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<script type="text/javascript" src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.boots.min.js"> </script><title>Identification of a Selective Allosteric Agonist of mGlu5 - Probe Reports from the NIH Molecular Libraries Program - NCBI Bookshelf</title>
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<meta name="citation_inbook_title" content="Probe Reports from the NIH Molecular Libraries Program [Internet]">
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<meta name="citation_title" content="Identification of a Selective Allosteric Agonist of mGlu5">
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<meta name="citation_publisher" content="National Center for Biotechnology Information (US)">
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<meta name="citation_date" content="2013/03/07">
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<meta name="citation_author" content="Jason Manka">
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<meta name="citation_author" content="Ya Zhou">
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<meta name="citation_author" content="Aspen Chun">
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<meta name="citation_author" content="Eric S. Dawson">
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<meta name="citation_author" content="Paige N. Vinson">
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<meta name="citation_author" content="Colleen M. Niswender">
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<meta name="citation_author" content="Meredith J. Noetzel">
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<meta name="citation_author" content="Jerri M. Rook">
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<meta name="citation_author" content="Thomas M. Bridges">
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<meta name="citation_author" content="J. Scott Daniels">
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<meta name="citation_author" content="Carrie Jones">
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<meta name="citation_author" content="P. Jeffrey Conn">
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<meta name="citation_author" content="Craig W. Lindsley">
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<meta name="citation_author" content="Shaun R. Stauffer">
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<meta name="citation_pmid" content="23762929">
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<meta name="DC.Title" content="Identification of a Selective Allosteric Agonist of mGlu5">
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<meta name="DC.Contributor" content="Jason Manka">
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<meta name="DC.Contributor" content="Ya Zhou">
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<meta name="DC.Contributor" content="Aspen Chun">
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<meta name="DC.Contributor" content="Eric S. Dawson">
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<meta name="DC.Contributor" content="Paige N. Vinson">
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<meta name="DC.Contributor" content="Colleen M. Niswender">
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<meta name="DC.Contributor" content="Meredith J. Noetzel">
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<meta name="DC.Contributor" content="Jerri M. Rook">
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<meta name="DC.Contributor" content="Thomas M. Bridges">
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<meta name="DC.Contributor" content="J. Scott Daniels">
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<meta name="DC.Contributor" content="Carrie Jones">
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<meta name="DC.Contributor" content="P. Jeffrey Conn">
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<meta name="DC.Contributor" content="Craig W. Lindsley">
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<meta name="DC.Contributor" content="Shaun R. Stauffer">
