pcsubstance/?term=ML301[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML301</a> in <a class="figpopup" href="/books/NBK184496/figure/ml314.f8/?report=objectonly" target="object" rid-figpopup="figml314f8" rid-ob="figobml314f8">Scheme 1</a>.
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Although the alternate method was fewer steps, its low yields and the high cost of 4-aminoquinoline
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building blocks made the longer method more preferred and practical for most cases of interest. In
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addition to standard Pinner conditions that generally do not work well for cases involving
|
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sterically hindered benzonitriles, many amidine-forming conditions were attempted<sup><a class="bk_pop" href="#ml314.r9">9</a>–<a class="bk_pop" href="#ml314.r14">14</a></sup>.
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Conditions (h), although inefficient, were the best we found for this sterically and electronically
|
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disfavorable case. For some analogs without the 2,6-dimethoxy moieties, the shorter route was more
|
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preferred. Importantly, both routes produced exclusively the key intermediate regioisomer
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<b>D</b> (shown in the box), and there is ample literature precedent<sup><a class="bk_pop" href="#ml314.r13">13</a>,<a class="bk_pop" href="#ml314.r15">15</a>–<a class="bk_pop" href="#ml314.r17">17</a></sup> for this assignment via the amidine (alternate) route. While it may appear that the preferred route could be shortened by performing the <i>N</i>-arylation step on the trifluoromethyl intermediate, followed by CF<sub>3</sub> hydrolysis and amino acid coupling, this was not possible because the CF<sub>3</sub> hydrolysis failed if the imidazole was N-arylated, and the N-arylation was not efficient when performed on the acid intermediate. Thus, it was necessary to first hydrolyze the CF<sub>3</sub> group (b), and then esterify (c) prior to <i>N</i>-arylation (d).</p><p><b>Preferred Route: A</b>, <a class="figpopup" href="/books/NBK184496/figure/ml314.f8/?report=objectonly" target="object" rid-figpopup="figml314f8" rid-ob="figobml314f8">Scheme 1</a>, Step
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a<sup><a class="bk_pop" href="#ml314.r8">8</a></sup>: A vessel containing sodium acetate (4.90 g, 59.8 mmol) was charged with 14 mL of water and 1,1-dibromo-3,3,3-trifluoroacetone (8.06 g, 3.54 mL, 29.9 mmol). Some heat was evolved, the vessel was purged with nitrogen, and placed in a 100°C oil bath. After 30 min, the solution was allowed to cool. 2,6-dimethoxybenzaldehyde (4.514 g, 27 mmol), concentrated ammonium hydroxide (28 mL) and methanol were combined and transferred into the vessel as a single solution. The vessel was swept with nitrogen, closed with a stopper, and the yellow solution was stirred at room temperature. White solid was apparent within one hour. After 19 hours, the mixture was concentrated and partitioned with 100 mL of water and 100 mL of ethyl acetate. The organics were dried over MgSO<sub>4</sub> and concentrated to give 7.08 g of an orange solid, which contained an approximately 1:1 ratio of product and unreacted 2,6-dimethoxybenzaldehyde. Flash chromatography (550 mL silica gel, 25% to 80% gradient of ethyl acetate / hexane) returned 3.836 g (52%) of 2-(2,6-dimethoxyphenyl)-4-(trifluoromethyl)-1H-imidazole (<b>A</b>) as a pale orange solid. <sup>1</sup>H NMR (400 MHz, CDCl<sub>3</sub>) δ 10.02 (br., 1H), 7.46 (s., 1H), 7.35 (t., J = 8.4 Hz, 1H), 6.66 (d., J = 8.4 Hz, 2H), 3.84 (s., 6H). ESI <i>m/z</i> 273.08 [M+H].</p><p><b>B</b>, <a class="figpopup" href="/books/NBK184496/figure/ml314.f8/?report=objectonly" target="object" rid-figpopup="figml314f8" rid-ob="figobml314f8">Scheme 1</a>, Step b<sup><a class="bk_pop" href="#ml314.r8">8</a></sup>: A vessel containing 2-(2,6-dimethoxyphenyl)-4-(trifluoromethyl)-1H-imidazole (<b>A</b>) (3.734 g, 13.7 mmol) was charged with 18 mL of 3.75 N sodium hydroxide. The vessel was equipped with a condenser and heated in a 100°C oil bath for 22 h. The mixture was cooled, diluted with 20 mL of water and washed once with 20 mL of ethyl acetate. The pH of the aqueous part was adjusted to ca. 3 with 3 M HCl. The turbid solution was placed in a refrigerator for 5 h before collecting a solid precipitate. The filtrate was refrigerated overnight to yield a smaller second crop for a combined recovery of 3.202 g (94%) of 2-(2,6-dimethoxyphenyl)-1H-imidazole-4-carboxylic acid (<b>B</b>) as a pale pink solid. <sup>1</sup>H NMR (400 MHz, DMSO-d<sub>6</sub>) δ 7.75 (br., 1H), 7.41 (t., J = 8.4 Hz, 1H), 6.74 (d., J = 8.4 Hz, 2H), 3.69 (s., 6H). ESI <i>m/z</i> 249.05 [M+H].</p><p><b>C</b>, <a class="figpopup" href="/books/NBK184496/figure/ml314.f8/?report=objectonly" target="object" rid-figpopup="figml314f8" rid-ob="figobml314f8">Scheme 1</a>, Step c: 2-(2,6-dimethoxyphenyl)-1H-imidazole-4-carboxylic acid (<b>B</b>) (318 mg, 1.28 mmol) was mostly dissolved in 10 mL of absolute ethanol. Thionyl chloride (0.5 mL, 6.9 mmol) was added, the vial was connected to nitrogen and placed in a 75°C block. After 17 h, the mixture was concentrated to an olive green solid, which was combined with 70 mL of brine containing 1.5 g of sodium bicarbonate. This mixture was extracted with five 40 mL portions of 2% EtOH/CHCl<sub>3</sub>. The extracts were dried over MgSO<sub>4</sub> and concentrated to give 242 mg (69%) of ethyl 2-(2,6-dimethoxyphenyl)-1H-imidazole-4-carboxylate (<b>C</b>), a pale yellow solid. <sup>1</sup>H NMR (500 MHz, CDCl<sub>3</sub>) δ 7.87 (br. s., 1H), 7.36 (t., <i>J</i> = 8.4 Hz, 1H), 6.68 (d., <i>J</i> = 8.4 Hz, 1H), 4.38 (q., <i>J</i> = 7.1 Hz, 2H), 3.89 (br. s., 6H), 1.40 (t., <i>J</i> = 7.1 Hz, 3H). ESI <i>m/z</i> 277.18 [M+H].