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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="Development of a Second Generation mGlu3 NAM Probe" /><meta name="citation_publisher" content="National Center for Biotechnology Information (US)" /><meta name="citation_date" content="2013/03/22" /><meta name="citation_author" content="Cody Wenthur" /><meta name="citation_author" content="J. Scott Daniels" /><meta name="citation_author" content="Ryan Morrison" /><meta name="citation_author" content="Julie L. Engers" /><meta name="citation_author" content="Colleen M. Niswender" /><meta name="citation_author" content="P. Jeffrey Conn" /><meta name="citation_author" content="Craig W. Lindsley" /><meta name="citation_pmid" content="23885366" /><meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK148852/" /><link rel="schema.DC" href="http://purl.org/DC/elements/1.0/" /><meta name="DC.Title" content="Development of a Second Generation mGlu3 NAM Probe" /><meta name="DC.Type" content="Text" /><meta name="DC.Publisher" content="National Center for Biotechnology Information (US)" /><meta name="DC.Contributor" content="Cody Wenthur" /><meta name="DC.Contributor" content="J. Scott Daniels" /><meta name="DC.Contributor" content="Ryan Morrison" /><meta name="DC.Contributor" content="Julie L. Engers" /><meta name="DC.Contributor" content="Colleen M. Niswender" /><meta name="DC.Contributor" content="P. Jeffrey Conn" /><meta name="DC.Contributor" content="Craig W. Lindsley" /><meta name="DC.Date" content="2013/03/22" /><meta name="DC.Identifier" content="https://www.ncbi.nlm.nih.gov/books/NBK148852/" /><meta name="description" content="Herein we report the discovery and structure activity relationship (SAR) of a novel, second generation metabotropic glutamate receptor 3 (mGlu3) negative allosteric modulator (NAM) probe (ML337) with >50-fold selectivity versus mGlu2 (IC50 >30 μM). The mGlu3 NAM was discovered via an iterative parallel synthesis optimization of the first generation mGlu3 NAM ML289, that was only ~15-fold selective. This mGlu3 NAM (60204017, ML337) displays an IC50 value of 592 nM and is inactive (>30 μM) on mGlu2 (as well as mGlu1,4,5,6,7,8) and clean in a Ricerca ancillary pharmacology panel. ML337 possesses favorable physiochemical properties, a good dystrophia myotonica protein kinase (DMPK) profile and is centrally penetrant. Thus, ML337 is a best-in-class in vitro and in vivo probe for studying non-competitive antagonism of mGlu3." /><meta name="og:title" content="Development of a Second Generation mGlu3 NAM Probe" /><meta name="og:type" content="book" /><meta name="og:description" content="Herein we report the discovery and structure activity relationship (SAR) of a novel, second generation metabotropic glutamate receptor 3 (mGlu3) negative allosteric modulator (NAM) probe (ML337) with >50-fold selectivity versus mGlu2 (IC50 >30 μM). The mGlu3 NAM was discovered via an iterative parallel synthesis optimization of the first generation mGlu3 NAM ML289, that was only ~15-fold selective. This mGlu3 NAM (60204017, ML337) displays an IC50 value of 592 nM and is inactive (>30 μM) on mGlu2 (as well as mGlu1,4,5,6,7,8) and clean in a Ricerca ancillary pharmacology panel. ML337 possesses favorable physiochemical properties, a good dystrophia myotonica protein kinase (DMPK) profile and is centrally penetrant. 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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="#__NBK148852_dtls__">Show details</a><div style="display:none" class="ui-widget" id="__NBK148852_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/ml338/" title="Previous page in this title">< Prev</a><a class="active page_link next" href="/books/n/mlprobe/ml336/" 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="_NBK148852_"><span class="title" itemprop="name">Development of a Second Generation mGlu<sub>3</sub> NAM Probe</span></h1><p class="contrib-group"><span itemprop="author">Cody Wenthur</span>, <span itemprop="author">J. Scott Daniels</span>, <span itemprop="author">Ryan Morrison</span>, <span itemprop="author">Julie L. Engers</span>, <span itemprop="author">Colleen M. Niswender</span>, <span itemprop="author">P. Jeffrey Conn</span>, and <span itemprop="author">Craig W. Lindsley</span>.</p><a data-jig="ncbitoggler" href="#__NBK148852_ai__" style="border:0;text-decoration:none">Author Information and Affiliations</a><div style="display:none" class="ui-widget" id="__NBK148852_ai__"><p class="contrib-group"><h4>Authors</h4><span itemprop="author">Cody Wenthur</span>, <span itemprop="author">J. Scott Daniels</span>, <span itemprop="author">Ryan Morrison</span>, <span itemprop="author">Julie L. Engers</span>, <span itemprop="author">Colleen M. Niswender</span>, <span itemprop="author">P. Jeffrey Conn</span>, and <span itemprop="author">Craig W. Lindsley</span><sup>,*</sup>.</p><h4>Affiliations</h4><div class="affiliation"><sup>1</sup> Vanderbilt Specialized Chemistry Center, Vanderbilt Center for Neuroscience Drug Discovery, Vanderbilt University Medical Center</div><div class="affiliation">
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<sup>*</sup>