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<meta name="DC.Date" content="2013/03/07">
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<meta name="DC.Identifier" content="https://www.ncbi.nlm.nih.gov/books/NBK143559/">
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<meta name="description" content="Allosteric modulators for G-protein-coupled receptors (GPCRs) provide numerous advantages over orthosteric ligands, including greater sub-type selectivity, reduced receptor desensitization, saturability of effect, and potential for enhanced therapeutic index. Positive allosteric modulators (PAMs) of the group I metabotropic glutamate receptor mGlu5 are being pursued as a novel approach to treat all three symptom domains of schizophrenia. Interestingly, we have noted that mGlu5 PAMs within a single chemotype have the propensity to demonstrate in vitro profiles ranging from pure potentiation, requiring the presence of orthosteric agonist for activation, to robust agonistic activity in the absence of an orthosteric ligand coupled with PAM activity (ago-PAM). Highly selective orthosteric agonists of mGlu5 are not available; additionally, effective agonists of mGlu5 with an allosteric mechanism of activation are not known. Herein we describe the SAR and in vitro profile of a series mGlu5 selective allosteric agonists within an acetylenic picolinamide scaffold. VU0424465 (ML273, SID 125311644/CID 53384845) is the most potent and efficacious ago-PAM within this series and is being declared as a MLPCN probe molecule. ML273 will serve as a significant ago-PAM tool compound for the field with potential for studies within native systems.">
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<meta name="og:description" content="Allosteric modulators for G-protein-coupled receptors (GPCRs) provide numerous advantages over orthosteric ligands, including greater sub-type selectivity, reduced receptor desensitization, saturability of effect, and potential for enhanced therapeutic index. Positive allosteric modulators (PAMs) of the group I metabotropic glutamate receptor mGlu5 are being pursued as a novel approach to treat all three symptom domains of schizophrenia. Interestingly, we have noted that mGlu5 PAMs within a single chemotype have the propensity to demonstrate in vitro profiles ranging from pure potentiation, requiring the presence of orthosteric agonist for activation, to robust agonistic activity in the absence of an orthosteric ligand coupled with PAM activity (ago-PAM). Highly selective orthosteric agonists of mGlu5 are not available; additionally, effective agonists of mGlu5 with an allosteric mechanism of activation are not known. Herein we describe the SAR and in vitro profile of a series mGlu5 selective allosteric agonists within an acetylenic picolinamide scaffold. VU0424465 (ML273, SID 125311644/CID 53384845) is the most potent and efficacious ago-PAM within this series and is being declared as a MLPCN probe molecule. ML273 will serve as a significant ago-PAM tool compound for the field with potential for studies within native systems.">
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match">◀</a><button id="jr-fip-matches">no matches yet</button><a id="jr-fip-next" class="wsprkl btn" title="Jump to next match">▶</a></nav></nav></div><div id="jr-epub-interstitial" class="hidden"></div><div id="jr-content"><article data-type="main"><div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><div class="fm-sec"><h1 id="_NBK143559_"><span class="title" itemprop="name">Identification of a Selective Allosteric Agonist of mGlu<sub>5</sub></span></h1><p class="contribs">Manka J, Zhou Y, Chun A, et al.