</p><p><b>D</b>, <a class="figpopup" href="/books/NBK184496/figure/ml314.f8/?report=objectonly" target="object" rid-figpopup="figml314f8" rid-ob="figobml314f8">Scheme 1</a>, Step d: Ethyl 2-(2,6-dimethoxyphenyl)-1H-imidazole-4-carboxylate (<b>C</b>) (85 mg, 0.31 mmol), 7-chloro-4-iodoquinoline (267 mg, 0.92 mmol), and cesium carbonate (502 mg, 1.53 mmol) were combined as solids in a reaction vial. Butyronitrile (1.5 mL) was added to produce a slurry. The mixture was heated at 110°C for 18 hours. After cooling, the mixture was charged with 25 mL of brine and extracted with two 25 mL portions of CHCl<sub>3</sub>. The organics were dried over MgSO<sub>4</sub> and concentrated to give 290 mg of a crude tan solid which was purified by flash chromatography (25 mL silica gel, 10% – 30% gradient of ethyl acetate in dichloromethane) to return 58.9 mg (43%) of ethyl 1-(7-chloroquinolin-4-yl)-2-(2,6-dimethoxyphenyl)-1H-imidazole-4-carboxylate (<b>D</b>) as a colorless film. <sup>1</sup>H NMR (500 MHz, CDCl<sub>3</sub>) δ 8.85 (s., 1H), 8.19 (s., 1H), 7.99 (s., 1H), 7.77 (d., <i>J</i> = 9.0 Hz, 1H), 7.55 (dd, <i>J</i> = 9.0, 2.0 Hz, 1H), 7.2 (m., 2H), 6.48 (br., 1H), 6.29 (br., 1H), 4.47 (q., <i>J</i> = 7.1 Hz, 2H), 3.80 (br., 3H), 3.27 (br., 3H), 1.45 (t., <i>J</i> = 7.1 Hz, 3H). ESI <i>m/z</i> 438.21, 440.21 [M+H].</p><p><b>E</b>. <a class="figpopup" href="/books/NBK184496/figure/ml314.f8/?report=objectonly" target="object" rid-figpopup="figml314f8" rid-ob="figobml314f8">Scheme 1</a>, Step e: Ethyl 1-(7-chloroquinolin-4-yl)-2-(2,6-dimethoxyphenyl)-1H-imidazole-4-carboxylate (<b>D</b>) (104 mg, 0.24 mmol) was dissolved in 4 mL of ethanol and 4 mL of water. The solution was treated with 53 mg (0.95 mmol) of solid KOH, and was then stirred at room temperature for 17 h. The mixture was diluted with 20 mL of water and washed once with 15 mL of ethyl acetate. The pH of the aqueous part was adjusted to ca. 2–3 with 1 N HCl, and this solution was extracted with three 20 mL portions of CHCl<sub>3</sub>. The chloroform extracts were dried over MgSO<sub>4</sub> and concentrated to give 84.3 mg (86%) of 1-(7-chloroquinolin-4-yl)-2-(2,6-dimethoxyphenyl)-1H-imidazole-4-carboxylic acid (<b>E</b>), which was carried forward without purification. <sup>1</sup>H NMR (500 MHz, CDCl<sub>3</sub>) δ 8.89 (s., 1H), 8.22 (s., 1H), 8.06 (s., 1H), 7.74 (d., J = 9.0 Hz, 1H), 7.58 (dd. J = 9.0, 2.0 Hz, 1H), 7.26 (t., <i>J</i> = 8.5 Hz, 1H), 7.21 (d., <i>J</i> = 4.6 Hz, 1H), 6.4 (br., 2H), 3.8 (br., 3H), 3.3 (br., 3H). ESI <i>m/z</i> 410.18, 412.18 [M+H].</p><p><b>F</b>, <a class="figpopup" href="/books/NBK184496/figure/ml314.f8/?report=objectonly" target="object" rid-figpopup="figml314f8" rid-ob="figobml314f8">Scheme 1</a>, Step f: Ethyl dimethylaminopropylcarbodiimide hydrochloride (27 mg, 0.14 mmol) and 1-hydroxybenzotriazole hydrate (22 mg, 0.14 mmol) were added to a vial containing 1-(7-chloroquinolin-4-yl)-2-(2,6-dimethoxyphenyl)-1H-imidazole-4-carboxylic acid (<b>E</b>) (58 mg, 0.14 mmol). The vial was then charged with N,N-dimethylformamide (2 mL) and triethylamine (0.06 mL, 0.4 mmol). After stirring for 25 min at room temperature, L-leucine <i>tert</i>-butyl ester (32 mg, 0.14 mmol) was added as solid, and the resulting mixture stirred at room temperature for 20 h. The mixture was transferred into 20 mL of water and extracted with two 25 mL portions of ethyl acetate. The organics were dried over MgSO<sub>4</sub> and concentrated to give 154 mg of a crude yellow liquid which was purified by flash chromatography (20 mL silica gel, 25% – 75% gradient of ethyl acetate in hexane) to return 67.6 mg (83%) of (S)-tert-butyl 2-(1-(7-chloroquinolin-4-yl)-2-(2,6-dimethoxyphenyl)-1H-imidazole-4-carboxamido)-4-methylpentanoate (<b>F</b>) as a clear film. <sup>1</sup>H NMR (500 MHz, CDCl<sub>3</sub>) δ 8.84 (br. s., 1H), 8.18 (br. s., 1H), 7.94 (s., 1H), 7.78 (m., 1H), 7.55 (m., 1H), 7.23 (t., <i>J</i> = 8.5 Hz, 1H), 7.16 (m., 1H), 6.5 (br., 1H), 6.3 (br., 1H), 4.76 (m., 1H), 3.8 (br., 3H), 3.25 (br., 3H), 1.95 – 1.55 (m., 3H), 1.52 (s., 9H), 1.03 (m., 6H). ESI <i>m/z</i> 579.36, 581.37 [M+H].</p><p><b>G</b>, <a class="figpopup" href="/books/NBK184496/figure/ml314.f8/?report=objectonly" target="object" rid-figpopup="figml314f8" rid-ob="figobml314f8">Scheme 1</a>, Step g: A solution of (S)-tert-butyl 2-(1-(7-chloroquinolin-4-yl)-2-(2,6-dimethoxyphenyl)-1H-imidazole-4-carboxamido)-4-methylpentanoate (<b>F</b>) (61 mg, 10.5 mmol) in 1 mL of trifluoroacetic acid and 1 mL of dichloromethane was stirred at room temperature for 5 h. The mixture was concentrated. The residue was dissolved in 1.5 mL of methanol and purified by preparative reverse phase HPLC, using a stepwise gradient with 0.1% formic acid (% water:% acetonitrile): t = 0 min, 90:10; t = 2.0 min, 80:20; t = 6.0 min, 30:70; t = 7.5 min, 2:98; t = 8.8 min, 2:98; t = 9.0 min, 90:10. This afforded 45 mg (82%) of <a href="/pcsubstance/?term=ML301[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML301</a> as a white powder after lyophilization. This sample was redissolved with a second batch, and lyophilized to return a uniform batch of 80 mg of material for testing and submission. <sup>1</sup>H NMR (500 MHz, DMSO-d<sub>6</sub>) δ 12.68 (m., 1H), 8.95 (s., 1H), 8.12 (s., 1H), 8.15 (s., 2H), 7.71 (m., 1H), 7.65 (m., 1H), 7.35 (br. m., 1H), 7.24 (t., <i>J</i> = 8.4 Hz, 1H), 6.58 (br. m., 1H), 6.43 (br. m., 1H), 4.50 (m., 1H), 3.70 (br. s., 3H), 3.3 (br. s., 3H), 1.85 (m., 1H), 1.70 (m., 1H), 1.59 (m., 1H), 0.93 (m., 6H). <sup>13</sup>C NMR (500 MHz, DMSO-d<sub>6</sub>) δ 174.3, 161.5, 152.0, 148.8, 141.7, 141.5, 136.8, 134.9, 132.2, 128.1, 127.7, 125.1, 124.9, 122.6, 119.2, 106.2, 103.6, 55.6, 55.2, 50.0, 40.1, 24.4, 23.0, 21.2. ESI <i>m/z</i> 523.30, 525.29 [M+H], HRMS (ESI+ve): Calculated for C<sub>27</sub>H<sub>28</sub>ClN<sub>4</sub>O<sub>5</sub>, [M+H] = 523.1743, observed [M+H] = 523.1723. (ESI+ve): Calculated for C<sub>27</sub>H<sub>27</sub>ClN<sub>4</sub>NaO<sub>5</sub>, [M+Na] = 545.1562, observed [M+Na] = 545.1576. [α<sub>D</sub><sup>24</sup>] = −3.5°, c = 0.10, methanol.</p><p><b>Alternative Route to <a href="/pcsubstance/?term=ML301[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML301</a></b>, <a class="figpopup" href="/books/NBK184496/figure/ml314.f8/?report=objectonly" target="object" rid-figpopup="figml314f8" rid-ob="figobml314f8">Scheme 1</a>, Step h: 2,6-dimethoxybenzonitrile (501 mg, 3.07 mmol) and 4-amino-7-chloroquinoline (548 mg, 3.07 mmol) were dissolved together in 20 mL of anhydrous tetrahydrofuran. The vessel was swept with nitrogen and chilled in an ice-water bath. Ethereal 3.0 M ethyl magnesium bromide (2.05 mL, 6.14 mmol) was added dropwise over 3 min. After briefly forming an off-white solid suspended in a yellow solution, within minutes the mixture became a dark amber homogenous solution with some off-white solid material remaining. The vessel was placed in a 75°C oil bath for 21 h before diluting with 60 mL of water. The pH was decreased to ca. 14 by addition of 4 pellets of NaOH. The mixture was then extracted with 60 mL of ethyl acetate, using solid NaCl to facilitate partitioning. The organics were dried over MgSO<sub>4</sub> and concentrated to 1.27 g of a crude brown oily paste containing mostly unreacted starting materials. Flash chromatography (150 mL silica gel, 50% ethyl acetate / hexane, then neat ethyl acetate, then 10% methanol in ethyl acetate) returned 100 mg (9.6%) of N-(7-chloroquinolin-4-yl)-2,6-dimethoxybenzimidamide (<b>G</b>). <sup>1</sup>H NMR (400 MHz, CDCl<sub>3</sub>) δ 8.4 (br., 1H), 8.3 (br., 2H), 7.9 (br., 1H), 7.4 (br., 2H), 6.6–6.3 (br. m, 4H), 5.25 (br., 1H), 3.6 (br. 6H). ESI <i>m/z</i> 342.09, 344.10 [M+H].