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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="Discovery of a potent, selective and orally active in vivo mGlu4 positive allosteric modulator" /><meta name="citation_publisher" content="National Center for Biotechnology Information (US)" /><meta name="citation_date" content="2013/03/14" /><meta name="citation_author" content="Corey R. Hopkins" /><meta name="citation_author" content="Darren W. Engers" /><meta name="citation_author" content="Colleen M. Niswender" /><meta name="citation_author" content="Carrie K. Jones" /><meta name="citation_author" content="Eric Dawson" /><meta name="citation_author" content="C. David Weaver" /><meta name="citation_author" content="J. Scott Daniels" /><meta name="citation_author" content="P. Jeffrey Conn" /><meta name="citation_author" content="Craig W. 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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="#__NBK143194_dtls__">Show details</a><div style="display:none" class="ui-widget" id="__NBK143194_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/ml186/" title="Previous page in this title">< Prev</a><a class="active page_link next" href="/books/n/mlprobe/ml181/" 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="_NBK143194_"><span class="title" itemprop="name">Discovery of a potent, selective and orally active <i>in vivo</i> mGlu<sub>4</sub> positive allosteric modulator</span></h1><p class="contrib-group"><span itemprop="author">Corey R. Hopkins</span>, <span itemprop="author">Darren W. Engers</span>, <span itemprop="author">Colleen M. Niswender</span>, <span itemprop="author">Carrie K. Jones</span>, <span itemprop="author">Eric Dawson</span>, <span itemprop="author">C. David Weaver</span>, <span itemprop="author">J. Scott Daniels</span>, <span itemprop="author">P. Jeffrey Conn</span>, and <span itemprop="author">Craig W. Lindsley</span>.</p><a data-jig="ncbitoggler" href="#__NBK143194_ai__" style="border:0;text-decoration:none">Author Information and Affiliations</a><div style="display:none" class="ui-widget" id="__NBK143194_ai__"><p class="contrib-group"><h4>Authors</h4><span itemprop="author">Corey R. Hopkins</span>,<sup>1</sup> <span itemprop="author">Darren W. Engers</span>,<sup>1</sup> <span itemprop="author">Colleen M. Niswender</span>,<sup>3</sup> <span itemprop="author">Carrie K. Jones</span>,<sup>3</sup> <span itemprop="author">Eric Dawson</span>,<sup>1</sup> <span itemprop="author">C. David Weaver</span>,<sup>2</sup> <span itemprop="author">J. Scott Daniels</span>,<sup>3</sup> <span itemprop="author">P. Jeffrey Conn</span>,<sup>3</sup> and <span itemprop="author">Craig W. Lindsley</span><sup>1</sup><sup>,<img src="/corehtml/pmc/pmcgifs/corrauth.gif" alt="corresponding author" /></sup>.</p><h4>Affiliations</h4><div class="affiliation"><sup>1</sup>
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Vanderbilt Specialized Chemistry Center for Accelerated Probe Development, Nashville, TN 37232</div><div class="affiliation"><sup>2</sup>
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Vanderbilt Screening Center for GPCRs, Ion Channels, and Transporters (MLSCN), Nashville, TN 37232</div><div class="affiliation"><sup>3</sup>
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Vanderbilt University, Vanderbilt Center for Neuroscience Drug Discovery, Nashville, TN 37232</div><div class="affiliation"><sup><img src="/corehtml/pmc/pmcgifs/corrauth.gif" alt="corresponding author" /></sup><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ude.tlibrednav@yelsdnil.giarc" class="oemail">ude.tlibrednav@yelsdnil.giarc</a></div></div><p class="small">Received: <span itemprop="datePublished">October 29, 2010</span>; Last Update: <span itemprop="dateModified">March 14, 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 href="/pcsubstance/?term=ML182[synonym]" ref="pagearea=abstract&targetsite=entrez&targetcat=term&targettype=pubchem">ML182</a> was identified through a medicinal chemistry campaign that was designed to improve the in vivo characteristics of <a href="/pcsubstance/?term=ML128[synonym]" ref="pagearea=abstract&targetsite=entrez&targetcat=term&targettype=pubchem">ML128</a>. <a href="/pcsubstance/?term=ML182[synonym]" ref="pagearea=abstract&targetsite=entrez&targetcat=term&targettype=pubchem">ML182</a> is a potent and novel positive allosteric modulator (PAM) of the metabotropic glutamate receptor 4 (mGlu<sub>4</sub>) – hEC<sub>50</sub> = 291 nM; rEC<sub>50</sub> = 376 nM. <a href="/pcsubstance/?term=ML182[synonym]" ref="pagearea=abstract&targetsite=entrez&targetcat=term&targettype=pubchem">ML182</a> shows excellent <i>in vitro</i> and <i>in vivo</i> pharmacokinetic characteristics and was shown to be active in an anti-Parkinsonian animal model after oral dosing (haloperidol-induced catalepsy). This will find utility in the Parkinson’s and mGlu community as a novel, selective and potent PAM of mGlu<sub>4</sub>.</p></div><div class="h2"></div><p><b>Assigned Assay Grant #:</b> NS053536-01</p><p><b>Screening Center Name & PI:</b> Vanderbilt Screening Center for GPCRs, Ion Channels and Transporters, C. David Weaver</p><p><b>Chemistry Center Name & PI:</b> Vanderbilt Specialized Chemistry Center for Accelerated Probe Development, Craig W. Lindsley</p><p><b>Assay Submitter & Institution:</b> Colleen M. Niswender, Vanderbilt University</p><p><b>PubChem Summary Bioassay Identifier (AID):</b>
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<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2437" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2437</a></p><div id="ml182.s1"><h2 id="_ml182_s1_">Probe Structure & Characteristics</h2><p><i>N</i>-(3-chloro-4-((3a<i>R</i>,4<i>S</i>,7<i>R</i>,7a<i>S</i>)-1,3-dioxo-3a,4,7,7a-tetrahydro-1<i>H</i>-4,7-methanoisoindol-2(3<i>H</i>)-yl)phenyl)picolinamide, MW = 393.8, clogP = 1.91, tPSA = 78.8 Å<sup>2</sup></p><div id="ml182.fu1" class="figure bk_fig"><div class="graphic"><img src="/books/NBK143194/bin/ml182fu1.jpg" alt="ML182." /></div><h3><span class="title">ML182</span></h3></div><div id="ml182.tu1" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK143194/table/ml182.tu1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml182.tu1_lrgtbl__"><table><thead><tr><th id="hd_h_ml182.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CID/ML#</th><th id="hd_h_ml182.tu1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Target Name</th><th id="hd_h_ml182.tu1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">IC<sub>50</sub>/EC<sub>50</sub> (nM) [SID, AID]</th><th id="hd_h_ml182.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_ml182.tu1_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">IC<sub>50</sub>/EC<sub>50</sub> (μM) [SID, AID]</th><th id="hd_h_ml182.tu1_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Fold Selective</th><th id="hd_h_ml182.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_ml182.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CID 46869947/<br /><br /><a href="/pcsubstance/?term=ML182[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML182</a></td><td headers="hd_h_ml182.tu1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">rmGlu<sub>4</sub><br />hmGlu<sub>4</sub></td><td headers="hd_h_ml182.tu1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">291 (hm), 376 (rat) [<a href="https://pubchem.ncbi.nlm.nih.gov/substance/99309089" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 99309089</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2197" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2197</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2185" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2185</a>]</td><td headers="hd_h_ml182.tu1_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">mGlu<sub>1</sub>,mGlu<sub>2</sub>, mGlu<sub>3</sub>, mGlu<sub>5</sub>, mGlu<sub>7</sub>, mGlu<sub>8</sub>, PanLabs (Ricerca)</td><td headers="hd_h_ml182.tu1_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">>10 μM, [<a href="https://pubchem.ncbi.nlm.nih.gov/substance/99309089" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 99309089</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2193" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2193</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2188" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2188</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2190" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2190</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2181" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2181</a>], 2.1 FS [<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2199" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2199</a>], 3.1 FS [<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2191" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2191</a>], 2.9 FS [<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2181" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2181</a>]</td><td headers="hd_h_ml182.tu1_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">>50</td><td headers="hd_h_ml182.tu1_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">11.2 (rat) mGlu<sub>4</sub> Fold-Shift [<a href="https://pubchem.ncbi.nlm.nih.gov/substance/99309089" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 99309089</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2179" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID
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2179</a>]</td></tr></tbody></table></div></div></div><div id="ml182.s2"><h2 id="_ml182_s2_">Recommendations for Scientific Use of the Probe</h2><p>This probe (CID 46869947) can be used to investigate the role of selective allosteric activation
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of mGlu<sub>4</sub>
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<i>in vitro</i> and <i>in vivo</i>. CID 46869947 is a potent (EC<sub>50</sub> = 291 ± 55 nM, 11.2 ± 0.8-fold shift) and selective (>30 μM vs. mGlu’s 1,2,3, and 8 and weak activity against mGlu<sub>5</sub> (2.1 FS), mGlu<sub>6</sub> (3.1 FS) and mGlu<sub>7</sub> (2.9 FS) and >10 μM vs. MDS Pharma Panel of 68 GPCRs, ion channels and transporters) mGlu<sub>4</sub> positive allosteric modulator (PAM). CID 46869947 is the most stable, centrally penetrant mGlu<sub>4</sub> PAM disclosed to date with excellent activity after oral dosing in an anti-Parkinsonian preclinical rodent model of Parkinson’s disease.</p></div><div id="ml182.s3"><h2 id="_ml182_s3_">1. Introduction</h2><p><b>Specific AIM:</b> To identify small molecule positive allosteric modulators (PAMs) of mGlu<sub>8</sub> and/or other group III mGlu’s. Probe candidates will be highly selective versus the other seven mGlu’s, and ideally be suitable for both <i>in vitro</i> and <i>in vivo</i> studies.</p><p><b>Significance:</b> The metabotropic glutamate receptors (mGluRs) are members of the GPCR family C, characterized by a large extracellular amino-terminal binding domain (agonist binding site) along with a seven-transmembrane spanning (7TM) domain which is the binding site for most known mGluR allosteric modulators.<sup><a class="bk_pop" href="#ml182.r1">1</a>–<a class="bk_pop" href="#ml182.r3">3</a></sup> The eight cloned mGluRs have been assigned to three groups (group I: mGluRs 1 and 5, group II: mGluRs 2 and 3, and group III: mGluRs 4,6,7,8) based on their structural similarity, ligand specificity, and preferred coupling mechanisms.<sup><a class="bk_pop" href="#ml182.r4">4</a></sup> Among the mGluRs, the group III receptors have thus far received less attention in terms of their therapeutic potential because of the paucity of selective ligands. However, recently there have been numerous reports detailing the potential benefits of mGluR4 activation in several disease models, most notably rodent models of Parkinson’s disease.<sup><a class="bk_pop" href="#ml182.r5">5</a>,<a class="bk_pop" href="#ml182.r6">6</a></sup> Parkinson’s disease (PD) is caused by the death of dopamine neurons in the basal ganglia and results in motor symptoms such as tremor and bradykinesia. Activation of metabotropic glutamate receptor 4 (mGluR4) has been shown to modulate neurotransmission in the basal ganglia, a mechanism that is expected to provide palliative benefit for the treatment of Parkinson’s disease (PD).<a class="bk_pop" href="#ml182.r7">7</a> In addition, there have been recent reports detailing the neuroprotective effects of an mGluR4 PAM in cultured neurons and <i>in vivo</i>.