</p><p class="fm-aai"><a href="#_NBK143559_pubdet_">Publication Details</a></p></div></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="_abs_rndgid_" itemprop="description"><p>Allosteric modulators for G-protein-coupled receptors (GPCRs) provide numerous advantages over orthosteric ligands, including greater sub-type selectivity, reduced receptor desensitization, saturability of effect, and potential for enhanced therapeutic index. Positive allosteric modulators (PAMs) of the group I metabotropic glutamate receptor mGlu<sub>5</sub> are being pursued as a novel approach to treat all three symptom domains of schizophrenia. Interestingly, we have noted that mGlu<sub>5</sub> PAMs within a single chemotype have the propensity to demonstrate in vitro profiles ranging from pure potentiation, requiring the presence of orthosteric agonist for activation, to robust agonistic activity in the absence of an orthosteric ligand coupled with PAM activity (ago-PAM). Highly selective orthosteric agonists of mGlu<sub>5</sub> are not available; additionally, effective agonists of mGlu<sub>5</sub> with an allosteric mechanism of activation are not known. Herein we describe the SAR and in vitro profile of a series mGlu<sub>5</sub> selective allosteric agonists within an acetylenic picolinamide scaffold. VU0424465 (<a href="/pcsubstance/?term=ML273[synonym]" ref="pagearea=abstract&targetsite=entrez&targetcat=term&targettype=pubchem">ML273</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/substance/125311644" ref="pagearea=abstract&targetsite=entrez&targetcat=link&targettype=pubchem">SID 125311644</a>/CID 53384845) is the most potent and efficacious ago-PAM within this series and is being declared as a MLPCN probe molecule. <a href="/pcsubstance/?term=ML273[synonym]" ref="pagearea=abstract&targetsite=entrez&targetcat=term&targettype=pubchem">ML273</a> will serve as a significant ago-PAM tool compound for the field with potential for studies within native systems.</p></div><div class="h2"></div><p><b>Assigned Assay Grant #:</b> <a href="/nuccore/1606713245" class="bk_tag" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=nuccore">MH062646</a></p><p><b>Chemistry Center Name & PI:</b> Vanderbilt Specialized Chemistry Center, Craig W. Lindsley</p><p><b>Assay Submitter & Institution:</b> P. Jeffrey Conn, Vanderbilt University</p><p><b>PubChem Summary Bioassay Identifier (AID):</b>
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<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588721" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">588721</a></p><div id="ml273.s1"><h2 id="_ml273_s1_">Probe Structure & Characteristics</h2><div id="ml273.fu1" class="figure"><div class="graphic"><img src="/books/NBK143559/bin/ml273fu1.jpg" alt="Image ml273fu1" /></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml273tu1"><a href="/books/NBK143559/table/ml273.tu1/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figml273tu1" rid-ob="figobml273tu1"><img class="small-thumb" src="/books/NBK143559/table/ml273.tu1/?report=thumb" src-large="/books/NBK143559/table/ml273.tu1/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ml273.tu1"><a href="/books/NBK143559/table/ml273.tu1/?report=objectonly" target="object" rid-ob="figobml273tu1">Table</a></h4></div></div></div><div id="ml273.s2"><h2 id="_ml273_s2_">1. Recommendations for scientific use of the probe</h2><p>This probe (<a href="/pcsubstance/?term=ML273[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML273</a>, CID 53382545, <a href="https://pubchem.ncbi.nlm.nih.gov/substance/125311644" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 125311644</a>) is an mGlu<sub>5</sub> allosteric agonist and a mGlu<sub>5</sub> potentiator of sub-threshold glutamate responses. In the absence of added agonist, <a href="/pcsubstance/?term=ML273[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML273</a> induces responses in low receptor expression level recombinant cell lines, rat cortical astrocytes, and in native electrophysiological recordings in rat SC-CA1. Importantly, <a href="/pcsubstance/?term=ML273[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML273</a> represents the first structurally non-glutamate based mGlu<sub>5</sub> agonist with high selectivity for mGlu<sub>5</sub> versus mGlu<sub>1</sub> and appears to be specific for mGlu<sub>5</sub> based upon the lack of detected activity at mGlu<sub>1</sub> in fold-shift format at the highest concentration tested (10 μM). In addition, <a