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<span class="before-email-separator"></span><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ude.tlibrednav@yelsdnil.giarc" class="oemail">ude.tlibrednav@yelsdnil.giarc</a></div></div><p class="small">Received: <span itemprop="datePublished">December 10, 2012</span>; Last Update: <span itemprop="dateModified">March 22, 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>Herein we report the discovery and structure activity relationship (SAR) of a novel, second generation metabotropic glutamate receptor 3 (mGlu<sub>3</sub>) negative allosteric modulator (NAM) probe (<a href="/pcsubstance/?term=ML337[synonym]" ref="pagearea=abstract&targetsite=entrez&targetcat=term&targettype=pubchem">ML337</a>) with >50-fold selectivity versus mGlu<sub>2</sub> (IC<sub>50</sub> >30 μM). The mGlu<sub>3</sub> NAM was discovered via an iterative parallel synthesis optimization of the first generation mGlu<sub>3</sub> NAM <a href="/pcsubstance/?term=ML289[synonym]" ref="pagearea=abstract&targetsite=entrez&targetcat=term&targettype=pubchem">ML289</a>, that was only ~15-fold selective. This mGlu<sub>3</sub> NAM (60204017, <a href="/pcsubstance/?term=ML337[synonym]" ref="pagearea=abstract&targetsite=entrez&targetcat=term&targettype=pubchem">ML337</a>) displays an IC<sub>50</sub> value of 592 nM and is inactive (>30 μM) on mGlu<sub>2</sub> (as well as mGlu<sub>1,4,5,6,7,8</sub>) and clean in a Ricerca ancillary pharmacology panel. <a href="/pcsubstance/?term=ML337[synonym]" ref="pagearea=abstract&targetsite=entrez&targetcat=term&targettype=pubchem">ML337</a> possesses favorable physiochemical properties, a good dystrophia myotonica protein kinase (DMPK) profile and is centrally penetrant. Thus, <a href="/pcsubstance/?term=ML337[synonym]" ref="pagearea=abstract&targetsite=entrez&targetcat=term&targettype=pubchem">ML337</a> is a best-in-class <i>in vitro</i> and <i>in vivo</i> probe for studying non-competitive antagonism of mGlu<sub>3</sub>.</p></div><div class="h2"></div><p><b>Assigned Assay Grant #:</b> R01 NS031373</p><p><b>Screening Center Name & PI:</b> A Medicinal Chemistry FastTrack</p><p><b>Chemistry Center Name & PI:</b> Vanderbilt Specialized Chemistry Center for Accelerated Probe Development, Craig W. Lindsley</p><p><b>Assay Submitter & Institution:</b> P. Jeffrey Conn, Vanderbilt University</p><p><b>PubChem Summary Bioassay Identifier (AID):</b>
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<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/612451" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">612451</a></p><div id="ml337.s1"><h2 id="_ml337_s1_">Probe Structure & Characteristics</h2><div id="ml337.fu1" class="figure bk_fig"><div class="graphic"><img src="/books/NBK148852/bin/ml337fu1.jpg" alt="ML337." /></div><h3><span class="title">ML337</span></h3></div><div id="ml337.tu1" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK148852/table/ml337.tu1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml337.tu1_lrgtbl__"><table><thead><tr><th id="hd_h_ml337.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CID/ML#</th><th id="hd_h_ml337.tu1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Target Name</th><th id="hd_h_ml337.tu1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">IC<sub>50</sub>/ (nM) [SID, AID]</th><th id="hd_h_ml337.tu1_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Anti-target Name(s)</th><th id="hd_h_ml337.tu1_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">IC<sub>50</sub> (μM) [SID, AID]</th><th id="hd_h_ml337.tu1_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Fold Selective</th><th id="hd_h_ml337.tu1_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Secondary Assay(s) Name: IC<sub>50</sub>/EC<sub>50</sub> (nM) [SID, AID]</th></tr></thead><tbody><tr><td headers="hd_h_ml337.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CID 60204017/<a href="/pcsubstance/?term=ML337[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML337</a></td><td headers="hd_h_ml337.tu1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">mGlu<sub>3</sub><br />(calcium)</td><td headers="hd_h_ml337.tu1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">592 nM, 0.3% [<a href="https://pubchem.ncbi.nlm.nih.gov/substance/144223348" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 144223348</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/602451" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 602451</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/651840" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 651840</a>]</td><td headers="hd_h_ml337.tu1_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">mGlu<sub>2</sub><br /><br />mGlu<sub>1,4,5,6,7,8</sub></td><td headers="hd_h_ml337.tu1_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">>30 μM<br /><br />>30 μM<br /><br />[<a href="https://pubchem.ncbi.nlm.nih.gov/substance/144223348" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 144223348</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/623929" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 623929</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588715" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 588715</a>]</td><td headers="hd_h_ml337.tu1_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">>50-fold<br />>50-fold</td><td headers="hd_h_ml337.tu1_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">mGlu<sub>3</sub> (GIRK)<br /><br />1.48 μM, −4.4%<br /><br />[<a href="https://pubchem.ncbi.nlm.nih.gov/substance/144223348" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 144223348</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/651830" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 651830</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/623885" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 623885</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588715" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 588715</a>]</td></tr></tbody></table></div></div></div><div id="ml337.s2"><h2 id="_ml337_s2_">1. Recommendations for Scientific Use of the Probe</h2><p><a href="/pcsubstance/?term=ML337[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML337</a> (CID 60204017) is the most potent (IC<sub>50</sub> = 592 nM, 0.3%) and selective mGlu<sub>3</sub> NAM reported to date with >60-fold selectivity vs. mGlu<sub>2</sub> as well as mGlu<sub>1,4,5,6,7,8</sub> (> 30 μM). <a href="/pcsubstance/?term=ML337[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML337</a> can be used both <i>in vitro</i> and <i>in vivo</i> to study the role of selective inhibition of mGlu<sub>3</sub> in the CNS in a manner previously unavailable with the prior art compounds. Moreover, <a href="/pcsubstance/?term=ML289[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML289</a> possess an attractive <i>in vitro</i> and <i>in vivo</i> DMPK profile, ancillary pharmacology (only two activities at 70% inhibition @10 μM in the Ricerca Panel) and affords excellent CNS exposure in both mouse (brain:plasma ratio of 0.92) and rat (brain:plasma ratio of 0.3). <a href="/pcsubstance/?term=ML337[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML337</a> can be used for basic biochemical and electrophysiological experiments as well as to help establish potential utility for mGlu<sub>3</sub> inhibition as a target for a wide variety of important CNS therapeutic indications.