</p><p><b>D</b>, <a class="figpopup" href="/books/NBK184496/figure/ml314.f8/?report=objectonly" target="object" rid-figpopup="figml314f8" rid-ob="figobml314f8">Scheme 1</a>, Step i: Sodium bicarbonate (49 mg, 0.58 mmol) was added to a flask containing N-(7-chloroquinolin-4-yl)-2,6-dimethoxybenzimidamide (<b>G</b>) (99 mg, 0.29 mmol). Ethyl bromopyruvate (73 mg, 0.38 mmol) was then transferred to the flask as a solution in 3 mL of ethanol. The vessel was swept with nitrogen and heated in an 85°C oil bath for 22 h. The mixture was partitioned with 20 mL of water and 20 mL of chloroform. The aqueous part was extracted with two additional 20 mL portions of chloroform. The combined organics were dried over MgSO<sub>4</sub> and concentrated to give 97 mg of a brown residue. The crude residue was combined with 110 mg of p-toluenesulfonic acid monohydrate and 3 mL of toluene. The vessel was swept with nitrogen and heated for 4 h in a 115°C oil bath. The mixture was partitioned with 25 mL of saturated sodium bicarbonate and 25 mL of chloroform. The aqueous part was extracted with two additional 20 mL portions of chloroform. The combined organics were dried over MgSO<sub>4</sub> and concentrated to give 74 mg of a brown oil which was purified by flash chromatography (20 mL silica gel, gradient 50% – 80% ethyl acetate in hexane) to return 22 mg (17%) of ethyl 1-(7-chloroquinolin-4-yl)-2-(2,6-dimethoxyphenyl)-1H-imidazole-4-carboxylate (<b>D</b>), the same intermediate furnished by Step d.</p><p><b><a href="/pcsubstance/?term=ML314[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML314</a> preparation:</b> The synthetic route to <a href="/pcsubstance/?term=ML314[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML314</a> was adapted
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from a previously reported procedure<sup><a class="bk_pop" href="#ml314.r18">18</a></sup>. Methyl 2-amino-4,5-dimethoxybenzoate (1.0 g, 4.73 mmol) and cyclopropyl carbonitrile (0. 95 g, 14.2 mmol) were weighed into a 40 mL vial and 15 mL of 4M HCl in 1,4-dioxane was added, the vial capped and the mixture heated to 100°C for 15 h. The reaction mixture was cooled and poured carefully into cold saturated NaHCO<sub>3</sub> solution (100 mL). The precipitate formed was collected by filtration, washed extensively with water and air-dried to afford the product 2-cyclopropyl-6,7-dimethoxyquinazolin-4-ol (<b>A</b>) as a gray solid (0.76 g, 65%) which was used without any further purification. <sup>1</sup>H NMR (500 MHz, DMSO) δ 7.42 (s, <i>J</i> = 1.4 Hz, 1H), 7.07 (s, <i>J</i> = 2.9 Hz, 1H), 3.86 (s, 3H), 3.83 (s, 3H), 1.95 – 1.88 (m, 1H), 1.08 – 1.01 (m, 2H), 1.01 – 0.95 (m, 2H); LRMS (ESI+ve): Calculated for C<sub>13</sub>H<sub>14</sub>N<sub>2</sub>O<sub>3</sub>, [M+H] = 247.11, observed [M+H] = 247.13.</p><p><b>A</b> (0.3 g, 1.22 mmol) was suspended in POCl<sub>3</sub> (10 mL) in a 40 mL vial and the mixture was heated at 110°C for 15 h during which time the suspension turned reddish brown The mixture was then allowed to cool to 23°C and POCl<sub>3</sub> was removed on a rotary evaporator. The residue was dissolved in 20 mL of dichloromethane and washed with saturated NaHCO<sub>3</sub> solution (3x, 10 mL). The organic layer was collected, dried over anhydrous Na<sub>2</sub>SO<sub>4</sub> and the solvent was evaporated to afford the intermediate 4-chloro-2-cyclopropyl-6,7-dimethoxyquinazoline (0.27 g, 84%). LRMS (ESI+ve): Calculated for C<sub>13</sub>H<sub>13</sub>ClN<sub>2</sub>O<sub>2</sub>, [M+H] = 265.07, observed [M+H] = 265.08. The intermediate was used in the next step without further purification. 1-(2-methoxyphenyl)piperazine hydrochloride (0.35 g, 1.53 mmol) and K<sub>2</sub>CO<sub>3</sub> (0.7 g, 5.1 mmol) were weighed into a 35 mL microwave reaction tube. 4-chloro-2-cyclopropyl-6,7-dimethoxyquinazoline (0.27 g, 1.02 mmol) solution in 1,4-dioxane(10 mL) was added and the mixture was heated in the microwave at 80°C for 1.5 hours. The mixture was diluted with 50 mL water and then extracted with ethyl acetate (3x, 25 mL). The organic layer was dried over anhydrous Na<sub>2</sub>SO<sub>4</sub> and the solvent was evaporated to afford a dark brown residue. The residue was subjected to silica gel flash chromatography (1:3 ethyl acetate/hexanes) to afford MLS-0463110 (0.105 g, 25%) as a pale yellow solid. <sup>1</sup>H NMR (500 MHz, CDCl<sub>3</sub>) δ 7.25 (s, 1H), 7.12 (s, 1H), 7.08 – 7.03 (m, 1H), 7.02 – 6.95 (m, 2H), 6.92 (d, <i>J</i> = 8.0 Hz, 1H), 4.03 (s, 3H), 3.98 (s, 3H), 3.92 (s, 3H), 3.89 – 3.81 (m, 4H), 3.33 – 3.20 (m, 4H), 2.28 – 2.16 (m, 1H), 1.25 – 1.10 (m, 2H), 1.06 – 0.96 (m, 2H); <sup>13</sup>C NMR (126 MHz, CDCl<sub>3</sub>) δ 165.58, 163.99, 154.50, 152.28, 147.47, 140.98, 123.32, 121.05, 118.39, 111.37, 109.26, 106.69, 103.34, 56.19, 56.01, 55.42, 50.56, 49.82, 17.93, 9.54; LRMS (ESI+ve): Calculated for C<sub>24</sub>H<sub>28</sub>N<sub>4</sub>O<sub>3</sub>, [M+H] = 421.22, observed [M+H] = 421.34; HRMS (ESI+ve): Calculated for C<sub>24</sub>H<sub>28</sub>N<sub>4</sub>O<sub>3</sub>, [M+H] = 421.2234, observed [M+H] = 421.2213.</p></div></div><div id="ml314.s10"><h2 id="_ml314_s10_">3. Results</h2><div id="ml314.s11"><h3>3.1. Dose Response Curves for Probe</h3><p>As shown in <a class="figpopup" href="/books/NBK184496/figure/ml314.f5/?report=objectonly" target="object" rid-figpopup="figml314f5" rid-ob="figobml314f5">Figure 5</a>, both probes <a href="/pcsubstance/?term=ML301[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML301</a> (A) and <a href="/pcsubstance/?term=ML314[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML314</a> (B) are near full agonists relative to NT-1 peptide and are selective against GPR35 and NTR2.