href="/pcsubstance/?term=ML273[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML273</a> acts as an allosteric modulator capable of potentiating sub-threshold glutamate responses in calcium mobilization assays using recombinant cell lines. Thus <a href="/pcsubstance/?term=ML273[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML273</a> has a bifunctional pharmacological profile, eliciting responses alone and in the presence of orthosteric agonist. It is anticipated that <a href="/pcsubstance/?term=ML273[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML273</a> will be useful in various in vitro and native settings where robust and selective activation of mGlu<sub>5</sub> is desired.</p></div><div id="ml273.s3"><h2 id="_ml273_s3_">2. Materials and Methods</h2><div id="ml273.s4"><h3>2.1. Assays</h3><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml273tu2"><a href="/books/NBK143559/table/ml273.tu2/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figml273tu2" rid-ob="figobml273tu2"><img class="small-thumb" src="/books/NBK143559/table/ml273.tu2/?report=thumb" src-large="/books/NBK143559/table/ml273.tu2/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ml273.tu2"><a href="/books/NBK143559/table/ml273.tu2/?report=objectonly" target="object" rid-ob="figobml273tu2">Table</a></h4></div></div></div><div id="ml273.s5"><h3>2.2. Probe Chemical Characterization</h3><p>Synthetic procedure and spectral data for <a href="/pcsubstance/?term=ML273[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML273</a> (CID 53384864, <a href="https://pubchem.ncbi.nlm.nih.gov/substance/126920341" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 126920341</a>, VU0424465-2, note <a href="/pcsubstance/?term=ML273[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML273</a> is also associated with CID 53382545/<a href="https://pubchem.ncbi.nlm.nih.gov/substance/125311644" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 125311644</a> which is used throughout Results and Discussion, also internally associated with VU0424465-1).</p><p>Probe compound <a href="/pcsubstance/?term=ML273[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML273</a> (CID 53384864) was prepared according to the scheme in <a class="figpopup" href="/books/NBK143559/figure/ml273.f1/?report=objectonly" target="object" rid-figpopup="figml273f1" rid-ob="figobml273f1">Figure 1</a> and provided the following characterization data: LC-MS (>98%) <i>m/z</i> = 327.1 [M+H], <sup>1</sup>H NMR (400 MHz, CDCl<sub>3</sub>) δ 8.67 (1H, d, <i>J</i>=1.6 Hz), 8.20 (2H, d, <i>J</i>=8.0 Hz), 7.96 (1H, d, <i>J</i>=8.2, 2.2 Hz), 7.36 (2H, m), 7.27 (1H, dd, <i>J</i>=8.2, 1.6 Hz), 7.14 – 7.09 (1H, m), 4.16 (1H, dq, <i>J</i>=9.2, 6.8 Hz), 2.6 (1H, br s), 1.31 (overlapping s and d, 9H, <i>J</i>=10.4 Hz); HRMS (ESI) <i>m/z</i> 327.1508 ([M+H]<sup>+</sup>, 100%) calcd for C<sub>19</sub>H<sub>20</sub>FN<sub>2</sub>O<sub>2</sub>, 327.1509.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml273f1" co-legend-rid="figlgndml273f1"><a href="/books/NBK143559/figure/ml273.f1/?report=objectonly" target="object" title="Figure 1" class="img_link icnblk_img figpopup" rid-figpopup="figml273f1" rid-ob="figobml273f1"><img class="small-thumb" src="/books/NBK143559/bin/ml273f1.gif" src-large="/books/NBK143559/bin/ml273f1.jpg" alt="Figure 1. (R)-5-((3-fluorophenyl)ethynyl)-N-(3-hydroxy-3-methylbutan-2-yl)picolinamide." /></a><div class="icnblk_cntnt" id="figlgndml273f1"><h4 id="ml273.f1"><a href="/books/NBK143559/figure/ml273.f1/?report=objectonly" target="object" rid-ob="figobml273f1">Figure 1</a></h4><p class="float-caption no_bottom_margin">(<i>R</i>)-5-((3-fluorophenyl)ethynyl)-N-(3-hydroxy-3-methylbutan-2-yl)picolinamide. </p></div></div><p><b>Solubility.</b> Solubility in PBS at pH 7.4 was determined to be >75 μM or >24.5 μg/mL based upon triplicate testing using an assay from Analiza Inc. labs (greater than control concentration). <a href="/pcsubstance/?term=ML273[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML273</a> shows excellent solubility up to 10 mM DMSO. In addition, solubility was determined in-house in Fassif (fasted simulated intestinal fluid) media at 37 °C for 24h. In Fassif <a href="/pcsubstance/?term=ML273[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML273</a> solubility was determined to be 104 μM (34 μg/mL). Collectively, these data demonstrate that <a href="/pcsubstance/?term=ML273[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML273</a> is a moderate to highly soluble tool compound at neutral pH.