<sup><a class="bk_pop" href="#ml182.r8">8</a>,<a class="bk_pop" href="#ml182.r9">9</a></sup> However, the leading mGluR4 probe compound is <i>N</i>-Phenyl-7-(hydroxyimino) cyclopropa[<i>b</i>]chromen-1a-carboxamide (PHCCC), a positive allosteric modulator (PAM) of mGluR4 that has been used to further validate the role of mGluR4 in PD; unfortunately, the compound suffers from a lack of selectivity, relatively low potency and poor solubility/PK (<a class="figpopup" href="/books/NBK143194/figure/ml182.f1/?report=objectonly" target="object" rid-figpopup="figml182f1" rid-ob="figobml182f1">Figure 1</a>).<sup><a class="bk_pop" href="#ml182.r8">8</a>,<a class="bk_pop" href="#ml182.r10">10</a>,<a class="bk_pop" href="#ml182.r11">11</a></sup> Moreover, it is not systemically active and must be administered i.c.v. to show efficacy in PD models. Clearly, there is room for significant improvement.<sup><a class="bk_pop" href="#ml182.r10">10</a>,<a class="bk_pop" href="#ml182.r11">11</a></sup> Our mGluR8 screen employed mGluR4 as a representative group III mGluR counter-screen, which led to the discovery of a highly optimized mGluR4 <i>in vitro</i> and <i>in vivo</i> probe.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml182f1" co-legend-rid="figlgndml182f1"><a href="/books/NBK143194/figure/ml182.f1/?report=objectonly" target="object" title="Figure 1" class="img_link icnblk_img figpopup" rid-figpopup="figml182f1" rid-ob="figobml182f1"><img class="small-thumb" src="/books/NBK143194/bin/ml182f1.gif" src-large="/books/NBK143194/bin/ml182f1.jpg" alt="Figure 1. (−)-PHCCC, the prototypical mGluR4 PAM – weak, non-selective, poor physiochemical properties and no CNS penetration." /></a><div class="icnblk_cntnt" id="figlgndml182f1"><h4 id="ml182.f1"><a href="/books/NBK143194/figure/ml182.f1/?report=objectonly" target="object" rid-ob="figobml182f1">Figure 1</a></h4><p class="float-caption no_bottom_margin">(−)-PHCCC, the prototypical mGluR4 PAM – weak, non-selective, poor physiochemical properties and no CNS penetration. </p></div></div><p><b>Rationale:</b> In the present study, we developed and implemented a fluorescence-based calcium assay for high-throughput screening (HTS) of chemical libraries for novel modulators of mGluR8 function, and developed the appropriate counter screens within the mGluR family to identify other selective mGluR ligands as well.<sup><a class="bk_pop" href="#ml182.r12">12</a></sup></p></div><div id="ml182.s4"><h2 id="_ml182_s4_">2. Materials and Methods</h2><div id="ml182.s5"><h3>2.1. Assays</h3><p><b>PubChem Primary Assay Description:</b> A thallium flux assay was performed with human mGluR8 cells. These cell lines were grown in growth media containing 45% DMEM, 45% Ham’s F-12, 10% FBS, 20 mM HEPES, 2 mM L-glutamine, antibiotic/antimycotic, nonessential amino acids, 700 mg/mL G418, and 0.6 μg/mL puromycin at 37 °C in the presence of 5% CO2. In brief, mGluR8 GIRK cells were plated into 384-well, black-walled, clear-bottomed, poly(D-lysine)-coated plates at a density of 15 × 10<sup>3</sup> cells/20 μL/well in plating medium and incubated overnight at 37 °C in the presence of 5% CO<sub>2</sub>. The following day, the medium from the cells and 20 μL/well of 1.7 μM concentration of the indicator dye BTC-AM (Invitrogen) in assay buffer was added. Cells were incubated for 1 h at room temperature and the dye was replaced with 20 μL/well of assay buffer. For these assays, compounds were added at two times the final concentration, and then 2.5 min later, either an EC<sub>20</sub> or EC<sub>80</sub> concentration of glutamate (mGluR4 or 8) was added using the FDSS 6000. Agonists were diluted in thallium buffer (125 mM sodium bicarbonate, 1 mM magnesium sulfate, 1.8 mM calcium sulfate, 5 mM glucose, 12 mM thallium sulfate, and 10 mM HEPES) at five times the final concentration to be assayed. Five frames of data were collected (excitation, 470 ± 20 nm; emission, 540 ± 30 nm) at 0.5 Hz before compound addition. Data collection continued at 0.5 Hz until 10 s before agonist addition, when the rate was increased to 1 Hz for 2 min after agonist addition. Human mGluR4 (hmGluR4)/CHO cells were stably transfected with the chimeric G protein G<sub>qi5</sub> in pIRESneo3 (Invitrogen, Carlsbad, CA), and single neomycin-resistant clones were isolated and screened for mGluR4-mediated calcium mobilization using the method described below. hmGluR4/CHO cells were cultured in 90% Dulbecco’s modified Eagle’s medium (DMEM), 10% dialyzed fetal bovine serum (FBS), 100 U/mL penicillin/streptomycin, 20 mM HEPES, pH 7.3, 1 mM sodium pyruvate, 2 mM glutamine, 400 μg/mL G418 sulfate, 20 μM proline (Mediatech, Inc., Herndon, VA), and 5 nM methotrexate (Calbiochem, EMD Chemicals, Gibbstown, NJ). Culture of human embryonic kidney (HEK) 293 cell lines co-expressing rat mGluR4 and the G protein-regulated inwardly rectifying K<sup>+</sup> channel (GIRK) have been described. All cell culture reagents were purchased from Invitrogen unless otherwise noted.</p><p><b>List of PubChem bioassay identifiers generated for this screening project:</b>
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<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2199" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2199</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2197" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2197</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2193" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2193</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2191" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2191</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2190" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2190</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2188" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2188</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2185" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2185</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2183" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2183</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2182" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2182</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2181" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2181</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2437" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2437</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2807" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2807</a></p></div><div id="ml182.s6"><h3>2.2. Probe Chemical Characterization</h3><div id="ml182.f2" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%202.%20Synthetic%20procedure%20(large%20scale)%20and%20spectral%20data%20for%20ML182%20(CID%2046869947).&p=BOOKS&id=143194_ml182f2.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/NBK143194/bin/ml182f2.jpg" alt="Figure 2. Synthetic procedure (large scale) and spectral data for ML182 (CID 46869947)." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 2</span><span class="title">Synthetic procedure (large scale) and spectral data for ML182 (CID 46869947)</span></h3></div><p>Probe compound <a href="/pcsubstance/?term=ML182[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML182</a> (CID 46869947, <a href="https://pubchem.ncbi.nlm.nih.gov/substance/99309089" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 99309089</a>) was prepared according to the above scheme and provided the following characterization data: LCMS (>98%) <i>m/z</i> = 394 [M+H<sup>+</sup>] (1.37 min retention, 254 nm). <sup>1</sup>H NMR (400MHz, MeOD): δ = 8.81 (d, 1 H, <i>J</i> = 4.4 Hz), 8.41 (d, 1 H, <i>J</i> = 7.6 Hz), 8.31–8.28 (m, 1 H), 8.20 (d, 1 H, <i>J</i> = 2.4 Hz), 7.84 (m, 1 H), 7.80 (d, 1 H, <i>J</i> = 2.4 Hz), 7.05 (d, 1 H, <i>J</i> = 8.4 Hz), 6.31 (s, 2 H), 3.61–3.56 (m, 2 H), 3.44–3.42 (m, 2 H), 1.79–1.76 (m, 1 H), 1.71–1.68 (m, 1 H). HRMS, calc’d for C<sub>21</sub>H<sub>17</sub>N<sub>3</sub>O<sub>3</sub>Cl [M + H]<sup>+</sup>, 394.0958; found 394.0959.</p><p><b>Solubility.</b> Solubility in PBS was determined to be 4.06 μM. Additionally, as its HCl salt, <a href="/pcsubstance/?term=ML182[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML182</a> shows good solubility in other acceptable vehicles (>10 mg/mL in 20% β-cyclodextrin, PEG400/H<sub>2</sub>O and pH 3 saline) and >100 μM in DMSO.</p><p><b>GSH Conjugates.</b> No glutathione conjugates detected.</p><p><b>Stability.</b> Stability was determined for <a href="/pcsubstance/?term=ML182[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML182</a> at 23 °C in PBS (no antioxidants
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or other protectorants and DMSO concentration below 0.1%) and is shown in <a class="figpopup" href="/books/NBK143194/table/ml182.t1/?report=objectonly" target="object" rid-figpopup="figml182t1" rid-ob="figobml182t1">Table 1</a> and <a class="figpopup" href="/books/NBK143194/figure/ml182.f3/?report=objectonly" target="object" rid-figpopup="figml182f3" rid-ob="figobml182f3">Figure 3</a>. After 48 hours, the percent of parent compound remaining was 126%, and at all time points measured was >90% remaining, indicating that this probe molecule was very stable to the assay conditions.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml182t1"><a href="/books/NBK143194/table/ml182.t1/?report=objectonly" target="object" title="Table 1" class="img_link icnblk_img figpopup" rid-figpopup="figml182t1" rid-ob="figobml182t1"><img class="small-thumb" src="/books/NBK143194/table/ml182.t1/?report=thumb" src-large="/books/NBK143194/table/ml182.t1/?report=previmg" alt="Table 1. Stability of ML182." /></a><div class="icnblk_cntnt"><h4 id="ml182.t1"><a href="/books/NBK143194/table/ml182.t1/?report=objectonly" target="object" rid-ob="figobml182t1">Table 1</a></h4><p class="float-caption no_bottom_margin">Stability of ML182. </p></div></div><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml182f3" co-legend-rid="figlgndml182f3"><a href="/books/NBK143194/figure/ml182.f3/?report=objectonly" target="object" title="Figure 3" class="img_link icnblk_img figpopup" rid-figpopup="figml182f3" rid-ob="figobml182f3"><img class="small-thumb" src="/books/NBK143194/bin/ml182f3.gif" src-large="/books/NBK143194/bin/ml182f3.jpg" alt="Figure 3. Stability of ML182." /></a><div class="icnblk_cntnt" id="figlgndml182f3"><h4 id="ml182.f3"><a href="/books/NBK143194/figure/ml182.f3/?report=objectonly" target="object" rid-ob="figobml182f3">Figure 3</a></h4><p class="float-caption no_bottom_margin">Stability of ML182. </p></div></div><p><b>Compounds added to the SMR collection (MLS#s):</b> 003171619 (<a href="/pcsubstance/?term=ML182[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML182</a>, CID 46869947, 25.1 mg), 003171620 (CID 46869941, 21.6 mg), 003171621 (CID 46869940, 22.4 mg), 003171622 (CID 45110765, 22.1 mg), 003171623 (CID 46869951, 19.9 mg), 003171624 (CID 46869952, 20.7 mg).</p></div><div id="ml182.s7"><h3>2.3. Probe Preparation</h3><div id="ml182.fu2" class="figure"><div class="graphic"><img src="/books/NBK143194/bin/ml182fu2.jpg" alt="Image ml182fu2" /></div></div><p><b>s(<i>tert</i>-butyl-2-chloro-4-nitrophenyl)carbamate (2).</b> To a solution of 2-chloro-4-nitroaniline, <b>1</b>, (5.0 g, 29 mmol) and DMAP (50 mg, 0.41 mmol) in dry THF (250 mL) was added Boc<sub>2</sub>O (16.0 g, 73.3 mmol). The rxn mixture was heated to reflux. After 1h, the solvent was removed. The residue was redissolved in EtOAc:0.5 N HCl (aqueous) and the organic layer was separated. The aqueous layer was extracted with EtOAc (3 × 50 mL) and the collected organic layers were washed with Brine (100 mL). The solution was dried (MgSO<sub>4</sub>), filtered and concentrated to afford bis(<i>tert</i>-butyl-2-chloro-4-nitrophenyl)carbamate, <b>2</b>.</p><p>LCMS: R<sub>T</sub> = 3.74 min., >98% @ 254 nM, <i>m/z</i> = 767.2 [2M + Na]<sup>+</sup>.</p><div id="ml182.fu3" class="figure"><div class="graphic"><img src="/books/NBK143194/bin/ml182fu3.jpg" alt="Image ml182fu3" /></div></div><p><b>bis(<i>tert</i>-butyl-4-amino-2-chlorophenyl)carbamate (3).</b> To a solution of bis(<i>tert</i>-butyl-2-chloro-4-nitrophenyl)carbamate, <b>2</b>, (29.0 mmol) in EtOAc (120 mL) was added 5% Pd/C (150 mg) and an H<sub>2</sub> atmosphere was applied. After 12 h, TLC confirmed loss of starting material. The reaction mixture was filtered through Celite and concentrated to afford bis(<i>tert</i>-butyl-4-amino-2-chlorophenyl)carbamate, <b>3</b>, which was used without further purification.</p><p><sup>1</sup>H NMR (400 MHz, CDCl<sub>3</sub>) δ 6.94 (d, 1 H, <i>J</i> = 8.4 Hz), 6.72 (d, 1 H, <i>J</i> = 2.8 Hz), 6.53 (dd, 1 H, <i>J</i> = 8.4, 2.8 Hz), 3.75 (br s, 2 H), 1.41 (s, 18 H).