</p></div><div id="ml337.s3"><h2 id="_ml337_s3_">2. Materials and Methods</h2><p><b>Cell culture.</b> Human Embryonic Kidney (HEK-293) cell lines co-expressing mGlu 2, 3, 4, 6, 7 or 8 and GIRK potassium channels were grown in growth medium containing 45% DMEM, 45% F-12, 10% FBS, 20 mM HEPES, 2 mM L-glutamine, antibiotic/antimycotic non-essential amino acids, 700 μg/ml G418, and 0.6 μg/ml puromycin. Rat mGlu<sub>1</sub> and mGlu<sub>5</sub> cells were cultured as described in Hempstapat et al., 2007. TREx293 cells stably expressing mGlu<sub>3</sub> and the promiscuous G protein Galpha15 were grown in Dulbecco’s Modified Eagle Media (DMEM), 10% Tet-tested fetal bovine serum (Atlanta Biologicals), 100 units/ml penicillin/streptomycin, 20 mM HEPES (pH 7.3), 1 mM sodium pyruvate, 2 mM glutamine, 1× MEM Non-Essential Amino Acids Solution, 500 ug/ml G418 (Mediatech, Inc., Herndon, VA), 100 μg/mL hygromycin, and 5 μg/mL blasticidin S (Growth Media). Cells for experiments were generally maintained for approximately 15–20 passages. All cell culture reagents were purchased from Invitrogen Corp. (Carlsbad, CA) unless otherwise noted. All cells were maintained at 37 °C in the presence of 5% CO<sub>2</sub>. All cell culture reagents were purchased from Invitrogen Corp. (Carlsbad, CA) unless otherwise noted.</p><p><b>Calcium mobilization assays.</b> Calcium assays were used to assess activity of compounds at mGlus 1, 3, and 5. Briefly, mGlu<sub>3</sub> TREx293, mGlu<sub>1</sub>, and mGlu<sub>5</sub> cells were plated into 384 well, black-walled, clear-bottom poly-D-lysine coated plates (Greiner) at a density of 15,000 cells/20 μL/well in DMEM containing 10% dialyzed FBS, 20 mM HEPES, and 100 units/ml penicillin/streptomycin (Assay Media). For the mGlu3 TREx293 cells, this assay medium was also supplemented with 25 ng/mL tetracycline for 20 hours. Plated cells were incubated overnight at 37 °C in the presence of 5% CO<sub>2</sub>. The following day, plated cells had their medium exchanged to Assay Buffer (Hanks Balanced Salt Solution (Invitrogen) containing 20 mM HEPES and 2.5 mM probenacid, pH 7.3) using an ELX405 microplate washer (BioTek), leaving 20 μL/well, followed by addition of with 20 μL of 4.5 μM Fluo 4 AM (Invitrogen, Carlsbad, CA) prepared as a 2.3 mM stock in DMSO and mixed in a 1:1 ratio with 10 percent (w/v) pluronic acid F-127 and diluted in Assay Buffer for 45 min at 37 °C. The dye was then exchanged to Assay Buffer using an ELX405, leaving 20 μL/well and the plates were incubated at room temperature for 10 min prior to assay. For concentration-response curve experiments, compounds were serially diluted 1:3 into 10 point concentration response curves in DMSO, were transferred to daughter plates using an Echo acoustic plate reformatter (Labcyte, Sunnyvale, CA), and diluted into Assay Buffer to generate a 2× stock. Calcium flux was measured using the Functional Drug Screening System 6000 or 7000 (FDSS6000 or FDSS7000, Hamamatsu, Japan). Baseline readings were taken (10 images at 1 Hz, excitation, 470+/−20 nm, emission, 540+/−30 nm) and then 20 μL/well test compounds were added using the FDSS’s integrated pipettor. Approximately 2.5 minutes later an EC<sub>20</sub> concentration of glutamate (10 μL of a 5× final concentration) was added followed approximately 2.0 minutes later by an EC<sub>80</sub> concentration of glutamate (12 μL of a 5× final concentration). For fold shift experiments, compounds were added at 2X their final concentration and then increasing concentrations of glutamate were added in the presence of vehicle or the appropriate concentration of test compound. Curves were fitted using a four point logistical equation using Microsoft XLfit (IDBS, Bridgewater, NJ). Subsequent confirmations of concentration response parameters were performed using independent serial dilutions of source compounds and data from multiple days experiments were integrated and fit using a four point logistical equation in GraphPad Prism (GraphPad Software, Inc., La Jolla, CA).</p><p><b>Thallium flux assays.</b> Compound activity at the group II and group III mGlus was assessed using thallium flux through GIRK channels, a method that has been described in detail.<a class="bk_pop" href="#ml337.r1">1</a> Briefly, cells were plated into 384 well, black-walled, clear-bottom poly-D-lysine coated plates (Greiner) at a density of 15,000 cells/20 μL/well in DMEM containing 10% dialyzed FBS, 20 mM HEPES, and 100 units/ml penicillin/streptomycin (Assay Media). Plated cells were incubated overnight at 37 °C in the presence of 5% CO<sub>2</sub>. The following day, plated cells had their medium exchanged to Assay Buffer (Hanks Balanced Salt Solution (Invitrogen) containing 20 mM HEPES pH 7.3) using an ELX405 microplate washer (BioTek), leaving 20 μL/well, followed by addition of with 20 μL of 330 nM FluoZin-2 AM (Invitrogen, Carlsbad, CA) prepared as a 2.85 mM stock in DMSO and mixed in a 1:1 ratio with 10 percent (w/v) pluronic acid F-127 and diluted in Assay Buffer for 1 hour at room temperature. The dye was then exchanged to Assay Buffer using an ELX405, leaving 20 μL/well and the plates were incubated at room temperature for 10 min prior to assay. For concentration-response experiments, compounds were serially diluted 1:3 into 10 point concentration response curves in DMSO, were transferred to daughter plates