<sup><a class="bibr" href="#ml273.r1" rid="ml273.r1">1</a></sup></p><p><b>Stability.</b> Stability was determined for <a href="/pcsubstance/?term=ML273[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML273</a> in PBS buffer at room temperature (Analiza Inc.) with time course evaluation over 48h. After 48 hours, the percent of parent compound remaining was ~100%, indicating excellent stability after prolonged exposure to PBS buffer.<sup><a class="bibr" href="#ml273.r1" rid="ml273.r1">1</a></sup></p><p><b>Compounds added to the SMR collection (MLS#s):</b> MLS003874879 (<a href="/pcsubstance/?term=ML273[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML273</a>, CID 53384864, 21 mg); MLS003874880 (CID 53384876, 7.4 mg); MLS003874881 (CID 53384838, 6.1 mg); MLS003874882 (CID 53384841, 7.6 mg); MLS003874883 (CID 53384852, 6.6 mg); MLS003874884 (CID 53384862, 7.2 mg).</p></div><div id="ml273.s6"><h3>2.3. Probe Preparation</h3><div id="ml273.fu2" class="figure"><div class="graphic"><img src="/books/NBK143559/bin/ml273fu2.jpg" alt="Image ml273fu2" /></div></div><p><b>Step 1: Preparation of 5-((3-fluorophenyl)ethynyl)picolinic acid.</b> 5-Bromopicolinic acid (2.0 g, 10.0 mmol), 1-ethynyl-3-fluorobenzene (1.0 mL, 12.0 mmol), Pd(PPh<sub>3</sub>)<sub>4</sub> (0.57 g, 0.5 mmol), CuI (0.2 g, 1.0 mmol), and diethylamine (6.2 mL, 60 mmol) were mixed in 15.0 mL of DMF in a sealed 10–20 mL microwave tube. The reaction was subjected to microwave irradiation at 90 °C for 45 min. <i>The crude reaction was diluted with H<sub>2</sub>O (60 mL). The product precipitate formed upon the addition of H<sub>2</sub>O. The mixture was filtered, affording the title compound as an off-white solid in 94% yield.</i></p><div id="ml273.fu3" class="figure"><div class="graphic"><img src="/books/NBK143559/bin/ml273fu3.jpg" alt="Image ml273fu3" /></div></div><p><b>Step 2: Preparation of (R)-5-((3-fluorophenyl)ethynyl)-N-(3-hydroxy-3-methylbutan-2-yl)picolinamide.</b> (R)-3-amino-2-methylbutan-2-ol (43 mg, 0.5 mmol, prepared from Boc-D-Ala-OMe according to literature procedures<sup>17, 18</sup>), 5-((3-fluorophenyl)ethynyl)picolinic acid (100 mg, 0.41 mmol), HATU (155 mg, 0.41 mmol) and <i>N</i>,<i>N</i>-<i>diisopropylethylamine (0.11 mL</i>, 0.8 mmol) were mixed in DMF (1.5 mL) at room temperature. The reaction mixture was stirred at the same temperature for 2 h, diluted with H<sub>2</sub>O (10 mL), and extracted with EtOAc (10.0 mL × 3). The organic layers were combined and washed with brine (15.0 mL), dried over MgSO<sub>4,</sub> and concentrated under reduced pressure. The crude material was purified by gradient column chromatography over silica (EtOAc:hexanes, 0–45%), affording the title compound as a while solid in 45% yield.</p></div></div><div id="ml273.s7"><h2 id="_ml273_s7_">3. Results</h2><div id="ml273.s8"><h3>3.1. Dose Response Curves for Probe</h3><div id="ml273.f2" class="figure bk_fig"><div class="graphic"><img src="/books/NBK143559/bin/ml273f2.jpg" alt="Figure 2. ML254 (SID 125305189) [3H]methoxyPEPy binding curve." /></div><h3><span class="label">Figure 2</span><span class="title">ML254 (SID 125305189) [3H]methoxyPEPy binding curve</span></h3></div></div><div id="ml273.s9"><h3>3.2. Cellular Activity</h3><p>The primary screening assay is a kinetic rat mGlu5 calcium Fluorescence assay using Fluo-4 AM Dye and HEK293A cell background. This biochemical in vitro fluorescence assay screens for potentiators of the glutamate promoted mGlu5-Ga/q-PLC-IPR cascade release of internal calcium stores. Activity from this assay indicates that <a href="/pcsubstance/?term=ML273[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML273</a> can gain access to its molecular target when applied to cells. <a href="/pcsubstance/?term=ML273[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML273</a> did not exhibit acute toxicity in cell based assays at concentrations up to 30 μM.