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml314f5" co-legend-rid="figlgndml314f5"><a href="/books/NBK184496/figure/ml314.f5/?report=objectonly" target="object" title="Figure 5" class="img_link icnblk_img figpopup" rid-figpopup="figml314f5" rid-ob="figobml314f5"><img class="small-thumb" src="/books/NBK184496/bin/ml314f5.gif" src-large="/books/NBK184496/bin/ml314f5.jpg" alt="Figure 5. Potency and selectivity of (A) ML301 and (B) ML314 for NTR1 vs. NTR2 and GPR35." /></a><div class="icnblk_cntnt" id="figlgndml314f5"><h4 id="ml314.f5"><a href="/books/NBK184496/figure/ml314.f5/?report=objectonly" target="object" rid-ob="figobml314f5">Figure 5</a></h4><p class="float-caption no_bottom_margin">Potency and selectivity of (A) ML301 and (B) ML314 for NTR1 vs. NTR2 and GPR35. </p></div></div></div><div id="ml314.s12"><h3>3.2. Cellular Activity</h3><p><a href="/pcsubstance/?term=ML301[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML301</a> and <a href="/pcsubstance/?term=ML314[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML314</a> are active in cells because the primary, confirmatory and secondary assays were all conducted in cell-based systems. Interestingly, neither probe shows significant cytotoxicity (LD<sub>50</sub>) relative to its potency (EC<sub>50</sub>) against a human hepatocyte cell line (<i>see</i><a class="figpopup" href="/books/NBK184496/table/ml314.t6/?report=objectonly" target="object" rid-figpopup="figml314t6" rid-ob="figobml314t6">Table 5</a> ADME/T properties). <a href="/pcsubstance/?term=ML301[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML301</a> has an LD<sub>50</sub>/EC<sub>50</sub> ratio of greater than 12–25 fold, while <a href="/pcsubstance/?term=ML314[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML314</a> has an LD<sub>50</sub>/EC<sub>50</sub> ratio of ~16-fold.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml314t6"><a href="/books/NBK184496/table/ml314.t6/?report=objectonly" target="object" title="Table 5" class="img_link icnblk_img figpopup" rid-figpopup="figml314t6" rid-ob="figobml314t6"><img class="small-thumb" src="/books/NBK184496/table/ml314.t6/?report=thumb" src-large="/books/NBK184496/table/ml314.t6/?report=previmg" alt="Table 5. Counter Assay Results for Neurotensin-1 Agonists." /></a><div class="icnblk_cntnt"><h4 id="ml314.t6"><a href="/books/NBK184496/table/ml314.t6/?report=objectonly" target="object" rid-ob="figobml314t6">Table 5</a></h4><p class="float-caption no_bottom_margin">Counter Assay Results for Neurotensin-1 Agonists. </p></div></div><p>The agonist activity for NTR1 in the primary HCS was confirmed in the DiscoveRx β-arrestin assay (<a class="figpopup" href="/books/NBK184496/table/ml314.t6/?report=objectonly" target="object" rid-figpopup="figml314t6" rid-ob="figobml314t6">Table 5</a>).</p><p>The probes tested in counterassays were selective for NTR1 over NTR2 and GPR35 (<a class="figpopup" href="/books/NBK184496/table/ml314.t6/?report=objectonly" target="object" rid-figpopup="figml314t6" rid-ob="figobml314t6">Table 5</a>). <a href="/pcsubstance/?term=ML301[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML301</a> data were consistent between this assay and the primary HCS. We also tested these compounds for agonist activity in a calcium mobilization assay (“Ca Mobilization” in <a class="figpopup" href="/books/NBK184496/table/ml314.t6/?report=objectonly" target="object" rid-figpopup="figml314t6" rid-ob="figobml314t6">Table 5</a>). <a href="/pcsubstance/?term=ML301[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML301</a> was active, consistent with its functioning via the G<sub>q</sub>-coupled pathway</p></div><div id="ml314.s13"><h3>3.3. Profiling Assays</h3><p>As a <i>pro forma</i> activity, the SBCCG is committed to profiling all final probe(s) compound(s) and in certain cases key informative analogs in the PanLabs full panel as negotiated by the MLPCN network. Additional commercial profiling services will be considered for funding by SBCCG as deemed appropriate and informative. The nominated probes and related compounds were evaluated in a detailed <i>in vitro</i> pharmacology screen as shown in <a class="figpopup" href="/books/NBK184496/table/ml314.t7/?report=objectonly" target="object" rid-figpopup="figml314t7" rid-ob="figobml314t7">Table 6</a>.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml314t7"><a href="/books/NBK184496/table/ml314.t7/?report=objectonly" target="object" title="Table 6" class="img_link icnblk_img figpopup" rid-figpopup="figml314t7" rid-ob="figobml314t7"><img class="small-thumb" src="/books/NBK184496/table/ml314.t7/?report=thumb" src-large="/books/NBK184496/table/ml314.t7/?report=previmg" alt="Table 6. Summary of in vitro ADME/T Properties of NTR1 agonists ML301 (& analogs) and ML314." /></a><div class="icnblk_cntnt"><h4 id="ml314.t7"><a href="/books/NBK184496/table/ml314.t7/?report=objectonly" target="object" rid-ob="figobml314t7">Table 6</a></h4><p class="float-caption no_bottom_margin">Summary of <i>in vitro</i> ADME/T Properties of NTR1 agonists ML301 (& analogs) and ML314. </p></div></div><p><b>ADME/T Profile of <a href="/pcsubstance/?term=ML301[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML301</a> (Probe 1):</b>
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<a href="/pcsubstance/?term=ML301[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML301</a> was evaluated in a detailed <i>in vitro</i> pharmacology screen as shown in <a class="figpopup" href="/books/NBK184496/table/ml314.t7/?report=objectonly" target="object" rid-figpopup="figml314t7" rid-ob="figobml314t7">Table 6</a> Despite its structural similarity (imidazole <i>vs.</i> pyrazole) to the prior art compound, <a href="/pcsubstance/?term=ML301[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML301</a> exhibited substantial advantages in this testing, especially with regard to plasma and microsomal stability.</p><p><a href="/pcsubstance/?term=ML301[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML301</a> exhibited good solubility due to the presence of the carboxylic acid moiety.