</p><div id="ml182.fu4" class="figure"><div class="graphic"><img src="/books/NBK143194/bin/ml182fu4.jpg" alt="Image ml182fu4" /></div></div><p><b>bis(<i>tert</i>-butyl 2-chloro-4-(picolinamido)phenyl)carbamate (4).</b> A solution of bis(<i>tert</i>-butyl-4-amino-2-chlorophenyl)carbamate, <b>3</b>, (29.0 mmol) in DCM (25 mL) at 0 °C was subjected to DIEA (10.2 mL, 72.5 mmol) followed by picolinoyl chloride hydrochloride (5.68 g, 31.9 mmol). After 12 h, the reaction was added to EtOAc:H<sub>2</sub>O (1:1, 120 mL). The organic layer was washed with water (2 × 50 mL), brine (50 mL) and dried (MgSO4). The mixture was filtered and concentrated to provide bis(<i>tert</i>-butyl 2-chloro-4-(picolinamido)phenyl)carbamate, <b>4</b>.</p><p><sup>1</sup>H NMR (400 MHz, CDCl<sub>3</sub>) δ 10.17 (br s, 1 H), 8.63 (d, 1 H, <i>J</i> = 4.0 Hz), 8.32 (d, 1 H, <i>J</i> = 8.0), 8.05 (d, 1 H, <i>J</i> = 2.4 Hz), 7.96 (ddd, 1 H, <i>J</i> = 8.0, 8.0, 1.2), 7.66 (dd, 1 H, <i>J</i> = 8.4, 2.4), 7.55–7.52 (m, 1 H), 7.20 (d, 1 H, <i>J</i> = 8.8 Hz), 1.40 (s, 18 H).</p><div id="ml182.fu5" class="figure"><div class="graphic"><img src="/books/NBK143194/bin/ml182fu5.jpg" alt="Image ml182fu5" /></div></div><p><b><i>N</i>-(4-amino-3-chlorophenyl)picolinamide (5).</b> To a solution of bis(<i>tert</i>-butyl 2-chloro-4-(picolinamido)phenyl)carbamate, <b>4</b>, (29.0 mmol) in DCM (300 mL) at 0 °C was added dropwise 4N HCl in dioxane (50 mL). After 15 min, the ice bath was removed. Once the starting material was no longer evident by TLC, the solvent was removed affording the HCl salt. The crude material was redissolved with EtOAc (100 mL) and washed with NaHCO<sub>3</sub> (aqueous). The organic layer was dried (MgSO4), filtered and concentrated to afford <i>N</i>-(4-amino-3-chlorophenyl)picolinamide, <b>5</b>.</p><p>LCMS: R<sub>T</sub> = 1.15 min., >98% @ 254 nM, <i>m/z</i> = 248.0 [M + H]<sup>+</sup>.</p><p><b><i>N</i>-(3-chloro-4-((3a<i>R</i>,4<i>S</i>,7<i>R</i>,7a<i>S</i>)-1,3-dioxo-3a,4,7,7a-tetrahydro-1<i>H</i>-4,7-methanoisoindol-2(3<i>H</i>)-yl)phenyl)picolinamide (</b><a href="/pcsubstance/?term=ML182[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML182</a><b>, CID 46869947).</b> To a solution of <i>N</i>-(4-amino-3-chlorophenyl)picolinamide, <b>5</b>, (1.0 equivalent) in toluene:acetic acid (3:1) was added (3aR,4S,7R,7aS)-3a,4,7,7a-tetrahydro-4,7-methanoisobenzofuran-1,3-dione (1.25 equivalents) and the mixture was heated to 150 °C in the microwave for 90 min. After LCMS confirmed the product, the rxn was added to EtOAc:NaHCO<sub>3</sub> (sat’d) (1:1) and the organic layer was separated, washed with Brine and dried (MgSO<sub>4</sub>). After the organic layer was filtered and concentrated, the material was purified by LC purification (Gilson) or crystallization (<a href="/pcsubstance/?term=ML182[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML182</a>, CID 46869947).</p></div></div><div id="ml182.s8"><h2 id="_ml182_s8_">3. Results</h2><p><b>Center Summary of Screen:</b> The initial mGluR screens were performed during the pilot phase of the the MLSCN, when the MLSMR compound collection at Vanderbilt only contained ~110,000 compounds. From the primary mGluR8 screen of 110,814 compounds in 384 well plates, few hits were identified, and the average Z’ score was 0.75. The confirmation screen (singles at 10 μM) produced no active compounds, but the counter-screen versus mGluR4 identified one mGluR4 positive allosteric modulator (PAM) hit, CID 308065 (<a href="https://pubchem.ncbi.nlm.nih.gov/substance/85240633" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 85240633</a>) that was devoid of activity at mGluR8.</p><p><b>Probe Chemical Lead Optimization Strategy:</b> The initial probe compound <a href="/pcsubstance/?term=ML128[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML128</a> (CID 44191096)<sup><a class="bk_pop" href="#ml182.r13">13</a></sup> was found to be a very potent and efficacious mGlu<sub>4</sub> positive allosteric modulator (PAM). However, drawbacks to this probe were the poor metabolic stability in both human and rat microsomes. Further refinement of this probe species was dedicated to solving the stability issues while maintaining potency in an effort to discover the first orally active mGlu<sub>4</sub> PAM.</p><div id="ml182.fu6" class="figure"><div class="graphic"><img src="/books/NBK143194/bin/ml182fu6.jpg" alt="Image ml182fu6" /></div></div><div id="ml182.tu2" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK143194/table/ml182.tu2/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml182.tu2_lrgtbl__"><table><thead><tr><th id="hd_h_ml182.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">SID (CID)</th><th id="hd_h_ml182.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">hEC<sub>50</sub> (nM)</th><th id="hd_h_ml182.tu2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">GluMax</th><th id="hd_h_ml182.tu2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">rEC<sub>50</sub> (nM)</th><th id="hd_h_ml182.tu2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">%GluMax</th><th id="hd_h_ml182.tu2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">hFS</th><th id="hd_h_ml182.tu2_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">rFS</th><th id="hd_h_ml182.tu2_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">HLM (% remaining)</th><th id="hd_h_ml182.tu2_1_1_1_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">RLM (% remaining)</th><th id="hd_h_ml182.tu2_1_1_1_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">hPPB (% fu)</th><th id="hd_h_ml182.tu2_1_1_1_11" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">rPPB (% fu)</th></tr></thead><tbody><tr><td headers="hd_h_ml182.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="/pcsubstance/?term=ML128[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML128</a><br /><a href="https://pubchem.ncbi.nlm.nih.gov/substance/85240643" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">85240643</a> (44191096)</td><td headers="hd_h_ml182.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">240 ± 40</td><td headers="hd_h_ml182.tu2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">182 ± 14</td><td headers="hd_h_ml182.tu2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">110 ± 30</td><td headers="hd_h_ml182.tu2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">109 ± 3</td><td headers="hd_h_ml182.tu2_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">28.1 ± 3.5</td><td headers="hd_h_ml182.tu2_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">35.3 ± 2.8</td><td headers="hd_h_ml182.tu2_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">5.3</td><td headers="hd_h_ml182.tu2_1_1_1_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1.8</td><td headers="hd_h_ml182.tu2_1_1_1_10" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2.2</td><td headers="hd_h_ml182.tu2_1_1_1_11" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2.4</td></tr></tbody></table></div></div><p>Optimization efforts were concentrated on the initial mGlu<sub>4</sub> probe, <a href="/pcsubstance/?term=ML128[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML128</a> (CID 44191096), and solving the issues of metabolic stability, while still maintaining potency (<500 nM (human and rat)) and efficacy (FS >10). Studies done at Vanderbilt University identified the metabolic soft spot as the methoxy group. In the course of the initial probe investigation we discovered the picolinamide (left-side) was critical for the potency of the compound; thus, the left-hand portion was kept constant.</p><div id="ml182.f4" class="figure bk_fig"><div class="graphic"><img src="/books/NBK143194/bin/ml182f4.jpg" alt="Figure 4. Starting structure of lead optimization efforts." /></div><h3><span class="label">Figure 4</span><span class="title">Starting structure of lead optimization efforts</span></h3></div><p>Starting from the original probe compound, <a href="/pcsubstance/?term=ML128[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML128</a> (CID 44191096) the R<sub>1</sub> substituent was first evaluated by extending the molecule with an amide subsitutent (<b>7</b>, CID 46869940) (<a class="figpopup" href="/books/NBK143194/table/ml182.t2/?report=objectonly" target="object" rid-figpopup="figml182t2" rid-ob="figobml182t2">Table 2</a>). The potency increased to 99.5 nM against human mGlu<sub>4</sub> and 106 nM against rat mGlu<sub>4</sub>. However, this compound still contained the metabolically unstable methoxy group; thus, halogen alternatives were investigated (<b>8</b>, CID 46869941, R = Cl, hEC<sub>50</sub> = 517 nM, rEC<sub>50</sub> = 570 nM; <b>9</b>, CID 46869942, R = F, hEC<sub>50</sub> = 556 nM, rEC<sub>50</sub> = 739 nM). As seen in the initial probe SAR, Cl was found to be a suitable replacement for the OMe group. Having the amide bond as a potent ‘extended’ molecule, we next wanted to eliminate the secondary amide NH as this was deemed an unwanted H-bond donor for CNS penetration. We had learned previously that the picolinamide NH was required for potency. Thus, cyclized alternatives to the amide were investigated. First, the sultam group was evaluated (<b>10</b>, CID 42443525), however this compound was inactive. This core phenyl group does not contain a halogen as the other compounds; however, the compound containing an internal halogen was not attainable by synthesis. Next, a series of imide compounds were investigated with excellent success. The initial five-membered imide compound was active (<b>11</b>, CID 46869943, hEC<sub>50</sub> = 6200 nM, rEC<sub>50</sub> = 6900 nM), however the compound lost ~20-fold activity compared to <a href="/pcsubstance/?term=ML128[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML128</a> (CID 44191096). Potency could be recovered by increasing the bulk of the right-hand side by utilizing phthalimide (and substituted phthalimides) (<b>12</b>, CID 45110131, hEC<sub>50</sub> = 59.4 nM, rEC<sub>50</sub> = 66.8 nM; <b>13</b>, CID 46869944, hEC<sub>50</sub> = 42 nM, rEC<sub>50</sub> = 34.9 nM). However, initial metabolic stability studies revealed these compounds also suffered from poor metabolic stability (results not shown). Suspecting oxidation of the phenyl moiety of the phthalimide as the predominant culprit of the metabolic instability, we next turned to saturated versions of the phthalimide (<b>6, 14 – 21</b>). The initial compound was the direct saturated comparator to CID 45110131 (<b>14</b>, CID 46869945, hEC<sub>50</sub> = 370 nM, rEC<sub>50</sub> = 650 nM). Although there was a ~10-fold loss of potency, <b>8</b>, still was <500 nM against hmGlu<sub>4</sub>. The <i>trans</i>-isomer was also evaluated with similar potency to the <i>cis</i>-<b>8</b> (results not shown). Increasing the bulk of the saturated six-membered ring resulted in interesting compounds. The [2.2.1]-bridged oxo compound (<b>15</b>, CID 46869446, hEC<sub>50</sub> = 1300 nM, rEC<sub>50</sub> = 2300 nM) led to a 4-fold loss of potency; however the unsaturated [2.2.1]-bridged carbon analog (<b>6</b>, CID 46869947, hEC<sub>50</sub> = 291 nM, rEC<sub>50</sub> = 376 nM) and unsaturated [2.2.2]-analog (<b>16</b>, CID 46869948, hEC<sub>50</sub> = 287 nM, rEC<sub>50</sub> = 246 nM) were more potent than CID 46869945. Reducing the ring size from 6-membered to substituted 3-membered ring resulted in an equipotent compound (<b>17</b>, CID 46869949, hEC<sub>50</sub> = 435 nM, rEC<sub>50</sub> = 690 nM). Substitution of the 5-membered imide led to a loss of activity (<b>18</b>, CID 46869950, hEC<sub>50</sub> = 1400 nM, rEC<sub>50</sub> = 2300 nM), but comparable to the initial 5-membered imide (CID 46869943). However, when the size of the substituent was increased from the <i>gem</i>-dimethyl to cyclohexyl (<b>19</b>, CID 46869951, hEC<sub>50</sub> = 158 nM, rEC<sub>50</sub> = 397 nM) there was a 10-fold increase in activity. Other bulky substituents were evaluated (<b>20</b>, CID 45110765, hEC<sub>50</sub> = 670 nM, rEC<sub>50</sub> = 491 nM; (<b>21</b>, CID 46869952, hEC<sub>50</sub> = 770 nM, rEC<sub>50</sub> = 540 nM); however, these compounds lost activity when compared to CID 46869951.</p><p>With our best compounds evaluated for human and rat potency, we next turned our attention to evaluation of the compounds’ ability to shift the glutamate response curve to the left (fold shift). For the most part, the GluMax (% PHCCC) was mirrored in the fold shift data, although a few exceptions are worth noting. Both the initial amide analogs (CID 46869940 and CID 46869941) had high GluMax values (147.0% and 128.2%, respectively); however, this relatively small difference produced a significant difference in fold shift (72.0 vs. 18.3). The fold shift value for CID 46869940 (72.0) is one of the largest fold shifts reported for an mGlu<sub>4</sub> PAM. Other similar discrepancies were noted, CID 45110131 (131.8%, FS = 23.6) and CID 46869944 (137.4%, FS = 83.0); again, a fold shift value among the highest ever reported for an mGlu<sub>4</sub> PAM. Other compounds of note, CID 46869947 (120.3%, FS = 11.2), CID 45110765 (137.8%, FS = 12.1) and CID 46869952 (130.7%, FS = 16.7).