</p></div><div id="ml273.s10"><h3>3.3. Profiling Assays</h3><p>Off-target ancillary pharmacology for <a href="/pcsubstance/?term=ML273[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML273</a> was assessed using the Ricerca Lead Profiler screen (68 GPCRs, ion channels and transporters screened at 10 μM). No significant activities were observed from this screen (<35% inhibition) indicating <a href="/pcsubstance/?term=ML273[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML273</a> is a highly selective probe.<sup><a class="bibr" href="#ml273.r2" rid="ml273.r2">2</a></sup></p></div></div><div id="ml273.s11"><h2 id="_ml273_s11_">4. Discussion</h2><div id="ml273.s12"><h3>4.1. Comparison to Existing Art and How the New Probe is an Improvement</h3><p>mGlu5 PAMs with different in vitro profiles are needed in order to fully understand the anticipated activity in vivo. Tool compounds have been limited by poor inherent physicochemical properties and a lack of assessment in systems other than recombinant cell lines. More recently diverse PAM chemotypes<sup><a class="bibr" href="#ml273.r3" rid="ml273.r3">3</a>–<a class="bibr" href="#ml273.r5" rid="ml273.r5">5</a></sup> have appeared and in some cases offer improvements in DMPK properties as well unique pharmacological profiles. In contrast, advances in allosteric agonist development do not exist and to our knowledge, <a href="/pcsubstance/?term=ML273[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML273</a> is the first. Thus, all prior agonists of mGlu<sub>5</sub> are mechanistically orthosteric in nature. The elegant work and discovery of orthosteric mGlu agonists in the 90’s based upon glutamate and phenyl glycine analogs paved the way to a handful of highly selective group I (mGlu<sub>1,5</sub>) vs. group II (mGlu<sub>2,3</sub>) and group III (mGlu<sub>4,6–8</sub>) orthosteric agonist tool compounds (<a class="figpopup" href="/books/NBK143559/table/ml273.t1/?report=objectonly" target="object" rid-figpopup="figml273t1" rid-ob="figobml273t1">Table 1</a>).<sup><a class="bibr" href="#ml273.r6" rid="ml273.r6">6</a>–<a class="bibr" href="#ml273.r7" rid="ml273.r7">7</a></sup></p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml273t1"><a href="/books/NBK143559/table/ml273.t1/?report=objectonly" target="object" title="Table 1" class="img_link icnblk_img figpopup" rid-figpopup="figml273t1" rid-ob="figobml273t1"><img class="small-thumb" src="/books/NBK143559/table/ml273.t1/?report=thumb" src-large="/books/NBK143559/table/ml273.t1/?report=previmg" alt="Table 1. Orthosteric-based mGlu agonists based upon glutamate." /></a><div class="icnblk_cntnt"><h4 id="ml273.t1"><a href="/books/NBK143559/table/ml273.t1/?report=objectonly" target="object" rid-ob="figobml273t1">Table 1</a></h4><p class="float-caption no_bottom_margin">Orthosteric-based mGlu agonists based upon glutamate. </p></div></div><p>To this end, quisqualate, 3,5-DHPG, and 3-HPG have had the greatest impact for group I mGlu receptor pharmacology based upon their overall potency and selectivity. Although these tool compounds have proven to be tremendously useful in vitro, it’s important to note they are not CNS pentrant and aside from intracerebroventricular (ICV) dosing studies, some previously described,<sup><a class="bibr" href="#ml273.r8" rid="ml273.r8">8</a></sup> the impact of orthorsteric agonists in vivo has been limited. Despite the success found with metabotropic group selective orthosteric ligands, mGlu<sub>1</sub> and/or mGlu<sub>5</sub> selective agonists are rare and CHPG (<a class="figpopup" href="/books/NBK143559/table/ml273.t1/?report=objectonly" target="object" rid-figpopup="figml273t1" rid-ob="figobml273t1">Table 1</a>) represents the first and only mGlu<sub>5</sub> selective agonist to our knowledge, with albeit weak potency for mGlu<sub>5</sub> with a reported EC<sub>50</sub> of 750 μM.