using an Echo acoustic plate reformatter (Labcyte, Sunnyvale, CA), and diluted into Assay Buffer to generate a 2X stock. Agonists were diluted in Thallium Buffer (125 mM sodium bicarbonate (added fresh the morning of the experiment), 1 mM magnesium sulfate, 1.8 mM calcium sulfate, 5 mM glucose, 12 mM thallium sulfate, 10 mM HEPES, pH 7.3) at 5X the final concentration to be assayed. Thallium flux was measured using the Functional Drug Screening System 6000 or 7000 (FDSS6000 or FDSS7000, Hamamatsu, Japan). Baseline readings were taken (10 images at 1 Hz, excitation, 470+/−20 nm, emission, 540+/−30 nm) and then 20 μL/well test compounds were added using the FDSS’s integrated pipettor. Approximately 2.5 minutes later 10 μL of Thallium Buffer +/− agonist was added. After the addition of agonist, data were collected for an approximately 3 additional min. Data were analyzed as described (Niswender et al., 2008). For fold shift experiments, compounds were added at 2X their final concentration and then increasing concentrations of glutamate were added in the presence of vehicle or the appropriate concentration of test compound. For selectivity experiments, full concentration-response curves of glutamate or L-AP4 (for mGlu<sub>7</sub>) were performed in the presence of a 10 μM concentration of compound, and compounds that affected the concentration-response by less than 2 fold in terms of potency or efficacy were designated as inactive.</p><p><b>DMPK Methods.</b>
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<u><i>In vitro</i>:</u> The metabolism of <a href="/pcsubstance/?term=ML337[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML337</a> was investigated in rat hepatic microsomes (BD Biosciences, Billerica, MA) using substrate depletion methodology (% test article remaining). A potassium phosphate-buffered reaction mixture (0.1 M, pH 7.4) of test article (1 μM) and microsomes (0.5 mg/mL) was pre-incubated (5 min) at 37°C prior to the addition of NADPH (1 mM). The incubations, performed in 96-well plates, were continued at 37 °C under ambient oxygenation and aliquots (80 μL) were removed at selected time intervals (0, 3, 7, 15, 25 and 45 min). Protein was precipitated by the addition of chilled acetonitrile (160 μL), containing glyburide as an internal standard (50 ng/mL), and centrifuged at 3000 rpm (4°C) for 10 min. Resulting supernatants were transferred to new 96-well plates in preparation for LC/MS/MS analysis. The <i>in vitro</i> half-life (<i>t</i><sub>1/2</sub>, min, <a href="#ml337.eq1">Eq. 1</a>), intrinsic clearance (CL<sub>int</sub>, mL/min/kg, <a href="#ml337.eq2">Eq. 2</a>) and subsequent predicted hepatic clearance (CL<sub>hep</sub>, mL/min/kg, <a href="#ml337.eq3">Eq. 3</a>) were determined employing the following equations:</p><div class="pmc_disp_formula whole_rhythm clearfix" id="ml337.eq1"><div class="inline_block pmc_inline_block pmc_va_middle pmc_hide_overflow eleven_col">
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<i>t</i><sub>1/2</sub> = Ln(2) / <i>k</i> ; where <i>k</i> represents the slope from linear regression analysis (% test article remaining)</div><div class="inline_block pmc_inline_block pmc_va_middle pmc_hide_overflow last bk_equ_label "><div><span class="nowrap">1</span></div></div></div><div class="pmc_disp_formula whole_rhythm clearfix" id="ml337.eq2"><div class="inline_block pmc_inline_block pmc_va_middle pmc_hide_overflow eleven_col">
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CL<sub>int</sub> = (0.693 / <i>t</i><sub>1/2</sub>) (rxn volume / mg of microsomes) (45 mg microsomes / gram of liver) (20<sup><i>a</i></sup> gm of liver / kg body weight); <sup><i>a</i></sup>scale-up factors of 20 (human) and 45 (rat)</div><div class="inline_block pmc_inline_block pmc_va_middle pmc_hide_overflow last bk_equ_label "><div><span class="nowrap">2</span></div></div></div><div class="pmc_disp_formula whole_rhythm clearfix" id="ml337.eq3"><div class="inline_block pmc_inline_block pmc_va_middle pmc_hide_overflow eleven_col">
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<math id="ml337.eq4" display="block"><semantics><mrow><mi>C</mi><mi>L</mi><mi>h</mi><mi>e</mi><mi>p</mi><mo>=</mo><mfrac><mrow><mi>Q</mi><mo>·</mo><mi>C</mi><mi>L</mi><mi> </mi><mtext>int</mtext></mrow><mrow><mi>Q</mi><mo>+</mo><mi>C</mi><mi>L</mi><mi> </mi><mtext>int</mtext></mrow></mfrac></mrow></semantics></math></div><div class="inline_block pmc_inline_block pmc_va_middle pmc_hide_overflow last bk_equ_label "><div><span class="nowrap">3</span></div></div></div><p><b>Plasma Protein Binding.</b> Protein binding of <a href="/pcsubstance/?term=ML337[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML337</a> was determined in rat plasma via equilibrium dialysis employing Single-Use RED Plates with inserts (ThermoFisher Scientific, Rochester, NY). Briefly plasma (220 μL) was added to the 96 well plate containing test article (5 μL) and mixed thoroughly. Subsequently, 200 μL of the plasma-test article mixture was transferred to the <i>cis</i> chamber (red) of the RED plate, with an accompanying 350 μL of phosphate buffer (25 mM, pH 7.4) in the <i>trans</i> chamber. The RED plate was sealed and incubated 4 h at 37 °C with shaking. At completion, 50 μL aliquots from each chamber were diluted 1:1 (50 μL) with either plasma (<i>cis</i>) or buffer (<i>trans</i>) and transferred to a new 96 well plate, at which time ice-cold acetonitrile (2 volumes) was added to extract the matrices. The plate was centrifuged (3000 rpm, 10 min) and supernatants transferred to a new 96 well plate. The sealed plate was stored at −20 °C until LC/MS/MS analysis.