</p><p>After the optimization phase we have identified a number of compounds that fulfill our initial potency (<500 nM) and efficacy (FS > 10) requirements and thus wanted to turn our attention to whether these compounds improved the physicokinetic (PK) properties, namely, metabolic stability. The initial probe compound, <a href="/pcsubstance/?term=ML128[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML128</a> (CID 44191096), was metabolically unstable (<5% remaining) in both rat and human liver microsomes. As noted above, two of the most potent and efficacious compounds (CID’s 45110131 and 46869944) were also unstable in LM’s (data not shown). Thus, we evaluated four additional analogs that had the best combination of potency and efficacy (CID’s 46869947, 45110765, 46869952, 46869951) for <i>in vitro</i> and <i>in vivo</i> PK evaluation. All four of the compounds showed a significant improvement in both RLM and HLM compared to <a href="/pcsubstance/?term=ML128[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML128</a> (CID 44191096) (<a class="figpopup" href="/books/NBK143194/table/ml182.t4/?report=objectonly" target="object" rid-figpopup="figml182t4" rid-ob="figobml182t4">Table 4</a>). These compounds had >20% remaining when exposed to HLM, and >50% remaining with RLM. Next, these compounds were tested for their ability to bind plasma proteins and from this evaluation CID 46869947 was a standout compound with free fractions >3% in both human and rat plasma proteins. Lastly, CID 46869947 was evaluated for brain homogenate binding to determine the free fraction in the brain, and again, this compound showed excellent free brain levels (>7%). In order to translate to <i>in vivo</i> animal model testing, all four compounds were evaluated in a snapshot IV PK study to determine the clearance rate of the molecules (another indication of stability). All four compounds had clearance values less than hepatic blood flow of the rat (~75 mL/min/kg). CID 46869952 exhibited the lowest clearance value (18.3 mL/min/kg); however, when all <i>in vitro</i> PK properties were evaluated (%fu, BHB, etc.), CID 46869947 still was the superior compound with low-to-moderate <i>in vivo</i> clearance (35.3 mL/min/kg) and good plasma and brain free fractions. These compounds were next evaluated for their potential drug-drug interactions by evaluating their abilities to inhibit P450 enzymes. Five of the major CYP isoforms were evaluated (2C9, 2D6, 3A4, 2C19, and 1A2). Again, CID 46869947 proved to be superior to the other compounds evaluated as this compound was selective against all of the five CYPs (>10-fold selectivity vs. 2C19; >100-fold against other four). Lastly, CID 46869947 was evaluated for its selectivity versus the mGlu family and CID 46869947 showed weak activity versus mGlu<sub>6</sub> and varying selectivity against other mGlu’s (<a class="figpopup" href="/books/NBK143194/table/ml182.t4/?report=objectonly" target="object" rid-figpopup="figml182t4" rid-ob="figobml182t4">Table 4</a>).</p><p>Although we have previously shown <a href="/pcsubstance/?term=ML128[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML128</a> (CID 44191096) to be active in the haloperidol induced catalepsy assay – due to the PK limitations this compound could only be dosed subcutaneously. In order to advance the mGlu<sub>4</sub> field, we were compelled to go deeper with this compound and determine if the <i>in vitro</i> and <i>in vivo</i> PK properties could be translated to a PO dosing regimen. CID 46869947 was active in the haloperidol induced catalepsy (0.75 mg haloperidol) anti-Parkinsonian rodent model (see <a class="figpopup" href="/books/NBK143194/figure/ml182.f5/?report=objectonly" target="object" rid-figpopup="figml182f5" rid-ob="figobml182f5">Figure 5</a>).</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml182f5" co-legend-rid="figlgndml182f5"><a href="/books/NBK143194/figure/ml182.f5/?report=objectonly" target="object" title="Figure 5" class="img_link icnblk_img figpopup" rid-figpopup="figml182f5" rid-ob="figobml182f5"><img class="small-thumb" src="/books/NBK143194/bin/ml182f5.gif" src-large="/books/NBK143194/bin/ml182f5.jpg" alt="Figure 5. In vivo efficacy of ML182 (SID 99309089) in haloperidol induced catalepsy after PO dosing." /></a><div class="icnblk_cntnt" id="figlgndml182f5"><h4 id="ml182.f5"><a href="/books/NBK143194/figure/ml182.f5/?report=objectonly" target="object" rid-ob="figobml182f5">Figure 5</a></h4><p class="float-caption no_bottom_margin">In vivo efficacy of ML182 (SID 99309089) in haloperidol induced catalepsy after PO dosing. </p></div></div><p>The calculated physical properties appearing in <a class="figpopup" href="/books/NBK143194/table/ml182.t4/?report=objectonly" target="object" rid-figpopup="figml182t4" rid-ob="figobml182t4">Table 4</a> for the mGlu<sub>4</sub> probe molecule (CID 46869947) was generated using a combination of AdrianaCode and TRIPOS Sybyl software. Also included in <a class="figpopup" href="/books/NBK143194/table/ml182.t4/?report=objectonly" target="object" rid-figpopup="figml182t4" rid-ob="figobml182t4">Table 4</a> are the averages from the MDDR database of compounds both entering Phase I and launched drugs. These numbers indicate that this probe is within the average values for Phase I compounds.</p><p>To more fully characterize this novel mGlu<sub>4</sub> PAM probe molecule, CID 46869947 was tested at Ricerca’s (formerly MDS Pharma’s) Lead Profiling Screen (binding assay panel of 68 GPCRs, ion channels and transporters screened at 10 μM), and was not found to be active in any of the 68 assays conducted (no inhibition of radio ligand binding > 50% at 10 μM).<sup>20</sup> Thus, CID 46869947 (<a href="/pcsubstance/?term=ML182[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML182</a>) is highly selective and can be used to dissect the role of hmGlu<sub>4</sub><i>in vitro</i> and potentially <i>in vivo</i> with non-human primates.</p><p>In summary, a lead optimization campaign around the initial mGlu<sub>4</sub> PAM probe <a href="/pcsubstance/?term=ML128[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML128</a> (CID 44191096) provided novel analogues with improved metabolic stability and physiochemical properties with comparable efficacy at human and rat mGlu<sub>4</sub> (EC<sub>50</sub> values ~300 nM) while retaining comparable fold-shift (>10x) of the glutamate CRC. Moreover, several close analogues displayed modest <i>in vivo</i> efficacy in reversing haloperidol induced catalepsy, a classic preclinical anti-Parkinsonian model. We have identified a novel compound (CID 46869947) that also shows efficacy when dosed orally in the haloperidol induced catalepsy model, a major advance over the initial probe compound.</p><div id="ml182.s9"><h3>3.1. Summary of Screening Results</h3><p>Lead Optimization started with previous probe (<a href="/pcsubstance/?term=ML128[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML128</a>; CID: 44191096)</p></div><div id="ml182.s10"><h3>3.2. Dose Response Curves for Probe</h3><div id="ml182.f6" class="figure bk_fig"><div class="graphic"><img src="/books/NBK143194/bin/ml182f6.jpg" alt="Figure 6. Potency at human mGluR4 receptor of CID 46869947/ML182." /></div><h3><span class="label">Figure 6</span><span class="title">Potency at human mGluR4 receptor of CID 46869947/ML182</span></h3></div><div id="ml182.f7" class="figure bk_fig"><div class="graphic"><img src="/books/NBK143194/bin/ml182f7.jpg" alt="Figure 7. Potency at rat mGluR4 receptor of CID 46869947." /></div><h3><span class="label">Figure 7</span><span class="title">Potency at rat mGluR4 receptor of CID 46869947</span></h3></div><div id="ml182.f8" class="figure bk_fig"><div class="graphic"><img src="/books/NBK143194/bin/ml182f8.jpg" alt="Figure 8. Fold shift analysis of CID 46869947/ML182." /></div><h3><span class="label">Figure 8</span><span class="title">Fold shift analysis of CID 46869947/ML182</span></h3></div></div><div id="ml182.s11"><h3>3.3. Scaffold/Moiety Chemical Liabilities</h3><p>No chemical liabilities for the probe molecule have been identified at the present time.</p></div><div id="ml182.s12"><h3>3.4. SAR Table</h3><div id="ml182.t2" class="table"><h3><span class="label">Table 2</span><span class="title">Human and Rat mGlu<sub>4</sub> potency and % GluMax response (as normalized to standard PHCCC) for selected western amide analogs</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK143194/table/ml182.t2/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml182.t2_lrgtbl__"><table class="no_margin"><thead><tr><th id="hd_h_ml182.t2_1_1_1_1" colspan="7" rowspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143194/bin/ml182fu7.jpg" alt="Image ml182fu7.jpg" /></div></th></tr><tr><th headers="hd_h_ml182.t2_1_1_1_1" id="hd_h_ml182.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Cmpd</th><th headers="hd_h_ml182.t2_1_1_1_1" id="hd_h_ml182.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">VU#</th><th headers="hd_h_ml182.t2_1_1_1_1" id="hd_h_ml182.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">SID (CID)</th><th headers="hd_h_ml182.t2_1_1_1_1" id="hd_h_ml182.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">R</th><th headers="hd_h_ml182.t2_1_1_1_1" id="hd_h_ml182.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">R<sub>1</sub></th><th headers="hd_h_ml182.t2_1_1_1_1" id="hd_h_ml182.t2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">hEC<sub>50</sub> (nM)/%GluMax</th><th headers="hd_h_ml182.t2_1_1_1_1" id="hd_h_ml182.t2_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">rEC<sub>50</sub> (nM)/%GluMax</th></tr></thead><tbody><tr><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>7</b></td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">VU0415374-1</td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/99309080" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">99309080</a> (46869940)</td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">OMe</td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143194/bin/ml182fu8.jpg" alt="Image ml182fu8.jpg" /></div></td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">99.5 ± 9/79.4 ± 1.7</td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">106 ± 28/147.0 ± 4.3</td></tr><tr><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>8</b></td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">VU0366037-2</td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/99309081" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">99309081</a> (46869941)</td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Cl</td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143194/bin/ml182fu8.jpg" alt="Image ml182fu8.jpg" /></div></td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">517 ± 57/77.9 ± 1.6</td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">570 ± 131/128.2 ± 5.6</td></tr><tr><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>9</b></td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">VU0362060-1</td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/99309082" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">99309082</a> (46869942)</td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">F</td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143194/bin/ml182fu8.jpg" alt="Image ml182fu8.jpg" /></div></td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">556 ± 76/59.7 ± 1.1</td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">739 ± 92/91.4 ± 2.9</td></tr><tr><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>10</b></td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">VU0364203-1</td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/99309083" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">99309083</a> (42443525)</td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">H</td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143194/bin/ml182fu9.jpg" alt="Image ml182fu9.jpg" /></div></td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">inactive/25.0 ± 2.5</td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">inactive/29.7 ± 