</p><p>The PAMPA (<b>P</b>arallel <b>A</b>rtificial <b>M</b>embrane <b>P</b>ermeability <b>A</b>ssay) assay is used as an <i>in vitro</i> model of passive, transcellular permeability. An artificial membrane immobilized on a filter is placed between a donor and acceptor compartment. At the start of the test, drug is introduced in the donor compartment. Following the permeation period, the concentration of drug in the donor and acceptor compartments is measured using UV spectroscopy. The compounds exhibited good overall permeability inversely related to the pH of the donor compartment. Because these NTR1 agonists are envisioned as predecessors of psychoactive drugs, a preliminary assessment of their potential to cross the blood brain barrier (BBB) was performed. When incubated with an artificial membrane that models the BBB, much lower permeability was observed. These observations are also consistent with the carboxylic acid function in the compounds, and may present an opportunity for future enhancements.</p><p>Plasma protein binding is a measure of a drug’s efficiency of binding proteins within blood plasma. The less bound a drug is, the more efficiently it can traverse cell membranes or diffuse. Highly plasma protein bound drugs are confined to the vascular space, and thus have relatively low volumes of distribution. In contrast, drugs that remain largely unbound in plasma are generally available for distribution to other organs and tissues. The imidazole scaffold compounds (<a href="/pcsubstance/?term=ML301[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML301</a> and its MLS-0446079) exhibited substantial protein binding, but significantly lower than that of the prior art pyrazole.</p><p>The stability of small molecules and peptides in plasma may strongly influence <i>in vivo</i> efficacy. Drug candidates are susceptible to enzymatic processes such as those mediated by proteases or esterases in plasma. They may also undergo intramolecular rearrangement or bind irreversibly (covalently) to proteins. <a href="/pcsubstance/?term=ML301[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML301</a> showed excellent stability in plasma, significantly better than that of either analog.</p><p>The microsomal stability assay is commonly used to rank compounds according to their metabolic stability, which influences how long the candidate may remain intact while circulating in plasma. <a href="/pcsubstance/?term=ML301[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML301</a> showed excellent stability in human and modest stability in mouse liver homogenates, which was much better than that observed for the prior art analog MLS-0437103. None of the compounds showed toxicity (>50 μM) toward human hepatocytes.</p><p><b>ADME/T Profile of <a href="/pcsubstance/?term=ML314[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML314</a> (Probe 2):</b> As described previously for <a href="/pcsubstance/?term=ML301[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML301</a>, <i>in vitro</i> pharmacology screening was also conducted for <a href="/pcsubstance/?term=ML314[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML314</a>. Consistent with its aqueous solubility data, <a href="/pcsubstance/?term=ML314[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML314</a> exhibited high permeability in the PAMPA assay with increasing pH of the donor compartment. When incubated with an artificial membrane that models the blood-brain-barrier (BBB), <a href="/pcsubstance/?term=ML314[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML314</a> was found to be highly permeable. <a href="/pcsubstance/?term=ML314[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML314</a> was highly plasma protein bound and exhibited very high plasma stability. <a href="/pcsubstance/?term=ML314[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML314</a> was metabolized rapidly when incubated <i>in vitro</i> with human and mouse liver homogenates. This result is not completely surprising because of the presence of several unsubstituted aryl and alkyl positions and Ar-OMe ethers which are prone to oxidation, hydrolysis, conjugation and other metabolic reactions. <a href="/pcsubstance/?term=ML314[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML314</a> showed a > 15-fold window for toxicity (LC<sub>50</sub> = 30 μM) towards human hepatocytes. Improving the metabolic stability and toxicity profile of <a href="/pcsubstance/?term=ML314[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML314</a> represents a challenge as well as an avenue for further optimization studies in future.</p><div id="ml314.s14"><h4>Profiling against other GPCRs</h4><p><a href="/pcsubstance/?term=ML301[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML301</a> and the prior art pyrazole (Entry 17, MLS-0437103) were submitted to the Psychoactive Drug Screening Program (PDSP) at the University of North Carolina (Bryan Roth, PI) for testing in a GPCR binding assay panel. The results (<a class="figpopup" href="/books/NBK184496/figure/ml314.f6/?report=objectonly" target="object" rid-figpopup="figml314f6" rid-ob="figobml314f6">Figure 6a</a>) indicate <a href="/pcsubstance/?term=ML301[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML301</a> shows very little potential for promiscuity across a range of GPCRs. Contrarily, the prior art analog MLS-0437103 showed somewhat higher potential for promiscuity. Follow up dose response studies revealed K<sub>i</sub> values of >10 μM (DAT) and 10 μM (NTS1) for <a href="/pcsubstance/?term=ML301[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML301</a>, and >10 μM (DAT), 5.2 μM (DOR), 3.4 μM (MOR), and 3.3 μM (NTS1) for MLS-0437103.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml314f6" co-legend-rid="figlgndml314f6"><a href="/books/NBK184496/figure/ml314.f6/?report=objectonly" target="object" title="Figure 6a" class="img_link icnblk_img figpopup" rid-figpopup="figml314f6" rid-ob="figobml314f6"><img class="small-thumb" src="/books/NBK184496/bin/ml314f6.gif" src-large="/books/NBK184496/bin/ml314f6.jpg" alt="Figure 6a. Comparison of ML301 and MLS-0437103 in a GPCR Panel of Assays." /></a><div class="icnblk_cntnt" id="figlgndml314f6"><h4 id="ml314.f6"><a href="/books/NBK184496/figure/ml314.f6/?report=objectonly" target="object" rid-ob="figobml314f6">Figure 6a</a></h4><p class="float-caption no_bottom_margin">Comparison of ML301 and MLS-0437103 in a GPCR Panel of Assays. </p></div></div><p><a href="/pcsubstance/?term=ML314[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML314</a> was also submitted to the Psychoactive Drug Screening Program (PDSP) at the University of North Carolina (Bryan Roth, PI) for testing in a GPCR binding assay panel. <a href="/pcsubstance/?term=ML314[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML314</a> (at 10 μM) was found to be moderately promiscuous, inhibiting (≥ 50 %) about one