<sup><a class="bibr" href="#ml273.r9" rid="ml273.r9">9</a></sup></p><p>Due to the limitations of CHPG and other orthosteric ligands as described in <a class="figpopup" href="/books/NBK143559/table/ml273.t1/?report=objectonly" target="object" rid-figpopup="figml273t1" rid-ob="figobml273t1">Table 1</a> and the lack of availability of allosteric agonists of mGlu<sub>5</sub>, <a href="/pcsubstance/?term=ML273[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML273</a> should prove to be an interesting and useful probe molecule for the field. <a href="/pcsubstance/?term=ML273[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML273</a> is the first fully characterized, systemically available brain penetrant ago-PAM with agonist activity in both recombinant and native systems. Further studies are warranted with <a href="/pcsubstance/?term=ML273[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML273</a> in order to understand the impact of its profile in our current understandings in basic mGlu<sub>5</sub> signaling.<sup><a class="bibr" href="#ml273.r10" rid="ml273.r10">10</a></sup> In addition, studies aimed at understanding therapeutic index of ago-PAMs versus pure-PAMs as it relates to therapeutic indications currently being explored for drug discovery using mGlu<sub>5</sub> PAMs are needed.</p></div></div><div id="ml273.s13"><h2 id="_ml273_s13_">5. References</h2><dl class="temp-labeled-list"><dl class="bkr_refwrap"><dt>1.</dt><dd><div class="bk_ref" id="ml273.r1">Solubility (PBS at pH = 7.4), Stability and Reactivity experiments were conducted at Analiza For additional information see: <a href="http://analiza.com" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">http://analiza<wbr style="display:inline-block"></wbr>​.com</a></div></dd></dl><dl class="bkr_refwrap"><dt>2.</dt><dd><div class="bk_ref" id="ml273.r2">For information on the Ricerca Lead Profiling Screen see: <a href="https://www.eurofinspanlabs.com/Catalog" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">https://www<wbr style="display:inline-block"></wbr>​.eurofinspanlabs.com/Catalog</a></div></dd></dl><dl class="bkr_refwrap"><dt>3.</dt><dd><div class="bk_ref" id="ml273.r3">Stauffer SR. Progress towards positive allosteric modulators of the metabotropic glutamate receptor subtype 5 (mGluR5). <span><span class="ref-journal">ACS Chemical Neuroscience. </span>2011;<span class="ref-vol">2</span>:450–470.</span> [<a href="/pmc/articles/PMC3369763/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3369763</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/22860171" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22860171</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>4.</dt><dd><div class="bk_ref" id="ml273.r4">Lindsley CW, Stauffer SR. Metabotropic glutamate receptor 5 (mGlu5) positive allosteric modulators (PAMs) for the treatment of schizophrenia: a review of the patent literature 2004–2012. <span><span class="ref-journal">Expert Opin Ther Patents. </span>2012.</span> in press.</div></dd></dl><dl class="bkr_refwrap"><dt>5.</dt><dd><div class="bk_ref" id="ml273.r5">Gilmour G, Broad LM, Wafford KA, Britton T, Colvin EM, Fivush A, Gastambide F, Getman B, Heinz BA, McCarthy AP, Preito L, Shanks E, Smith JW, Taboada L, Edgar DM, Tricklebank MD. In vitro characterization of the novel positive allosteric modulators of the mGlu5 receptor LSN2463359 and LSN2814617, and their effects on sleep architecture and operant responding in the rat. <span><span class="ref-journal">Neuropharam. </span>2013;<span class="ref-vol">64</span>:224.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/22884720" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22884720</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>6.</dt><dd><div class="bk_ref" id="ml273.r6">Schoepp DD, Conn PJ. Metabotropic glutamate receptors in brain function and pathology. <span><span class="ref-journal">Trends Pharmacol Sci. </span>1993;<span class="ref-vol">14</span>:13–20.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/7680175" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 7680175</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>7.