1.1</td></tr><tr><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>11</b></td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">VU0365385-1</td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/99309084" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">99309084</a> (46869943)</td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Cl</td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143194/bin/ml182fu10.jpg" alt="Image ml182fu10.jpg" /></div></td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">6200 ± 1700/74.0±4.5</td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">6900 ± 1400/89.6 ± 1.6</td></tr><tr><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>12</b></td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">VU0405622-1</td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/99309085" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">99309085</a> (45110131)</td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Cl</td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143194/bin/ml182fu11.jpg" alt="Image ml182fu11.jpg" /></div></td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">59.4±7.9/103.7 ± 1.2</td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">66.8 ± 0.4/131.8 ± 3.9</td></tr><tr><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>13</b></td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">VU0405623-1</td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/99309086" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">99309086</a> (46869944)</td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Cl</td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143194/bin/ml182fu12.jpg" alt="Image ml182fu12.jpg" /></div></td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">41.9 ± 5.5/130.3±3.4</td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">34.9 ± 5.2/137.4 ± 3.2</td></tr><tr><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>14</b></td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">VU0366515-1</td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/99309087" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">99309087</a> (46869945)</td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Cl</td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143194/bin/ml182fu13.jpg" alt="Image ml182fu13.jpg" /></div></td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">370 ± 23/107.0 ± 4.5</td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">650 ± 63/129.1 ± 2.8</td></tr><tr><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>15</b></td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">VU0405235-1</td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/99309088" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">99309088</a> (46869946)</td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Cl</td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143194/bin/ml182fu14.jpg" alt="Image ml182fu14.jpg" /></div></td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1300 ± 180/90.0 ± 1.7</td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2300 ± 182/119.4 ± 1.8</td></tr><tr><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>6</b></td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">VU0400195-3</td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/99309089" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">99309089</a> (46869947)</td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Cl</td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143194/bin/ml182fu15.jpg" alt="Image ml182fu15.jpg" /></div></td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">291 ± 55/122.3 ± 1.5</td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">376 ± 23/120.3 ± 3.2</td></tr><tr><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>16</b></td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">VU0404304-2</td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/99309090" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">99309090</a> (46869948)</td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Cl</td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
|
||
<div class="graphic"><img src="/books/NBK143194/bin/ml182fu16.jpg" alt="Image ml182fu16.jpg" /></div></td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">287 ± 62/120.3 ± 5.9</td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">246 ± 12/122.2 ± 4.5</td></tr><tr><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>17</b></td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">VU0410425-1</td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/99309091" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">99309091</a> (46869949)</td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Cl</td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
|
||
<div class="graphic"><img src="/books/NBK143194/bin/ml182fu17.jpg" alt="Image ml182fu17.jpg" /></div></td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">435 ± 118/100.3 ± 2.9</td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">690 ± 32/105.1 ± 0.1</td></tr><tr><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>18</b></td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">VU0400070-1</td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/99309092" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">99309092</a> (46869950)</td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Cl</td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
|
||
<div class="graphic"><img src="/books/NBK143194/bin/ml182fu18.jpg" alt="Image ml182fu18.jpg" /></div></td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1400 ± 214/82.0 ± 3.5</td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2300 ± 391/120.5 ± 4.2</td></tr><tr><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>19</b></td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">VU0400193-3</td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/99309093" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">99309093</a> (46869951)</td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Cl</td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
|
||
<div class="graphic"><img src="/books/NBK143194/bin/ml182fu19.jpg" alt="Image ml182fu19.jpg" /></div></td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">158 ± 20/78.7 ± 4.2</td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">397 ± 38/114.2 ± 1.5</td></tr><tr><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>20</b></td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">VU0400071-3</td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/99309094" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">99309094</a> (45110765)</td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Cl</td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
|
||
<div class="graphic"><img src="/books/NBK143194/bin/ml182fu20.jpg" alt="Image ml182fu20.jpg" /></div></td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">670 ± 153/116.7 ± 8.3</td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">491 ± 57/137.8 ± 2.0</td></tr><tr><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>21</b></td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">VU0404997-2</td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/99309095" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">99309095</a> (46869952)</td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Cl</td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
|
||
<div class="graphic"><img src="/books/NBK143194/bin/ml182fu21.jpg" alt="Image ml182fu21.jpg" /></div></td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">770 ± 126/123.7 ± 3.5</td><td headers="hd_h_ml182.t2_1_1_1_1 hd_h_ml182.t2_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">540 ± 105/130.7 ± 3.9</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt>a</dt><dd><div id="ml182.tfn1"><p class="no_margin">EC<sub>50</sub> and GluMax, are the average of at least three independent determinations performed in triplicate (Mean ± SEM shown in table). PHCCC is run as a control compound each day, and the maximal response generated in mGlu<sub>4</sub> CHO cells in the presence of mGlu<sub>4</sub> PAMs varies slightly in each experiment. Therefore, data were further normalized to the relative PHCCC response obtained in each day’s run.</p></div></dd></dl></div></div></div><div id="ml182.t3" class="table"><h3><span class="label">Table 3</span><span class="title">Fold shift data for selected compounds</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK143194/table/ml182.t3/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml182.t3_lrgtbl__"><table class="no_top_margin"><thead><tr><th id="hd_h_ml182.t3_1_1_1_1" colspan="6" rowspan="1" style="text-align:center;vertical-align:middle;">
|
||
<div class="graphic"><img src="/books/NBK143194/bin/ml182fu7.jpg" alt="Image ml182fu7.jpg" /></div></th></tr><tr><th headers="hd_h_ml182.t3_1_1_1_1" id="hd_h_ml182.t3_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Cmpd</th><th headers="hd_h_ml182.t3_1_1_1_1" id="hd_h_ml182.t3_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">VU#</th><th headers="hd_h_ml182.t3_1_1_1_1" id="hd_h_ml182.t3_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">SID (CID)</th><th headers="hd_h_ml182.t3_1_1_1_1" id="hd_h_ml182.t3_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">R</th><th headers="hd_h_ml182.t3_1_1_1_1" id="hd_h_ml182.t3_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">R<sub>1</sub></th><th headers="hd_h_ml182.t3_1_1_1_1" id="hd_h_ml182.t3_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">rFS</th></tr></thead><tbody><tr><td headers="hd_h_ml182.t3_1_1_1_1 hd_h_ml182.t3_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>7</b></td><td headers="hd_h_ml182.t3_1_1_1_1 hd_h_ml182.t3_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">VU0415374-1</td><td headers="hd_h_ml182.t3_1_1_1_1 hd_h_ml182.t3_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/99309080" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">99309080</a> (46869940)</td><td headers="hd_h_ml182.t3_1_1_1_1 hd_h_ml182.t3_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">OMe</td><td headers="hd_h_ml182.t3_1_1_1_1 hd_h_ml182.t3_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
|
||
<div class="graphic"><img src="/books/NBK143194/bin/ml182fu8.jpg" alt="Image ml182fu8.jpg" /></div></td><td headers="hd_h_ml182.t3_1_1_1_1 hd_h_ml182.t3_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">71.99 ± 4.49</td></tr><tr><td headers="hd_h_ml182.t3_1_1_1_1 hd_h_ml182.t3_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>8</b></td><td headers="hd_h_ml182.t3_1_1_1_1 hd_h_ml182.t3_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">VU0366037-2</td><td headers="hd_h_ml182.t3_1_1_1_1 hd_h_ml182.t3_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/99309081" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">99309081</a> (46869941)</td><td headers="hd_h_ml182.t3_1_1_1_1 hd_h_ml182.t3_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Cl</td><td headers="hd_h_ml182.t3_1_1_1_1 hd_h_ml182.t3_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
|
||
<div class="graphic"><img src="/books/NBK143194/bin/ml182fu8.jpg" alt="Image ml182fu8.jpg" /></div></td><td headers="hd_h_ml182.t3_1_1_1_1 hd_h_ml182.t3_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">18.31 ± 1.32</td></tr><tr><td headers="hd_h_ml182.t3_1_1_1_1 hd_h_ml182.t3_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>9</b></td><td headers="hd_h_ml182.t3_1_1_1_1 hd_h_ml182.t3_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">VU0362060-1</td><td headers="hd_h_ml182.t3_1_1_1_1 hd_h_ml182.t3_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/99309082" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">99309082</a> (46869942)</td><td headers="hd_h_ml182.t3_1_1_1_1 hd_h_ml182.t3_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">F</td><td headers="hd_h_ml182.t3_1_1_1_1 hd_h_ml182.t3_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
|
||
<div class="graphic"><img src="/books/NBK143194/bin/ml182fu8.jpg" alt="Image ml182fu8.jpg" /></div></td><td headers="hd_h_ml182.t3_1_1_1_1 hd_h_ml182.t3_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4.61 ± 0.09</td></tr><tr><td headers="hd_h_ml182.t3_1_1_1_1 hd_h_ml182.t3_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>12</b></td><td headers="hd_h_ml182.t3_1_1_1_1 hd_h_ml182.t3_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">VU0405622-1</td><td headers="hd_h_ml182.t3_1_1_1_1 hd_h_ml182.t3_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/99309085" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">99309085</a> (45110131)</td><td headers="hd_h_ml182.t3_1_1_1_1 hd_h_ml182.t3_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Cl</td><td headers="hd_h_ml182.t3_1_1_1_1 hd_h_ml182.t3_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