third of the GPCRs screened in the panel (<a class="figpopup" href="/books/NBK184496/figure/ml314.f7/?report=objectonly" target="object" rid-figpopup="figml314f7" rid-ob="figobml314f7">Figure 6b</a>). Follow up dose response studies revealed Ki values of 0.4 μM (5-HT1A) 1.0 μM (5-HT3), 0.93 μM (5-HT7), > 10 μM (Beta3), > 10 μM (D5), 1.42 μM (H1) 1.54 μM (MOR), 2.54 μM (PBR) and 0.41 μM (sigma1) for <a href="/pcsubstance/?term=ML314[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML314</a>. It is not known whether these activities in binding assays are translated into functional antagonism or agonism of these receptors or downstream signaling. We also highlight the “<i>comment from the PDSP program”: The PDSP has a low threshold for "hits" at primary assays. We perform a large number of secondary assays using a relatively low threshold in order not to miss potential high-affinity compounds. The likelihood of an actual, high-affinity, "hit" is still very low. Thus, one should not over-interpret results from primary assays.</i></p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml314f7" co-legend-rid="figlgndml314f7"><a href="/books/NBK184496/figure/ml314.f7/?report=objectonly" target="object" title="Figure 6b" class="img_link icnblk_img figpopup" rid-figpopup="figml314f7" rid-ob="figobml314f7"><img class="small-thumb" src="/books/NBK184496/bin/ml314f7.gif" src-large="/books/NBK184496/bin/ml314f7.jpg" alt="Figure 6b. Evaluation of ML314 (MLS-0463110) and MLS-0233108 in a GPCR Panel of Assays." /></a><div class="icnblk_cntnt" id="figlgndml314f7"><h4 id="ml314.f7"><a href="/books/NBK184496/figure/ml314.f7/?report=objectonly" target="object" rid-ob="figobml314f7">Figure 6b</a></h4><p class="float-caption no_bottom_margin">Evaluation of ML314 (MLS-0463110) and MLS-0233108 in a GPCR Panel of Assays. </p></div></div></div></div></div><div id="ml314.s15"><h2 id="_ml314_s15_">4. Discussion</h2><p>Currently, small molecule drug-like compounds are not available for treating methamphetamine abuse. Neurotensin receptor 1 (NTR1) peptide agonists produce behaviors that are exactly opposite to the psychostimulant effects observed with methamphetamine abuse, such as hyperactivity, neurotoxicity, psychotic episodes, and cognitive deficits, and repeated administrations of NTR1 agonists do not lead to the development of tolerance<sup><a class="bk_pop" href="#ml314.r1">1</a>,<a class="bk_pop" href="#ml314.r2">2</a></sup>. Recent supporting data from the Hanson laboratory<sup><a class="bk_pop" href="#ml314.r3">3</a></sup>, collaborators on this project, suggesting that NT receptor agonists may have a role in addiction therapy are: (a) in a methamphetamine self-administration rat model the substitution of the peptide NT agonist (Lys(CH2NH)lys-Pro,Trp-<i>tert</i>-Leu-Leu-Oet) for methamphetamine, did not significantly affect motor activity but dramatically reduced lever pressing (b) the peptide agonist was not self-administered, and (c) the effects were associated with nucleus accumbens dopamine D1 receptors. These findings strengthen the hypothesis that neurotensin receptors are valid targets for antagonizing drug seeking behaviors and preventing relapses.</p><p>The NTR1 receptors and molecules relevant to them were reviewed in 2009<sup><a class="bk_pop" href="#ml314.r4">4</a></sup>. Previously starting from the potent NTR1 antagonists SR48692 or SR142948 were reported<sup><a class="bk_pop" href="#ml314.r5">5</a>,<a class="bk_pop" href="#ml314.r6">6</a></sup>. Additionally, three partial agonists were identified using a Ca mobilization FLIPR assay<sup><a class="bk_pop" href="#ml314.r5">5</a>,<a class="bk_pop" href="#ml314.r6">6</a></sup>. Researchers at Wyeth reported two different chemotypes, each of which showed partial agonist activity for NTR1 in the FLIPR assay<sup><a class="bk_pop" href="#ml314.r7">7</a></sup>.</p><div id="ml314.s16"><h3>4.1. Comparison to Existing Art and How the New Probe is an Improvement</h3><p><a href="/pcsubstance/?term=ML301[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML301</a> was designed via a scaffold hop approach based on the previously disclosed molecule with a pyrazole moiety. That molecule was designed in part from knowledge of SR48692. Taken together, these advances underscore the value of drug design via iterative / intuitive structural enhancement of an identified scaffold. Despite having substantial structural similarity to the pyrazole analog, the nominated probe <a href="/pcsubstance/?term=ML301[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML301</a> (imidazole) enjoys intriguing differences / advantages in chemical and biological properties. Despite being less potent than the pyrazole analog and comparably potent to a naphthyl analog, <a href="/pcsubstance/?term=ML301[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML301</a> is a more effective agonist than the pyrzaole analog in the calcium mobilization assay. Identification of a full agonist was a primary objective for this program. <a href="/pcsubstance/?term=ML301[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML301</a> also showed a much better pharmacology profile, including superior protein binding, plasma stability, and hepatic microsomal stability. These improvements over the existing art may enable <a href="/pcsubstance/?term=ML301[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML301</a> or future analogs of <a href="/pcsubstance/?term=ML301[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML301</a> to achieve a distribution profile more favorably disposed toward <i>in vivo</i> activity. It is tractable from a synthetic chemistry perspective and appears much more tolerant of substitution on the imidazolium nitrogen, making the future planned studies practical to execute. Finally, it showed minimal and it has a relatively favorable standing with respect to prior art and potential for intellectual property. Overall, <a href="/pcsubstance/?term=ML301[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML301</a> represents a strong platform on which to launch a medicinal chemistry-based program for enhancement.