</p><p><b>Liquid Chromatography/Mass Spectrometry Analysis</b>. <i>In vitro</i> experiments. <a href="/pcsubstance/?term=ML337[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML337</a> was analyzed via electrospray ionization (ESI) on an AB Sciex API-4000 (Foster City, CA) triple-quadrupole instrument that was coupled with Shimadzu LC-10AD pumps (Columbia, MD) and a Leap Technologies CTC PAL auto-sampler (Carrboro, NC). Analytes were separated by gradient elution using a Fortis C18 2.1 × 50 mm, 3.5 μm column (Fortis Technologies Ltd, Cheshire, UK) thermostated at 40 °C. HPLC mobile phase A was 0.1% NH<sub>4</sub>OH (pH unadjusted), mobile phase B was acetonitrile. The gradient started at 30% B after a 0.2 min hold and was linearly increased to 90% B over 0.8 min; held at 90% B for 0.5 min and returned to 30% B in 0.1 min followed by a re-equilibration (0.9 min). The total run time was 2.5 min and the HPLC flow rate was 0.5 mL/min. The source temperature was set at 500°C and mass spectral analyses were performed using multiple reaction monitoring (MRM) utilizing a Turbo-Ionspray® source in positive ionization mode (5.0 kV spray voltage). LC/MS/MS analysis was performed employing a TSQ Quantum<sup>ULTRA</sup> that was coupled to a ThermoSurveyor LC system (Thermoelectron Corp., San Jose, CA) and a Leap Technologies CTC PAL auto-sampler (Carrboro, NC). Chromatographic separation of analytes was achieved with an Acquity BEH C18 2.1 × 50 mm, 1.7 μm column (Waters, Taunton, MA).</p><div id="ml337.s4"><h3>2.1. Assays</h3><ul><li class="half_rhythm"><div><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/602451" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 602451</a> (mGluR3_NAM_Summary)</div></li><li class="half_rhythm"><div><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/651840" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 651840</a> (Negative Allosteric Modulators mGlu3 Galpha15 Calcium Potency)</div></li><li class="half_rhythm"><div><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/623888" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 623888</a> (mGlu3_GIRK_Schild)</div></li><li class="half_rhythm"><div><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/651839" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 651839</a> (Negative Allosteric Modulators, mGlu3 GIRK Potency)</div></li><li class="half_rhythm"><div><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/623929" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 623929</a> (mGluR2_NAM)</div></li><li class="half_rhythm"><div><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588715" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 588715</a> (mGlu5_PAM_Secondary)</div></li><li class="half_rhythm"><div><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/651830" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 651830</a> (<a href="/pcsubstance/?term=ML337[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML337</a> mGlu3 NAM Competition in Radioligand Binding assays (Eurofins PanLabs)</div></li></ul></div><div id="ml337.s5"><h3>2.2. Probe Chemical Characterization</h3><p>Probe compound <a href="/pcsubstance/?term=ML337[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML337</a> (CID 60204017, <a href="https://pubchem.ncbi.nlm.nih.gov/substance/144223348" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 144223348</a>) was prepared according <a class="figpopup" href="/books/NBK148852/figure/ml337.f3/?report=objectonly" target="object" rid-figpopup="figml337f3" rid-ob="figobml337f3">Scheme 1</a> and had the following characterization. <b>(<i>R</i>)-(2-fluoro-(4-((4-methoxyphenyl) ethynyl)phenyl)(3-(hydroxypiperidin-1-yl)methanone.</b> [α]<sub>D</sub><sup>23</sup> = −27.6° (<i>c =</i> 1, MeOH). LC (254 nm) 0.704 min (>99%); MS (ESI) <i>m/z</i> = 354.1. HRMS (TOF, ES+) C<sub>21</sub>H<sub>20</sub>FNO<sub>3.</sub>[M+H]<sup>+</sup> calc. mass 354.1505, found 354.1507. <sup>1</sup>H NMR (400.1 MHz, <i>d</i>6-DMSO) δ (ppm) [* = Rotamers]: 7.51 (d, <i>J</i> = 8.4 Hz, 2H); 7.46 (d, <i>J</i> = 10.2 Hz, 1H); 7.39 (m, 2H); 6.99 (d, <i>J</i> = 8.9 Hz, 2H); 5.00 (dd, <i>J</i><sub><i>1</i></sub> = 76.0 Hz, <i>J</i><sub><i>2</i></sub> = 4.2 Hz, 1H); 4.17 (m, 1H*); 3.78 (s, 3H); 3.32 (d, <i>J</i> = 12.5 Hz, 1H*); 3.19 (m, 1H*); 2.99 (m, 1H*); 2.89 (m, 1H); 1.75 (m, 2H); 1.37 (m, 2H). <sup>13</sup>C NMR (100.6 MHz, <i>d</i>6-DMSO) δ (ppm): 164.03 (d, <i>J</i> = 19.4 Hz), 160.31, 158.91, 156.47, 133.60, 129.39, 128.15 (d, <i>J</i> =9.7 Hz), 125.79, 124.90*, 124.77*, 118.52 (d, <i>J</i> =22.6 Hz), 114.87, 113.84, 91.91*, 91.88*, 86.73, 65.48*,65.32*, 55.69, 53.76, 48.68*, 47.05*, 41.82, 33.05*, 32.69*, 23.52.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml337f3" co-legend-rid="figlgndml337f3"><a href="/books/NBK148852/figure/ml337.f3/?report=objectonly" target="object" title="Scheme 1" class="img_link icnblk_img figpopup" rid-figpopup="figml337f3" rid-ob="figobml337f3"><img class="small-thumb" src="/books/NBK148852/bin/ml337f3.gif" src-large="/books/NBK148852/bin/ml337f3.jpg" alt="Scheme 1. Probe preparation of ML337." /></a><div class="icnblk_cntnt" id="figlgndml337f3"><h4 id="ml337.f3"><a href="/books/NBK148852/figure/ml337.f3/?report=objectonly" target="object" rid-ob="figobml337f3">Scheme 1</a></h4><p class="float-caption no_bottom_margin">Probe preparation of ML337. </p></div></div><p><b>Solubility.</b> Solubility for <a href="/pcsubstance/?term=ML337[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML337</a> in PBS was determined to be 7.8 μM (3.2 μg/mL), which is ~13-fold higher than the cellular IC<sub>50</sub> for mGlu<sub>3</sub> inhibition.</p><p><b>GSH Conjugates.</b> No glutathione conjugates detected.</p><p><b>Stability.</b> Stability was determined for <a href="/pcsubstance/?term=ML337[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML337</a> at 23 °C in PBS (no antioxidants or other protectorants and DMSO concentration below 0.1%). See <a class="figpopup" href="/books/NBK148852/table/ml337.t1/?report=objectonly" target="object" rid-figpopup="figml337t1" rid-ob="figobml337t1">Table 1</a>. After 48 hours, ~35% of the initial concentration of <a href="/pcsubstance/?term=ML337[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML337</a> remained in solution. The loss is most likely due to limited solubility in buffer. In plasma, <a href="/pcsubstance/?term=ML337[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML337</a> is very stable <i>in vitro</i> as well as <i>in vivo</i> (<i>vide infra</i>).