|
||
<div class="graphic"><img src="/books/NBK143194/bin/ml182fu11.jpg" alt="Image ml182fu11.jpg" /></div></td><td headers="hd_h_ml182.t3_1_1_1_1 hd_h_ml182.t3_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">23.6 ± 3.1</td></tr><tr><td headers="hd_h_ml182.t3_1_1_1_1 hd_h_ml182.t3_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>13</b></td><td headers="hd_h_ml182.t3_1_1_1_1 hd_h_ml182.t3_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">VU0405623-1</td><td headers="hd_h_ml182.t3_1_1_1_1 hd_h_ml182.t3_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/99309086" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">99309086</a> (46869944)</td><td headers="hd_h_ml182.t3_1_1_1_1 hd_h_ml182.t3_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Cl</td><td headers="hd_h_ml182.t3_1_1_1_1 hd_h_ml182.t3_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
|
||
<div class="graphic"><img src="/books/NBK143194/bin/ml182fu12.jpg" alt="Image ml182fu12.jpg" /></div></td><td headers="hd_h_ml182.t3_1_1_1_1 hd_h_ml182.t3_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">83.0 ± 16.8</td></tr><tr><td headers="hd_h_ml182.t3_1_1_1_1 hd_h_ml182.t3_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>14</b></td><td headers="hd_h_ml182.t3_1_1_1_1 hd_h_ml182.t3_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">VU0366515-1</td><td headers="hd_h_ml182.t3_1_1_1_1 hd_h_ml182.t3_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/99309087" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">99309087</a> (46869945)</td><td headers="hd_h_ml182.t3_1_1_1_1 hd_h_ml182.t3_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Cl</td><td headers="hd_h_ml182.t3_1_1_1_1 hd_h_ml182.t3_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
|
||
<div class="graphic"><img src="/books/NBK143194/bin/ml182fu13.jpg" alt="Image ml182fu13.jpg" /></div></td><td headers="hd_h_ml182.t3_1_1_1_1 hd_h_ml182.t3_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">8.3 ± 0.5</td></tr><tr><td headers="hd_h_ml182.t3_1_1_1_1 hd_h_ml182.t3_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>6</b></td><td headers="hd_h_ml182.t3_1_1_1_1 hd_h_ml182.t3_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">VU0400195-1</td><td headers="hd_h_ml182.t3_1_1_1_1 hd_h_ml182.t3_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/99309089" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">99309089</a> (46869947)</td><td headers="hd_h_ml182.t3_1_1_1_1 hd_h_ml182.t3_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Cl</td><td headers="hd_h_ml182.t3_1_1_1_1 hd_h_ml182.t3_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
|
||
<div class="graphic"><img src="/books/NBK143194/bin/ml182fu15.jpg" alt="Image ml182fu15.jpg" /></div></td><td headers="hd_h_ml182.t3_1_1_1_1 hd_h_ml182.t3_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">11.2 ± 0.8</td></tr><tr><td headers="hd_h_ml182.t3_1_1_1_1 hd_h_ml182.t3_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>16</b></td><td headers="hd_h_ml182.t3_1_1_1_1 hd_h_ml182.t3_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">VU0404304-2</td><td headers="hd_h_ml182.t3_1_1_1_1 hd_h_ml182.t3_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/99309090" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">99309090</a> (46869948)</td><td headers="hd_h_ml182.t3_1_1_1_1 hd_h_ml182.t3_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Cl</td><td headers="hd_h_ml182.t3_1_1_1_1 hd_h_ml182.t3_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
|
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<div class="graphic"><img src="/books/NBK143194/bin/ml182fu16.jpg" alt="Image ml182fu16.jpg" /></div></td><td headers="hd_h_ml182.t3_1_1_1_1 hd_h_ml182.t3_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">5.2 ± 1.2</td></tr><tr><td headers="hd_h_ml182.t3_1_1_1_1 hd_h_ml182.t3_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>17</b></td><td headers="hd_h_ml182.t3_1_1_1_1 hd_h_ml182.t3_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">VU0410425-1</td><td headers="hd_h_ml182.t3_1_1_1_1 hd_h_ml182.t3_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/99309091" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">99309091</a> (46869949)</td><td headers="hd_h_ml182.t3_1_1_1_1 hd_h_ml182.t3_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Cl</td><td headers="hd_h_ml182.t3_1_1_1_1 hd_h_ml182.t3_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
|
||
<div class="graphic"><img src="/books/NBK143194/bin/ml182fu17.jpg" alt="Image ml182fu17.jpg" /></div></td><td headers="hd_h_ml182.t3_1_1_1_1 hd_h_ml182.t3_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">5.5 ± 0.5</td></tr><tr><td headers="hd_h_ml182.t3_1_1_1_1 hd_h_ml182.t3_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>19</b></td><td headers="hd_h_ml182.t3_1_1_1_1 hd_h_ml182.t3_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">VU0400193-1</td><td headers="hd_h_ml182.t3_1_1_1_1 hd_h_ml182.t3_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/99309093" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">99309093</a> (46869951)</td><td headers="hd_h_ml182.t3_1_1_1_1 hd_h_ml182.t3_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Cl</td><td headers="hd_h_ml182.t3_1_1_1_1 hd_h_ml182.t3_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
|
||
<div class="graphic"><img src="/books/NBK143194/bin/ml182fu19.jpg" alt="Image ml182fu19.jpg" /></div></td><td headers="hd_h_ml182.t3_1_1_1_1 hd_h_ml182.t3_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4.8 ± 0.2</td></tr><tr><td headers="hd_h_ml182.t3_1_1_1_1 hd_h_ml182.t3_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>20</b></td><td headers="hd_h_ml182.t3_1_1_1_1 hd_h_ml182.t3_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">VU0400071-3</td><td headers="hd_h_ml182.t3_1_1_1_1 hd_h_ml182.t3_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/99309094" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">99309094</a> (45110765)</td><td headers="hd_h_ml182.t3_1_1_1_1 hd_h_ml182.t3_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Cl</td><td headers="hd_h_ml182.t3_1_1_1_1 hd_h_ml182.t3_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
|
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<div class="graphic"><img src="/books/NBK143194/bin/ml182fu20.jpg" alt="Image ml182fu20.jpg" /></div></td><td headers="hd_h_ml182.t3_1_1_1_1 hd_h_ml182.t3_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">12.1 ± 1.0</td></tr><tr><td headers="hd_h_ml182.t3_1_1_1_1 hd_h_ml182.t3_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>21</b></td><td headers="hd_h_ml182.t3_1_1_1_1 hd_h_ml182.t3_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">VU0404997-2</td><td headers="hd_h_ml182.t3_1_1_1_1 hd_h_ml182.t3_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/99309095" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">99309095</a> (46869952)</td><td headers="hd_h_ml182.t3_1_1_1_1 hd_h_ml182.t3_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Cl</td><td headers="hd_h_ml182.t3_1_1_1_1 hd_h_ml182.t3_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
|
||
<div class="graphic"><img src="/books/NBK143194/bin/ml182fu21.jpg" alt="Image ml182fu21.jpg" /></div></td><td headers="hd_h_ml182.t3_1_1_1_1 hd_h_ml182.t3_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">16.7 ±1.7</td></tr></tbody></table></div></div><div id="ml182.t4" class="table"><h3><span class="label">Table 4</span><span class="title"><i>In vivo</i> Cassette clearance and <i>in vitro</i> pharmacokinetic values of selected compounds</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK143194/table/ml182.t4/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml182.t4_lrgtbl__"><table class="no_top_margin"><tbody><tr><td colspan="5" rowspan="1" style="text-align:center;vertical-align:top;">
|
||
<div class="graphic"><img src="/books/NBK143194/bin/ml182fu22.jpg" alt="Image ml182fu22.jpg" /></div></td></tr><tr><td rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">CID</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">46869947<br />
|
||
<div class="graphic"><img src="/books/NBK143194/bin/ml182fu23.jpg" alt="Image ml182fu23.jpg" /></div></td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">45110765<br />
|
||
<div class="graphic"><img src="/books/NBK143194/bin/ml182fu24.jpg" alt="Image ml182fu24.jpg" /></div></td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">46869952<br />
|
||
<div class="graphic"><img src="/books/NBK143194/bin/ml182fu25.jpg" alt="Image ml182fu25.jpg" /></div></td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">46869951<br />
|
||
<div class="graphic"><img src="/books/NBK143194/bin/ml182fu26.jpg" alt="Image ml182fu26.jpg" /></div></td></tr><tr><th id="hd_b_ml182.t4_1_1_3_1" colspan="5" rowspan="1" style="text-align:center;vertical-align:top;"><i>In vitro</i> PK Parameters</th></tr><tr><td headers="hd_b_ml182.t4_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">HLM (% remain.)</td><td headers="hd_b_ml182.t4_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">33.1</td><td headers="hd_b_ml182.t4_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">22.6</td><td headers="hd_b_ml182.t4_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">20</td><td headers="hd_b_ml182.t4_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">35.9</td></tr><tr><td headers="hd_b_ml182.t4_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">RLM (% remain.)</td><td headers="hd_b_ml182.t4_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">50.7</td><td headers="hd_b_ml182.t4_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">93.2</td><td headers="hd_b_ml182.t4_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">83</td><td headers="hd_b_ml182.t4_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">15.5</td></tr><tr><td headers="hd_b_ml182.t4_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">hPPB (%fu)</td><td headers="hd_b_ml182.t4_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">4.1</td><td headers="hd_b_ml182.t4_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.02</td><td headers="hd_b_ml182.t4_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.14</td><td headers="hd_b_ml182.t4_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.62</td></tr><tr><td headers="hd_b_ml182.t4_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">rPPB (%fu)</td><td headers="hd_b_ml182.t4_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">3.2</td><td headers="hd_b_ml182.t4_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.17</td><td headers="hd_b_ml182.t4_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.89</td><td headers="hd_b_ml182.t4_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.5</td></tr><tr><td headers="hd_b_ml182.t4_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">BHB (rat, %fu)</td><td headers="hd_b_ml182.t4_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">7.6</td><td headers="hd_b_ml182.t4_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">1.4</td><td headers="hd_b_ml182.t4_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></td><td headers="hd_b_ml182.t4_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">1.7</td></tr><tr><th id="hd_b_ml182.t4_1_1_9_1" colspan="5" rowspan="1" style="text-align:center;vertical-align:top;"><i>Rat</i></th></tr><tr><td headers="hd_b_ml182.t4_1_1_9_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Cl (mL/min/kg)</td><td headers="hd_b_ml182.t4_1_1_9_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">35.3 ± 5.1</td><td headers="hd_b_ml182.t4_1_1_9_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">40.9 ± 25.2</td><td headers="hd_b_ml182.t4_1_1_9_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">18.3</td><td headers="hd_b_ml182.t4_1_1_9_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">50.4 ± 2.3</td></tr><tr><td headers="hd_b_ml182.t4_1_1_9_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Vss (L/kg)</td><td headers="hd_b_ml182.t4_1_1_9_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">1.3 ± 0.2</td><td headers="hd_b_ml182.t4_1_1_9_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">1.5 ± 0.8</td><td headers="hd_b_ml182.t4_1_1_9_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">1.19</td><td headers="hd_b_ml182.t4_1_1_9_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.98 ± 0.03</td></tr><tr><td headers="hd_b_ml182.t4_1_1_9_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">t<sub>½</sub> (min)</td><td