</p><p><a href="/pcsubstance/?term=ML314[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML314</a> represents the first described β-arrestin pathway selective small molecule NTR1 agonist. It also represents a distinct chemical phenotype compared to <a href="/pcsubstance/?term=ML301[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML301</a> as well as the previously described pyrazole analog. In addition, in contrast to this peptide-based reference agonist, <a href="/pcsubstance/?term=ML314[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML314</a> displays much higher blood-brain barrier permeability and thus has a higher probability of efficacy after systemic dosing, although this may be confounded by its poor microsomal stability. However, <a href="/pcsubstance/?term=ML314[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML314</a> may be suitable for acute experiments.</p></div></div><div id="ml314.s17"><h2 id="_ml314_s17_">5. References</h2><dl class="temp-labeled-list"><dt>1.</dt><dd><div class="bk_ref" id="ml314.r1">Gully D, Labeeuw B, Boigegraiin R, Oury-Donat F, Bachy A, Poncelet M, Steinberg R, Suaud-Chagny MF, Santucci V, Vita N, Pecceu F, Labbe-Jullio C, Kitabgi P, Soubrie P, Le Fur G, Maffrand JP. Biochemical and Pharmacological Activities of SR 142948A, a New Potent Neurotensin Resceptor Antagonist. <span><span class="ref-journal">J Pharmacol Exper Therapeut. </span>1997;<span class="ref-vol">280</span>:802–812.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/9023294" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9023294</span></a>]</div></dd><dt>2.</dt><dd><div class="bk_ref" id="ml314.r2">Gully D, Canton M, Boigegraiin R, Jeanjean F, Molimard JC, Poncelet M, Gueudet C, Heaulme M, Leyris R, Brouard A, Pelaprat D, Labbe-Jullio C, Mazellai J, Soubrie P, Rostene W, Kitabgi P, Le Fur G. <span><span class="ref-journal">Proc Natl Acad Sci USA. </span>1993;<span class="ref-vol">90</span>:65–69.</span> [<a href="/pmc/articles/PMC45600/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC45600</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/8380498" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8380498</span></a>]</div></dd><dt>3.</dt><dd><div class="bk_ref" id="ml314.r3">Hanson GR, Hoonakker AJ, Alburges ME, McFadden LM, Robson CM, Frankel PS. Response of limbic neurotensin systems to methamphetamine self-administration. <span><span class="ref-journal">Neuroscience. </span>2012;<span class="ref-vol">203</span>:99–107.</span> [<a href="/pmc/articles/PMC3275099/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3275099</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/22245499" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22245499</span></a>]</div></dd><dt>4.</dt><dd><div class="bk_ref" id="ml314.r4">Myers RM, Shearman JW, Kitching MO, Ramos-Montoya A, Neal DE, Ley SV. Cancer, Chemistry, and the Cell: Molecules that Interact with the Neurotensin Receptors. <span><span class="ref-journal">ACS Chem. Bio. </span>2009;<span class="ref-vol">4</span>(7):503–525.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/19462983" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19462983</span></a>]</div></dd><dt>5.</dt><dd><div class="bk_ref" id="ml314.r5">Thomas JB, Navarro H, Warner KR, Gilmour B. The identification of nonpeptide neurotensin receptor partial agonists from the potent antagonist SR48692 using a calcium mobilization assay. <span><span class="ref-journal">Bioorg Med Chem Lett. </span>2009;<span class="ref-vol">19</span>:1438–1441.</span> [<a href="/pmc/articles/PMC4418176/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4418176</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19195889" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19195889</span></a>]</div></dd><dt>6.</dt><dd><div class="bk_ref" id="ml314.r6">Thomas JB, Runyon SP. WO 2011/156557 A2. <span><span class="ref-journal">Compounds Active at the Neurotensin Receptor. </span>2011</span></div></dd><dt>7.</dt><dd><div class="bk_ref" id="ml314.r7">Fan Y, Lai MH, Sullivan K, Popiolek M, Andree TH, Dollings P, Pausch MH. The identification of neurotensin NTS1 receptor partial agonists through a ligand-based virtual screening approach. <span><span class="ref-journal">Bioorg Med Chem Lett. </span>2008;<span class="ref-vol">18</span>:5789–5791.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/18849166" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18849166</span></a>]</div></dd><dt>8.</dt><dd><div class="bk_ref" id="ml314.r8">Adams, R.S., Duffey, M., Gould, A.E., Greenspan, P.D., Kulkarni, B.a., and Vos, T.J. 2008. Certain Pyrazoline Derivatives with Kinase Inhibitory Activity. US 2008/0171754.</div></dd><dt>9.</dt><dd><div class="bk_ref" id="ml314.r9">Lange, J.H., van Stuivenberg, H.H., Coolen, H.K.A.C, Adolfs, T.J.P., McCreary, A.C., Keizer, H.G., Wals, H.C., Veerman, W., Borst, A.J.M., de Looff, W., Verveer, P.C., and Kruse, C.G. 2005. Bioisosteric Replacements of the Pyrazole Moiety of Rimonabant: Synthesis, Biological Properties, and Molecular Modeling Investigations of Thiazoles, Triazoles, and Imidazoles as Potent and Selective CB1 Cannabinoid Receptor Antagonists. J. Med. Chem. 48:1823-1838. [<a href="https://pubmed.ncbi.nlm.nih.gov/15771428" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15771428</span></a>]</div></dd><dt>10.</dt><dd><div class="bk_ref" id="ml314.r10">Singh, B. and Collins, J.C. 1971. Simple New Synthesis of 4,6-Diaryl-2-hydroxy-s-triazines and Amidines. J. Chem. Soc. Chem. Comm. 498-499.</div></dd><dt>11.</dt><dd><div class="bk_ref" id="ml314.r11">Weintraub, L., Oles, S.R., and Kalish, N. 1968. A Convenient General Synthesis of Amidines. J. Org., Chem. 33(4):1679-1681.</div></dd><dt>12.</dt><dd><div class="bk_ref" id="ml314.r12">Smith, R.A., Fathi, Z., Achebe, F., Akuche, C., Brown, S.E., Choi, S., Fan, J., Jenkins, S., Kluender, H.C.E., Konkar, A., Lavoie, R., Mays, R., Natoli, J., O’Connor, S.J., Ortiz, A.A., Su, N., Taing, C., Tomlinson, S., Tritto, T., Wang, G., Wirtz, S.N., Wong, W., Yand, X.F., Ying, S., and Zhang, Z. 2007. Optimization of imidazole amide derivatives as cannabinoid-1 receptor antagonists for the treatment of obesity. Bioorg. Med. Chem. Lett. 17:2706-2711. [<a href="https://pubmed.ncbi.nlm.nih.gov/17383180" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17383180</span></a>]</div></dd><dt>13.</dt><dd><div class="bk_ref" id="ml314.r13">Ogonor, J.I. 1981. Preparation of N-Substituted Amidines. Tetrahedron 37(16):2909-2910.</div></dd><dt>14.</dt><dd><div class="bk_ref" id="ml314.r14">McCarthy, J.R., Wright, D.L., Schuster, A.J., Abdallah, A.H., Shea, P.J., and Eyster, R. 1985. New Bicyclic Antidepressant Agent. Synthesis and Activity of Napactadine and Related Compounds. J. Med. Chem. 28:1721-1727. [<a href="https://pubmed.ncbi.nlm.nih.gov/4067998" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 4067998</span></a>]</div></dd><dt>15.