</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml337t1"><a href="/books/NBK148852/table/ml337.t1/?report=objectonly" target="object" title="Table 1" class="img_link icnblk_img figpopup" rid-figpopup="figml337t1" rid-ob="figobml337t1"><img class="small-thumb" src="/books/NBK148852/table/ml337.t1/?report=thumb" src-large="/books/NBK148852/table/ml337.t1/?report=previmg" alt="Table 1. Stability of ML337." /></a><div class="icnblk_cntnt"><h4 id="ml337.t1"><a href="/books/NBK148852/table/ml337.t1/?report=objectonly" target="object" rid-ob="figobml337t1">Table 1</a></h4><p class="float-caption no_bottom_margin">Stability of ML337. </p></div></div><p>MLS004580699 (<a href="/pcsubstance/?term=ML337[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML337</a>, CID 60204017, 26.0 mg); MLS004580700 (CID 60204018, 5.7 mg); MLS004580701 (CID 60210783, 5.2 mg); MLS004580702 (CID 60210757, 5.0 mg); MLS004580703 (CID 60204019, 5.1 mg); MLS004580704 (CID 60210795; 4.8 mg)</p></div><div id="ml337.s6"><h3>2.3. Probe Preparation</h3><p>Probe compound <a href="/pcsubstance/?term=ML337[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML337</a> (CID 60204017, <a href="https://pubchem.ncbi.nlm.nih.gov/substance/144223348" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 144223348</a>) was prepared according to <a class="figpopup" href="/books/NBK148852/figure/ml337.f4/?report=objectonly" target="object" rid-figpopup="figml337f4" rid-ob="figobml337f4">Scheme 2</a> and had the following characterization. <b>(<i>R</i>)-(2-fluoro-(4-((4-methoxyphenyl) ethynyl)phenyl)(3-(hydroxypiperidin-1-yl)methanone. 2-fluoro-4-((4-methoxyphenyl)ethynyl)benzoic acid, (6).</b> To a solution of 4-Iodo-2-fluorobenzoic acid (798 mg, 3 mmol) in N,N’-dimethyformamide (5 mL) was added CuI (23 mg, 0.12 mmol), Pd(Ph<sub>3</sub>P)<sub>4</sub> (70 mg, 0.06 mmol), Diethylamine (241 mg, 3.3 mmol), and 1-ethynyl-4-methoxybenzene (475 mg, 3.6 mmol) under argon in a sealed microwave vial. The mixture was allowed to stir and was placed in a microwave reactor and heated to 100 °C for 1 hour. The reaction was allowed to cool to room temperature and was diluted with EtOAc (10 mL), washed with water (10 mL), 5% LiCl (aqueous, 2 × 10 mL), and brine (10 mL). The organic layer was passed through a Celite pad, dried with MgSO4, filtered, and solvent was removed under vacuum. <b>6</b> (750 mg, 92.5%) was isolated following purification on HPLC. LC (254nm) 0.752min (>99%); MS (ESI) <i>m/z</i> = 271.1, C<sub>16</sub>H<sub>11</sub>FO<sub>3</sub></p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml337f4" co-legend-rid="figlgndml337f4"><a href="/books/NBK148852/figure/ml337.f4/?report=objectonly" target="object" title="Scheme 2" class="img_link icnblk_img figpopup" rid-figpopup="figml337f4" rid-ob="figobml337f4"><img class="small-thumb" src="/books/NBK148852/bin/ml337f4.gif" src-large="/books/NBK148852/bin/ml337f4.jpg" alt="Scheme 2. Probe preparation of ML337." /></a><div class="icnblk_cntnt" id="figlgndml337f4"><h4 id="ml337.f4"><a href="/books/NBK148852/figure/ml337.f4/?report=objectonly" target="object" rid-ob="figobml337f4">Scheme 2</a></h4><p class="float-caption no_bottom_margin">Probe preparation of ML337. </p></div></div><p><b>(<i>R</i>)-(2-fluoro-4-((4-methoxyphenyl)ethynyl)phenyl)(3-hydroxypiperidin-1-yl)methanone, (7, <a href="/pcsubstance/?term=ML337[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML337</a>).</b> To a solution of compound <b>2</b> (675 mg, 2.5 mmol) in 20 mL DMF, was added diisopropylethylamine (1.07 g, 8.25 mmol) while stirring. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (560 mg, 3 mmol), hydroxybenzotriazole (337 mg, 2.5 mmol), and (R)-3-hydroxypiperidine hydrochloride (342 mg, 2.5 mmol) were then added. The reaction was allowed to stir for 4 hours at room temperature, then quenched with a solution of saturated NaHCO<sub>3</sub> (20 mL), washed with 5% LiCl (aqueous, 2 × 20 mL), and brine (20 mL). The reaction was extracted into dichloromethane (50 mL), and solvent was removed under vacuum. The residue was purified using HPLC, and amine <b>3</b> was obtained as an ivory solid (420 mg, 47%). [α]<sub>D</sub><sup>23</sup> = −27.6° (<i>c =</i> 1, MeOH). LC (254 nm) 0.704 min (>99%); MS (ESI) <i>m/z</i> = 354.1. HRMS (TOF, ES+) C<sub>21</sub>H<sub>20</sub>FNO<sub>3.</sub>[M+H]<sup>+</sup> calc. mass 354.1505, found 354.1507. <sup>1</sup>H NMR (400.1 MHz, <i>d</i>6-DMSO) δ (ppm) [* = Rotamers]: 7.51 (d, <i>J</i> = 8.4 Hz, 2H); 7.46 (d, <i>J</i> = 10.2 Hz, 1H); 7.39 (m, 2H); 6.99 (d, <i>J</i> = 8.9 Hz, 2H); 5.00 (dd, <i>J</i><sub><i>1</i></sub> = 76.0 Hz, <i>J</i><sub><i>2</i></sub> = 4.2 Hz, 1H); 4.17 (m, 1H*); 3.78 (s, 3H); 3.32 (d, <i>J</i> = 12.5 Hz, 1H*); 3.19 (m, 1H*); 2.99 (m, 1H*); 2.89 (m, 1H); 1.75 (m, 2H); 1.37 (m, 2H). <sup>13</sup>C NMR (100.6 MHz, <i>d</i>6-DMSO) δ (ppm): 164.03 (d, <i>J</i> = 19.4 Hz), 160.31, 158.91, 156.47, 133.60, 129.39, 128.15 (d, <i>J</i> =9.7 Hz), 125.79, 124.90*, 124.77*, 118.52 (d, <i>J</i> =22.6 Hz), 114.87, 113.84, 91.91*, 91.88*, 86.73, 65.48*,65.32*, 55.69, 53.76, 48.68*, 47.05*, 41.82, 33.05*, 32.69*, 23.52.</p></div></div><div id="ml337.s7"><h2 id="_ml337_s7_">3. Results</h2><div id="ml337.s8"><h3>3.1. Dose Response Curves for Probe</h3><div id="ml337.f1" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%201.%20In%20vitro%20molecular%20pharmacology%20characterization%20of%20ML337%20and%20three%20closely%20related%20mGlu3%20NAMs.&p=BOOKS&id=148852_ml337f1.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/NBK148852/bin/ml337f1.jpg" alt="Figure 1. In vitro molecular pharmacology characterization of ML337 and three closely related mGlu3 NAMs." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 1</span><span class="title"><i>In vitro</i> molecular pharmacology characterization of ML337 and three closely related mGlu<sub>3</sub> NAMs</span></h3><div class="caption"><p>Concentration-response curves of mGlu<sub>2</sub> and mGlu<sub>3</sub> calcium (antagonist mode) for the four lead mGlu<sub>3</sub> NAMs, including <a href="/pcsubstance/?term=ML337[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML337</a>. All four provide complete inhibition of mGlu<sub>3</sub> and are devoid of activity at mGlu<sub>2</sub>. In addition, all four have no activity (PAM or NAM) at mGlu<sub>1,4,5,6,7,8</sub>.</p></div></div></div><div id="ml337.s9"><h3>3.2. Cellular Activity</h3><p>The primary screening assays (both GIRK and Calcium) are cell-based assays, indicating that <a href="/pcsubstance/?term=ML337[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML337</a> can gain access to its molecular target when applied to cells. The compound did not exhibit acute toxicity in cell based assays at concentrations up to 30 μM, and cytotoxicity assays aimed at this parameter indicated <a href="/pcsubstance/?term=ML337[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML337</a> had no cytotoxicity in non-transformed HEK293.</p></div><div id="ml337.s10"><h3>3.3. Profiling Assays</h3><p>To more fully characterize this potent, selective mGlu<sub>3</sub> NAM <a href="/pcsubstance/?term=ML337[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML337</a> was tested using Ricerca’s (formerly MDS Pharma’s) Lead Profiling Screen (binding assay panel of 68 GPCRs, ion channels and transporters screened at 10 μM).<a class="bk_pop" href="#ml337.r2">2</a> Included in the Ricerca screening panel are a number of ion channels (Calcium Channel, L-Type and N-Type; Potassium channel [K<sub>ATP</sub>]; Potassium channel [hERG]) and class A GPCRs (D<sub>1–5</sub>, H<sub>1–3</sub>, etc.). <a href="/pcsubstance/?term=ML337[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML337</a> was found to only inhibit two targets (DAT: 71%@10 μM and 5-HT<sub>2B</sub> 74%@10 μM) out of the 68 assays (<a class="figpopup" href="/books/NBK148852/table/ml337.t2/?report=objectonly" target="object" rid-figpopup="figml337t2" rid-ob="figobml337t2">Table 2</a>) conducted (inhibition of radio ligand binding > 50% at 10 μM).<a class="bk_pop" href="#ml337.r2">2</a>
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<a href="/pcsubstance/?term=ML289[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML289</a> hit the same two targets, but at 88% and 77% inhibition@ 10 μM, respectively for DAT and 5-HT<sub>2B</sub>. <a class="figpopup" href="/books/NBK148852/table/ml337.t3/?report=objectonly" target="object" rid-figpopup="figml337t3" rid-ob="figobml337t3">Table 3</a> highlights calculated properties for <a href="/pcsubstance/?term=ML337[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML337</a>, which compares favorably with the MDDR.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml337t2"><a href="/books/NBK148852/table/ml337.t2/?report=objectonly" target="object" title="Table 2" class="img_link icnblk_img figpopup" rid-figpopup="figml337t2" rid-ob="figobml337t2"><img class="small-thumb" src="/books/NBK148852/table/ml337.t2/?report=thumb" src-large="/books/NBK148852/table/ml337.t2/?report=previmg" alt="Table 2. Ricerca Profiling of ML337." /></a><div class="icnblk_cntnt"><h4 id="ml337.t2"><a href="/books/NBK148852/table/ml337.t2/?report=objectonly" target="object" rid-ob="figobml337t2">Table 2</a></h4><p class="float-caption no_bottom_margin">Ricerca Profiling of ML337. </p></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml337t3"><a href="/books/NBK148852/table/ml337.t3/?report=objectonly" target="object" title="Table 3" class="img_link icnblk_img figpopup" rid-figpopup="figml337t3" rid-ob="figobml337t3"><img class="small-thumb" src="/books/NBK148852/table/ml337.t3/?report=thumb" src-large="/books/NBK148852/table/ml337.t3/?report=previmg" alt="Table 3. Calculated Property Comparison with MDDR Compounds." /></a><div class="icnblk_cntnt"><h4 id="ml337.t3"><a href="/books/NBK148852/table/ml337.t3/?report=objectonly" target="object" rid-ob="figobml337t3">Table 3</a></h4><p class="float-caption no_bottom_margin">Calculated Property Comparison with MDDR Compounds. </p></div></div></div></div><div id="ml337.s11"><h2 id="_ml337_s11_">4. Discussion</h2><div id="ml337.s12"><h3>4.1. Comparison to Existing Art and How the New Probe is an Improvement</h3><p><a href="/pcsubstance/?term=ML337[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML337</a> (CID 60204017) is the most potent (IC<sub>50</sub> = 592 nM, 0.3%) and selective mGlu<sub>3</sub> NAM reported to date with >50-fold selectivity vs. mGlu<sub>2</sub> and inactive on mGlu<sub>1,4,5,6,7,8</sub>. The existing art, represented by <b>1–3</b> (see <a class="figpopup" href="/books/NBK148852/figure/ml337.f2/?report=objectonly" target="object" rid-figpopup="figml337f2" rid-ob="figobml337f2">Figure 2</a>), are inferior to the probe <a href="/pcsubstance/?term=ML337[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML337</a> in terms of both potency and mGlu<sub>3</sub> selectivity. <a href="/pcsubstance/?term=ML337[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML337</a> can be used both <i>in vitro</i> and <i>in vivo</i> to study the role of selective inhibition of mGlu<sub>3</sub> in the CNS in a manner previously unavailable with the prior art compounds. Moreover, <a href="/pcsubstance/?term=ML337[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML337</a> possess an attractive <i>in vitro</i> and <i>in vivo</i> DMPK profile, ancillary pharmacology (only two activities at 10 μM in the Ricerca Panel) and affords excellent CNS exposure in both mouse (brain:plasma ratio of 0.92) and rat (brain:plasma ratio of 0.3). <a href="/pcsubstance/?term=ML337[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML337</a> can be used for basic biochemical and electrophysiological experiments as well as to help establish potential utility for mGlu<sub>3</sub> inhibition as a target for a wide variety of important CNS therapeutic indications. Finally, <a href="/pcsubstance/?term=ML337[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML337</a> is free from IP constraints, which will allow the MLPCN to freely provide this probe to the biomedical research community.