headers="hd_b_ml182.t4_1_1_9_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">35.3 ± 4.6</td><td headers="hd_b_ml182.t4_1_1_9_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">31.6 ± 0.6</td><td headers="hd_b_ml182.t4_1_1_9_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">56</td><td headers="hd_b_ml182.t4_1_1_9_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">18.7 ± 0.8</td></tr><tr><th id="hd_b_ml182.t4_1_1_13_1" colspan="5" rowspan="1" style="text-align:center;vertical-align:top;">P450 IC<sub>50</sub> (μM)</th></tr><tr><td headers="hd_b_ml182.t4_1_1_13_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2C9</td><td headers="hd_b_ml182.t4_1_1_13_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">>30</td><td headers="hd_b_ml182.t4_1_1_13_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">8.67</td><td headers="hd_b_ml182.t4_1_1_13_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">5.16</td><td headers="hd_b_ml182.t4_1_1_13_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">>30</td></tr><tr><td headers="hd_b_ml182.t4_1_1_13_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2D6</td><td headers="hd_b_ml182.t4_1_1_13_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">>30</td><td headers="hd_b_ml182.t4_1_1_13_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">>30</td><td headers="hd_b_ml182.t4_1_1_13_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">>30</td><td headers="hd_b_ml182.t4_1_1_13_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">>30</td></tr><tr><td headers="hd_b_ml182.t4_1_1_13_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">3A4</td><td headers="hd_b_ml182.t4_1_1_13_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">>30</td><td headers="hd_b_ml182.t4_1_1_13_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">>30</td><td headers="hd_b_ml182.t4_1_1_13_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">>30</td><td headers="hd_b_ml182.t4_1_1_13_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">>30</td></tr><tr><td headers="hd_b_ml182.t4_1_1_13_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2C19</td><td headers="hd_b_ml182.t4_1_1_13_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">3.2</td><td headers="hd_b_ml182.t4_1_1_13_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">17.58</td><td headers="hd_b_ml182.t4_1_1_13_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></td><td headers="hd_b_ml182.t4_1_1_13_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">>30</td></tr><tr><td headers="hd_b_ml182.t4_1_1_13_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">1A2</td><td headers="hd_b_ml182.t4_1_1_13_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">>30</td><td headers="hd_b_ml182.t4_1_1_13_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">8.93</td><td headers="hd_b_ml182.t4_1_1_13_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">>30</td><td headers="hd_b_ml182.t4_1_1_13_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">>30</td></tr><tr><th id="hd_b_ml182.t4_1_1_19_1" colspan="5" rowspan="1" style="text-align:center;vertical-align:top;">mGlu selectivity</th></tr><tr><td headers="hd_b_ml182.t4_1_1_19_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">mGlu<sub>1</sub></td><td headers="hd_b_ml182.t4_1_1_19_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">inactive</td><td headers="hd_b_ml182.t4_1_1_19_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></td><td headers="hd_b_ml182.t4_1_1_19_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></td><td headers="hd_b_ml182.t4_1_1_19_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></td></tr><tr><td headers="hd_b_ml182.t4_1_1_19_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">mGlu<sub>2</sub></td><td headers="hd_b_ml182.t4_1_1_19_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">inactive</td><td headers="hd_b_ml182.t4_1_1_19_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></td><td headers="hd_b_ml182.t4_1_1_19_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></td><td headers="hd_b_ml182.t4_1_1_19_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></td></tr><tr><td headers="hd_b_ml182.t4_1_1_19_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">mGlu<sub>3</sub></td><td headers="hd_b_ml182.t4_1_1_19_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">inactive</td><td headers="hd_b_ml182.t4_1_1_19_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></td><td headers="hd_b_ml182.t4_1_1_19_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></td><td headers="hd_b_ml182.t4_1_1_19_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></td></tr><tr><td headers="hd_b_ml182.t4_1_1_19_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">mGlu<sub>5</sub></td><td headers="hd_b_ml182.t4_1_1_19_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">PAM, 2.1 FS</td><td headers="hd_b_ml182.t4_1_1_19_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></td><td headers="hd_b_ml182.t4_1_1_19_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></td><td headers="hd_b_ml182.t4_1_1_19_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></td></tr><tr><td headers="hd_b_ml182.t4_1_1_19_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">mGlu<sub>6</sub></td><td headers="hd_b_ml182.t4_1_1_19_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">PAM, 3.1 FS</td><td headers="hd_b_ml182.t4_1_1_19_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></td><td headers="hd_b_ml182.t4_1_1_19_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></td><td headers="hd_b_ml182.t4_1_1_19_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></td></tr><tr><td headers="hd_b_ml182.t4_1_1_19_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">mGlu<sub>7</sub></td><td headers="hd_b_ml182.t4_1_1_19_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">PAM, 2.9 FS</td><td headers="hd_b_ml182.t4_1_1_19_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></td><td headers="hd_b_ml182.t4_1_1_19_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></td><td headers="hd_b_ml182.t4_1_1_19_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></td></tr><tr><td headers="hd_b_ml182.t4_1_1_19_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">mGlu<sub>8</sub></td><td headers="hd_b_ml182.t4_1_1_19_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">inactive</td><td headers="hd_b_ml182.t4_1_1_19_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></td><td headers="hd_b_ml182.t4_1_1_19_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></td><td headers="hd_b_ml182.t4_1_1_19_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></td></tr></tbody></table></div></div><div id="ml182.t5" class="table"><h3><span class="label">Table 5</span><span class="title">Calculated Property Comparison with MDDR Compounds</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK143194/table/ml182.t5/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml182.t5_lrgtbl__"><table class="no_top_margin"><thead><tr><th id="hd_h_ml182.t5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Property</th><th id="hd_h_ml182.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><a href="/pcsubstance/?term=ML182[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML182</a>, CID 46869947</th><th id="hd_h_ml182.t5_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">MDDR Phase I</th><th id="hd_h_ml182.t5_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">MDDR Launched</th></tr></thead><tbody><tr><td headers="hd_h_ml182.t5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">MW</td><td headers="hd_h_ml182.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">393.82</td><td headers="hd_h_ml182.t5_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">438.98</td><td headers="hd_h_ml182.t5_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">415.20</td></tr><tr><td headers="hd_h_ml182.t5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">cLogP</td><td headers="hd_h_ml182.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">1.91</td><td headers="hd_h_ml182.t5_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">3.21</td><td headers="hd_h_ml182.t5_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">2.21</td></tr><tr><td headers="hd_h_ml182.t5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">TPSA</td><td headers="hd_h_ml182.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">79.37</td><td headers="hd_h_ml182.t5_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">97.06</td><td headers="hd_h_ml182.t5_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">91.78</td></tr><tr><td headers="hd_h_ml182.t5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Hdon</td><td headers="hd_h_ml182.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">1.00</td><td headers="hd_h_ml182.t5_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">2.12</td><td headers="hd_h_ml182.t5_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">2.13</td></tr><tr><td headers="hd_h_ml182.t5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Hacc</td><td headers="hd_h_ml182.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">5.00</td><td headers="hd_h_ml182.t5_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">7.06</td><td headers="hd_h_ml182.t5_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">6.47</td></tr><tr><td headers="hd_h_ml182.t5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">LogS</td><td headers="hd_h_ml182.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">−4.42</td><td headers="hd_h_ml182.t5_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">−4.96</td><td headers="hd_h_ml182.t5_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">−3.73</td></tr><tr><td headers="hd_h_ml182.t5_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">NrotB</td><td headers="hd_h_ml182.t5_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">3.00</td><td headers="hd_h_ml182.t5_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">7.08</td><td headers="hd_h_ml182.t5_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">5.71</td></tr></tbody></table></div></div></div><div id="ml182.s13"><h3>3.5. Cellular Activity</h3><p>This series of positive allosteric modulators displayed functional activity (Ca<sup>+2</sup> mobilzation/thallium flux) in CHO cells stably expressing the human and rat mGlu<sub>4</sub> receptor [<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2185" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2185</a> and <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2197" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2197</a>]. In addition, <a href="/pcsubstance/?term=ML182[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML182</a> showed significant effects after oral dosing in the haloperidol induced hyperlocomotion rodent assay.</p></div><div id="ml182.s14"><h3>3.6. Profiling Assays</h3><p><a href="/pcsubstance/?term=ML182[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML182</a> was tested at Ricerca’s (formerly MDS Pharma’s) Lead Profiling Screen (binding assay panel of 68 GPCRs, ion channels and transporters screened at 10 μM), and was found to not significantly interact with 66 out of the 68 assays conducted (no inhibition of radio ligand binding > 50% at 10 μM).<sup>20</sup> CID 46869947 (<a href="/pcsubstance/?term=ML182[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML182</a>) did have activity against the following 2 targets (human targets at 10 μM): Adenosine A<sub>2A</sub> (66%) and Serotonin (5-hydroxytryptamine) 5-HT<sub>2B</sub> (63%). However it should be pointed out that these are only single-point values and that functional selectivity may be significantly better than suggested by these “% activities.”</p></div></div><div id="ml182.s15"><h2 id="_ml182_s15_">4. Discussion</h2><div id="ml182.s16"><h3>4.1. Comparison to Existing Art and How the New Probe is an Improvement</h3><p>Relative to our initial mGlu<sub>4</sub> PAM probe (<a href="/pcsubstance/?term=ML128[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML128</a>; CID 44191096) this second generation probe (<a href="/pcsubstance/?term=ML182[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML182</a>) possesses improved metabolic stability and physiochemical properties, while retaining comparable potency (EC<sub>50</sub> ~300 nM at both the rat and human receptor) with a slight loss of fold-shift (11x) of the glutamate CRC. In addition, this second generation probe (<a href="/pcsubstance/?term=ML182[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML182</a>) displayed a superior <i>in vivo</i> PK profile. This improved PK profile translated into <i>in vivo</i> efficacy in an anti-Parkinsonian rodent model after PO dosing – a major advancement for the mGlu<sub>4</sub> community. Lastly, this probe (<a href="/pcsubstance/?term=ML182[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML182</a>), along with our initial probe (<a href="/pcsubstance/?term=ML128[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML128</a>; CID 44191096), is not encumbered with patent restrictions and rests firmly in the public domain.