</dt><dd><div class="bk_ref" id="ml314.r15">Zhu, C., Hansen, A.R., Bateman, T., Chen, Z., Holt, T.G., Hubert, J.A., Karanam, B.V., Lee, S.J., Pan, J., Qian, S., Reddy, V.B.G., Reitman, M.L., Strack, A.M., Tong, V., Weingarth, D.T., Wolff, M.S., MacNeil, D.J., Weber, A.E., Duffy, and J.L., Edmondson, S.D. 2008. Discovery of imidazole carboxamides as potent and selective CCK1R agonists. Bioorg. Med. Chem. Lett. 18:4393-4396. [<a href="https://pubmed.ncbi.nlm.nih.gov/18614364" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18614364</span></a>]</div></dd><dt>16.</dt><dd><div class="bk_ref" id="ml314.r16">Asproni, B., Pau, A., Bitti, M., Melosu, M., Cerri, R., Dazzi, L., Seu, E., Maciocco, E., Sanna, E., Busonero, F., Talani, G., Pusceddu, L., Altomare, C., Trapani, G., and Biggio, G. 2002. Synthesis and Pharmacolgical Evaluation of 1-[(1,2-Diphenyl-1H-4-imidazolyl)methyl]-4-phenylpiperazines with Clozapine-Like Mixed Activities at Dopamine D2, Seratonin, and GABAA Receptors. J. Med. Chem. 45:4655-4668. [<a href="https://pubmed.ncbi.nlm.nih.gov/12361392" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12361392</span></a>]</div></dd><dt>17.</dt><dd><div class="bk_ref" id="ml314.r17">Khanna, I.K., Weier, R.M., Yu, Y., Xu, X.D., Koszyk, F.J., Collins, P.W., Koboldt, C.M., Veenhuizen, A.W., Perkins, W.E., Casler, J.J., MAsferrer, J.L., Zhang, Y.Y., Gregory, S.A., Seibert, K., and Isakson, P.C. 1997. 1,2-Diarylimidazoles as Potent, Cyclooxygenase-2 Selective, and Orally Active Antiinflammatory Agents. J. Med., Chem. 40:1634-1647. [<a href="https://pubmed.ncbi.nlm.nih.gov/9171873" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9171873</span></a>]</div></dd><dt>18.</dt><dd><div class="bk_ref" id="ml314.r18">Bridges, A. J.; Zhou, H.; Cody, D. R.; Rewcastle, G. W.; McMichael, A.; Showalter, H. D. H.; Fry, D. W.; Kraker, A. J.; Denny, W. A. J. Med. Chem. 1996, 39, 267-276. [<a href="https://pubmed.ncbi.nlm.nih.gov/8568816" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8568816</span></a>]</div></dd></dl></div><div><dl class="temp-labeled-list small"><dt>*</dt><dd><div id="ml314.fn2"><p class="no_top_margin">The two authors have contributed equally to the current work.</p></div></dd></dl></div><div id="bk_toc_contnr"></div></div></div>
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<div xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Views</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="PDF_download" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="/books/NBK184496/?report=reader">PubReader</a></li><li><a href="/books/NBK184496/?report=printable">Print View</a></li><li><a data-jig="ncbidialog" href="#_ncbi_dlg_citbx_NBK184496" data-jigconfig="width:400,modal:true">Cite this Page</a><div id="_ncbi_dlg_citbx_NBK184496" style="display:none" title="Cite this Page"><div class="bk_tt">Hershberger P, Hedrick M, Peddibhotla S, et al. Small Molecule Agonists for the Neurotensin 1 Receptor (NTR1 Agonists) 2012 Apr 8 [Updated 2013 Mar 7]. 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></div></div></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>In this Page</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="page-toc" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="#ml314.rp" ref="log$=inpage&link_id=inpage">Resulting Publications</a></li><li><a href="#ml314.s1" ref="log$=inpage&link_id=inpage">Probe Structure & Characteristics</a></li><li><a href="#ml314.s2" ref="log$=inpage&link_id=inpage">Recommendations for Scientific Use of the Probe</a></li><li><a href="#ml314.s3" ref="log$=inpage&link_id=inpage">Materials and Methods</a></li><li><a href="#ml314.s10" ref="log$=inpage&link_id=inpage">Results</a></li><li><a href="#ml314.s15" ref="log$=inpage&link_id=inpage">Discussion</a></li><li><a href="#ml314.s17" ref="log$=inpage&link_id=inpage">References</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Related information</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="discovery_db_links" id="Shutter"></a></div><div class="portlet_content"><ul><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=pmc&DbFrom=books&Cmd=Link&LinkName=books_pmc_refs&IdsFromResult=3071510" ref="log$=recordlinks">PMC</a><div class="brieflinkpop offscreen_noflow">PubMed Central citations</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=pcsubstance&DbFrom=books&Cmd=Link&LinkName=books_pcsubstance&IdsFromResult=3071510" ref="log$=recordlinks">PubChem Substance</a><div class="brieflinkpop offscreen_noflow">Related PubChem Substances</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=pubmed&DbFrom=books&Cmd=Link&LinkName=books_pubmed_refs&IdsFromResult=3071510" ref="log$=recordlinks">PubMed</a><div class="brieflinkpop offscreen_noflow">Links to PubMed</div></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Similar articles in PubMed</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="PBooksDiscovery_RA" id="Shutter"></a></div><div class="portlet_content"><ul><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/24611085" ref="ordinalpos=1&linkpos=1&log$=relatedarticles&logdbfrom=pubmed">Discovery of ML314, a Brain Penetrant Non-Peptidic β-Arrestin Biased Agonist of the Neurotensin NTR1 Receptor.</a><span class="source">[ACS Med Chem Lett. 2013]</span><div class="brieflinkpop offscreen_noflow">Discovery of ML314, a Brain Penetrant Non-Peptidic β-Arrestin Biased Agonist of the Neurotensin NTR1 Receptor.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Peddibhotla S, Hedrick MP, Hershberger P, Maloney PR, Li Y, Milewski M, Gosalia P, Gray W, Mehta A, Sugarman E, et al. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">ACS Med Chem Lett. 2013 Jul 20; 4(9):846-851. </em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/24332089" ref="ordinalpos=1&linkpos=2&log$=relatedarticles&logdbfrom=pubmed">Imidazole-derived agonists for the neurotensin 1 receptor.</a><span class="source">[Bioorg Med Chem Lett. 2014]</span><div class="brieflinkpop offscreen_noflow">Imidazole-derived agonists for the neurotensin 1 receptor.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Hershberger PM, Hedrick MP, Peddibhotla S, Mangravita-Novo A, Gosalia P, Li Y, Gray W, Vicchiarelli M, Smith LH, Chung TD, et al. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">Bioorg Med Chem Lett. 2014 Jan 1; 24(1):262-7. 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