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml337f2" co-legend-rid="figlgndml337f2"><a href="/books/NBK148852/figure/ml337.f2/?report=objectonly" target="object" title="Figure 2" class="img_link icnblk_img figpopup" rid-figpopup="figml337f2" rid-ob="figobml337f2"><img class="small-thumb" src="/books/NBK148852/bin/ml337f2.gif" src-large="/books/NBK148852/bin/ml337f2.jpg" alt="Figure 2. Structures of mGlu3 NAMs RO4491533 (1) and LY2399575 (2), both dual mGlu2/mGlu3 NAMs, and the first mGlu3 selective NAM, ML289, with ~15-fold selectivity versus mGlu2." /></a><div class="icnblk_cntnt" id="figlgndml337f2"><h4 id="ml337.f2"><a href="/books/NBK148852/figure/ml337.f2/?report=objectonly" target="object" rid-ob="figobml337f2">Figure 2</a></h4><p class="float-caption no_bottom_margin">Structures of mGlu<sub>3</sub> NAMs RO4491533 (1) and LY2399575 (2), both dual mGlu<sub>2</sub>/mGlu<sub>3</sub> NAMs, and the first mGlu<sub>3</sub> selective NAM, ML289, with ~15-fold selectivity versus mGlu<sub>2</sub>. </p></div></div></div></div><div id="ml337.s13"><h2 id="_ml337_s13_">5. References</h2><dl class="temp-labeled-list"><dt>1.</dt><dd><div class="bk_ref" id="ml337.r1">Niswender CM, Johnson KA, Luo Q, Ayala JE, Kim C, Conn PJ, Weaver CD. <span><span class="ref-journal">Mol. Pharm. </span>2008;<span class="ref-vol">73</span>:1213–1224.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/18171729" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18171729</span></a>]</div></dd><dt>2.</dt><dd><div class="bk_ref" id="ml337.r2">For full information on the targets in the Lead Profiling Screen at Ricerca, please see: <a href="http://www.ricerca.com" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">www<wbr style="display:inline-block"></wbr>.ricerca.com</a></div></dd></dl></div><div id="bk_toc_contnr"></div></div></div>
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<div class="post-content"><div><div class="half_rhythm"><a href="/books/about/copyright/">Copyright Notice</a></div><div class="small"><span class="label">Bookshelf ID: NBK148852</span><span class="label">PMID: <a href="https://pubmed.ncbi.nlm.nih.gov/23885366" title="PubMed record of this page" ref="pagearea=meta&targetsite=entrez&targetcat=link&targettype=pubmed">23885366</a></span></div><div style="margin-top:2em" class="bk_noprnt"><a class="bk_cntns" href="/books/n/mlprobe/">Contents</a><div class="pagination bk_noprnt"><a class="active page_link prev" href="/books/n/mlprobe/ml338/" title="Previous page in this title">< Prev</a><a class="active page_link next" href="/books/n/mlprobe/ml336/" title="Next page in this title">Next ></a></div></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/NBK148852/?report=reader">PubReader</a></li><li><a href="/books/NBK148852/?report=printable">Print View</a></li><li><a data-jig="ncbidialog" href="#_ncbi_dlg_citbx_NBK148852" data-jigconfig="width:400,modal:true">Cite this Page</a><div id="_ncbi_dlg_citbx_NBK148852" style="display:none" title="Cite this Page"><div class="bk_tt">Wenthur C, Daniels JS, Morrison R, et al. Development of a Second Generation mGlu3 NAM Probe. 2012 Dec 10 [Updated 2013 Mar 22]. 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="#ml337.s1" ref="log$=inpage&link_id=inpage">Probe Structure & Characteristics</a></li><li><a href="#ml337.s2" ref="log$=inpage&link_id=inpage">Recommendations for Scientific Use of the Probe</a></li><li><a href="#ml337.s3" ref="log$=inpage&link_id=inpage">Materials and Methods</a></li><li><a href="#ml337.s7" ref="log$=inpage&link_id=inpage">Results</a></li><li><a href="#ml337.s11" ref="log$=inpage&link_id=inpage">Discussion</a></li><li><a href="#ml337.s13" ref="log$=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=pcsubstance&DbFrom=books&Cmd=Link&LinkName=books_pcsubstance&IdsFromResult=3044024" ref="log$=recordlinks">PubChem Substance</a><div class="brieflinkpop offscreen_noflow">Related PubChem Substances</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=pubmed&DbFrom=books&Cmd=Link&LinkName=books_pubmed_refs&IdsFromResult=3044024" ref="log$=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/23762947" ref="ordinalpos=1&linkpos=1&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Development of the First Selective mGlu(3) NAM from an mGlu(5) PAM Hit.</a><span class="source">[Probe Reports from the NIH Mol...]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Development of the First Selective mGlu(3) NAM from an mGlu(5) PAM Hit.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Sheffler DJ, Wenthur CJ, Brunner JA, Daniels JS, Morrison RD, Blobaum AL, Dawson ES, Engers JL, Niswender CM, Conn PJ, et al. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">Probe Reports from the NIH Molecular Libraries Program. 2010</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/23718281" ref="ordinalpos=1&linkpos=2&log$=relatedarticles&logdbfrom=pubmed">Discovery of (R)-(2-fluoro-4-((-4-methoxyphenyl)ethynyl)phenyl) (3-hydroxypiperidin-1-yl)methanone (ML337), an mGlu3 selective and CNS penetrant negative allosteric modulator (NAM).</a><span class="source">[J Med Chem. 2013]</span><div class="brieflinkpop offscreen_noflow">Discovery of (R)-(2-fluoro-4-((-4-methoxyphenyl)ethynyl)phenyl) (3-hydroxypiperidin-1-yl)methanone (ML337), an mGlu3 selective and CNS penetrant negative allosteric modulator (NAM).<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Wenthur CJ, Morrison R, Felts AS, Smith KA, Engers JL, Byers FW, Daniels JS, Emmitte KA, Conn PJ, Lindsley CW. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">J Med Chem. 2013 Jun 27; 56(12):5208-12. 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