</p></div><div id="ml182.s17"><h3>4.2. Mechanism of Action Studies</h3><p>It is believed that this probe is functioning by positive allosteric modulation of the metabotropic glutamate 4 receptor (mGlu<sub>4</sub>) given its lack of activity (or diminished activity) on the other glutamate receptor subtypes (mGlu<sub>1–3,5–8</sub>), its dependence on the presence of glutamate to elicit functional activity and its nearly clean profile in the Ricerca lead profiling screen.</p></div><div id="ml182.s18"><h3>4.3. Planned Future Studies</h3><p>At the present time no further studies are planned with this probe molecule. However, given its excellent selectivity profile it will continue to be used as a reference standard for <i>in vitro</i> experiments exploring hmGlu<sub>4</sub> receptor activation and downstream signaling. Ultimately, if the opportunity arises to study selective mGlu<sub>4</sub> receptor activation in non-human primates this probe will be among our top candidates for initial testing.</p></div></div><div id="ml182.s19"><h2 id="_ml182_s19_">5. References</h2><dl class="temp-labeled-list"><dt>1.</dt><dd><div class="bk_ref" id="ml182.r1">Conn PJ, Pin J.-P. Pharmacology and functions of metabotropic glutamate receptors. <span><span class="ref-journal">Ann Rev Pharmacol Toxicol. </span>1997;<span class="ref-vol">37</span>:205–237.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/9131252" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9131252</span></a>]</div></dd><dt>2.</dt><dd><div class="bk_ref" id="ml182.r2">Marino MJ, Conn PJ. Glutamate-based therapeutic approaches: allosteric modulators of metabotropic glutamate receptors. <span><span class="ref-journal">Curr Opin Pharm. </span>2006;<span class="ref-vol">6</span>:98–102.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16368268" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16368268</span></a>]</div></dd><dt>3.</dt><dd><div class="bk_ref" id="ml182.r3">Conn PJ, Christopoulos A, Lindsley CW. Allosteric modulators of GPCRs: a novel approach for the treatment of CNS disorders. <span><span class="ref-journal">Nature Rev Drug Dis. </span>2009;<span class="ref-vol">8</span>:41–54.</span> [<a href="/pmc/articles/PMC2907734/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2907734</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19116626" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19116626</span></a>]</div></dd><dt>4.</dt><dd><div class="bk_ref" id="ml182.r4">Schoepp DD, Jane DE, Monn JA. Pharmacological agents acting at subtypes of metabotropic glutamate receptors. <span><span class="ref-journal">Neuropharmacology. </span>1999;<span class="ref-vol">38</span>:1431–1476.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/10530808" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10530808</span></a>]</div></dd><dt>5.</dt><dd><div class="bk_ref" id="ml182.r5">Hopkins CR, Lindsley CW, Niswender CM. mGluR4 Positive Allosteric Modulation as Potential Treatment of Parkinson’s. <span><span class="ref-journal">Disease Future Med Chem. </span>2009;<span class="ref-vol">1</span>:501–513.</span> [<a href="/pmc/articles/PMC2790174/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2790174</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/20161443" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20161443</span></a>]</div></dd><dt>6.</dt><dd><div class="bk_ref" id="ml182.r6">Hefti FF. <span><span class="ref-journal">Parkinson’s Disease Drug Discovery for Nervous System Diseases. </span>2005:183–204.</span></div></dd><dt>7.</dt><dd><div class="bk_ref" id="ml182.r7">Valenti O, Marino MJ, Wittmann M, Lis E, DiLella AG, Kinney GG, Conn PJ. Group III metabotropic glutamate receptor-mediated modulation of the striatopallidal synapse. <span><span class="ref-journal">J Neuroscience. </span>2003;<span class="ref-vol">23</span>:7218–7226.</span> [<a href="/pmc/articles/PMC6740663/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6740663</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/12904482" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12904482</span></a>]</div></dd><dt>8.</dt><dd><div class="bk_ref" id="ml182.r8">Maj M, Bruno V, Dragic Z, Yamamoto R, Battaglia G, Inderbitzin W, Stoehr N, Stein T, Gasparini F, Vranesic I, Kuhn R, Nicoletti F, Flor PJ. (−)-PHCCC, a positive allosteric modulator of mGluR4: characterization, mechanism of action, and neuroprotection. <span><span class="ref-journal">Neuropharmacology. </span>2003;<span class="ref-vol">45</span>:895–906.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/14573382" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 14573382</span></a>]</div></dd><dt>9.</dt><dd><div class="bk_ref" id="ml182.r9">Battaglia G, Busceti CL, Molinaro G, Giagioni F, Traficante A, Nicoletti F, Bruno V. Pharmacological activation of mGluR4 metabotropic glutamate receptors reduces nigrostriatal degeneration in mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. <span><span class="ref-journal">J Neuroscience. </span>2006;<span class="ref-vol">26</span>:7222–7229.</span> [<a href="/pmc/articles/PMC6673941/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC6673941</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/16822979" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16822979</span></a>]</div></dd><dt>10.</dt><dd><div class="bk_ref" id="ml182.r10">Annoura H, Fukunaga A, Uesugi M. A novel class of antagonists for metabotropic glutamate receptors, 7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylates. <span><span class="ref-journal">Bioorg Med Chem Lett. </span>1996;<span class="ref-vol">6</span>:763–766.</span></div></dd><dt>11.</dt><dd><div class="bk_ref" id="ml182.r11">Marino MJ, Williams DL Jr, O’Brien JA, Valenti O, McDonald TP, Clements MK, Wang R, DiLella AG, Kinney GG, Conn PJ. Allosteric modulation of group III metabotropic glutamate receptor 4: a potential approach to Parkinson’s disease treatment. <span><span class="ref-journal">Proc Nat Acad Sci. </span>2003;<span class="ref-vol">100</span>:13668–13673.</span> [<a href="/pmc/articles/PMC263871/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC263871</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/14593202" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 14593202</span></a>]</div></dd><dt>12.</dt><dd><div class="bk_ref" id="ml182.r12">Niswender CM, Johnson KA, Weaver CD, Jones CK, Xiang Z, Luo Q, Rodriguez AL, Marlo JE, de Paulis T, Thompson AD, Days EL, Nalywajko T, Austin CA, Williams MB, Ayala JE, Williams R, Lindsley CW, Conn PJ. Discovery, characterization, and antiparkinsonian effect of novel positive allosteric modulators of metabotropic glutamate receptor 4. <span><span class="ref-journal">Mol Pharmacol. </span>2008;<span class="ref-vol">74</span>:1345–1358.</span> [<a href="/pmc/articles/PMC2574552/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2574552</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/18664603" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18664603</span></a>]</div></dd><dt>13.</dt><dd><div class="bk_ref" id="ml182.r13">Engers DW, Niswender CM, Weaver CD, Jadhav S, Menon UN, Zamorano R, Conn PJ, Lindsley CW, Hopkins CR. Synthesis and evaluation of a series of heterobiarylamides that are centrally penetrant metabotropic glutamate receptor 4 (mGluR4) positive allosteric modulators (PAMs). <span><span class="ref-journal">J Med Chem. </span>2009;<span class="ref-vol">52</span>:4115–4118.</span> [<a href="/pmc/articles/PMC2765192/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2765192</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19469556" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19469556</span></a>]</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/NBK143194/?report=reader">PubReader</a></li><li><a href="/books/NBK143194/?report=printable">Print View</a></li><li><a data-jig="ncbidialog" href="#_ncbi_dlg_citbx_NBK143194" data-jigconfig="width:400,modal:true">Cite this Page</a><div id="_ncbi_dlg_citbx_NBK143194" style="display:none" title="Cite this Page"><div class="bk_tt">Hopkins CR, Engers DW, Niswender CM, et al. Discovery of a potent, selective and orally active in vivo mGlu4 positive allosteric modulator. 2010 Oct 29 [Updated 2013 Mar 14]. In: Probe Reports from the NIH Molecular Libraries Program [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2010-. <span class="bk_cite_avail"></span></div></div></li><li><a href="/books/NBK143194/pdf/Bookshelf_NBK143194.pdf">PDF version of this page</a> (611K)</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="#ml182.s1" ref="log$=inpage&link_id=inpage">Probe Structure & Characteristics</a></li><li><a href="#ml182.s2" ref="log$=inpage&link_id=inpage">Recommendations for Scientific Use of the Probe</a></li><li><a href="#ml182.s3" ref="log$=inpage&link_id=inpage">Introduction</a></li><li><a href="#ml182.s4" ref="log$=inpage&link_id=inpage">Materials and Methods</a></li><li><a href="#ml182.s8" ref="log$=inpage&link_id=inpage">Results</a></li><li><a href="#ml182.s15" ref="log$=inpage&link_id=inpage">Discussion</a></li><li><a href="#ml182.s19" ref="log$=inpage&link_id=inpage">References</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Related information</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="discovery_db_links" id="Shutter"></a></div><div class="portlet_content"><ul><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=pmc&DbFrom=books&Cmd=Link&LinkName=books_pmc_refs&IdsFromResult=3034104" ref="log$=recordlinks">PMC</a><div class="brieflinkpop offscreen_noflow">PubMed Central citations</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" 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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/23658969" ref="ordinalpos=1&linkpos=1&log$=relatedreviews&logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Discovery of a novel metabotropic glutamate receptor 4 (mGlu(4)) positive allosteric modulator (PAM) extended probe: Characterization of ML292, a potent and selective mGlu(4) PAM which produces efficacy alone or in combination with L-DOPA in preclinical rodent models of Parkinson's disease.</a><span class="source">[Probe Reports from the NIH Mol...]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" 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Epub 2013 Aug 2.</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/21433377" ref="ordinalpos=1&linkpos=5&log$=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> Discovery of a potent, selective and in vivo active mGluR4 positive allosteric modulator.</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> Discovery of a potent, selective and in vivo active mGluR4 positive allosteric modulator.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Hopkins CR, Niswender CM, Lewis LM, Weaver CD, Lindsley CW. </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></ul><a class="seemore" href="/sites/entrez?db=pubmed&cmd=link&linkname=pubmed_pubmed_reviews&uid=23762961" ref="ordinalpos=1&log$=relatedreviews_seeall&logdbfrom=pubmed">See reviews...</a><a class="seemore" href="/sites/entrez?db=pubmed&cmd=link&linkname=pubmed_pubmed&uid=23762961" ref="ordinalpos=1&log$=relatedarticles_seeall&logdbfrom=pubmed">See all...</a></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Recent Activity</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="recent_activity" id="Shutter"></a></div><div class="portlet_content"><div xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" id="HTDisplay" class=""><div class="action"><a href="javascript:historyDisplayState('ClearHT')">Clear</a><a href="javascript:historyDisplayState('HTOff')" class="HTOn">Turn Off</a><a href="javascript:historyDisplayState('HTOn')" class="HTOff">Turn On</a></div><ul id="activity"><li class="ra_rcd ralinkpopper two_line"><a class="htb ralinkpopperctrl" ref="log$=activity&linkpos=1" href="/portal/utils/pageresolver.fcgi?recordid=67d66bd867c23b31e0b2d57d">Discovery of a potent, selective and orally active in vivo mGlu4 positive allost...</a><div class="ralinkpop offscreen_noflow">Discovery of a potent, selective and orally active in vivo mGlu4 positive allosteric modulator - 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