</dt><dd><div class="bk_ref" id="ml273.r7">Ayala JE, Chen Y, Banko JL, Sheffler DJ, Williams R, Telk AN, Watson NL, Xiang Z, Zhang Y, Jones PJ, Lindsley CW, Olive MF, Conn PJ. mGluR5 positive allosteric modulators facilitate both hippocampal LTP and LTD and enhance spatial learning. <span><span class="ref-journal">Neuropsychopharmacology. </span>2009;<span class="ref-vol">34</span>:2057–71.</span> [<a href="/pmc/articles/PMC2884290/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2884290</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19295507" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19295507</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>8.</dt><dd><div class="bk_ref" id="ml273.r8">Merlin LR, Wong RK. Role of group I metabotropic glutamate receptors in the patterning of epileptiform activities in vitro. <span><span class="ref-journal">J Neurophysiol. </span>1997;<span class="ref-vol">78</span>:539–44.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/9242303" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9242303</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>9.</dt><dd><div class="bk_ref" id="ml273.r9">Liu F, Grauer S, Kelley C, Navarra R, Graf R, Zhang G, Atkinson PJ, Popiolek M, Wantuch C, Khawaja X, Smith D, Olsen M, Kouranova E, Lai M, Pruthi F, Pulicicchio C, Day M, Gilbert A, Pausch MH, Brandon NJ, Beyer CE, Comery TA, Logue S, Rosenzweig-Lipson S, Marquis KL. ADX47273 [S-(4-fluoro-phenyl)-{3-[3-(4-fluoro-phenyl)-[1,2,4]-oxadiazol-5-yl]-piper idin-1-yl}-methanone]: a novel metabotropic glutamate receptor 5-selective positive allosteric modulator with preclinical antipsychotic-like and procognitive activities. <span><span class="ref-journal">J Pharmacol Exp Ther 2008. </span><span class="ref-vol">327</span>:827–39.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/18753411" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18753411</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>10.</dt><dd><div class="bk_ref" id="ml273.r10">Rook JM, Noetzel MJ, Pouliot WA, Bridges TM, Vinson PN, Cho HP, Zhou Y, Gogliotti RD, Manka JT, Gregory KJ, Stauffer SR, Dudek FE, Xiang Z, Niswender CM, Daniels JS, Jones CK, Lindsley CW, Conn PJ. Unique Signaling Profiles of Positive Allosteric Modulators of Metabotropic Glutamate Receptor Subtype 5 Determine Differences in InVivo Activity. <span><span class="ref-journal">Biol Psych. </span>2012.</span> in press. [<a href="/pmc/articles/PMC3572342/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3572342</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/23140665" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 23140665</span></a>]</div></dd></dl></dl></div><div id="bk_toc_contnr"></div></div></div><div class="fm-sec"><h2 id="_NBK143559_pubdet_">Publication Details</h2><h3>Author Information and Affiliations</h3><p class="contrib-group"><h4>Authors</h4><span itemprop="author">Jason Manka</span>, <span itemprop="author">Ya Zhou</span>, <span itemprop="author">Aspen Chun</span>, <span itemprop="author">Eric S. Dawson</span>, <span itemprop="author">Paige N. Vinson</span>, <span itemprop="author">Colleen M. Niswender</span>, <span itemprop="author">Meredith J. Noetzel</span>, <span itemprop="author">Jerri M. Rook</span>, <span itemprop="author">Thomas M. Bridges</span>, <span itemprop="author">J. Scott Daniels</span>, <span itemprop="author">Carrie Jones</span>, <span itemprop="author">P. Jeffrey Conn</span>, <span itemprop="author">Craig W. Lindsley</span>, and <span itemprop="author">Shaun R. Stauffer</span><sup>*</sup>.</p><h4>Affiliations</h4><div class="affiliation">
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<span class="before-email-separator"></span><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ude.tlibrednav@reffuats.nuahs" class="oemail">ude.tlibrednav@reffuats.nuahs</a></div><h3>Publication History</h3><p class="small">Received: <span itemprop="datePublished">December 16, 2011</span>; Last Update: <span itemprop="dateModified">March 7, 2013</span>.</p><h3>Copyright</h3><div><div class="half_rhythm"><a href="/books/about/copyright/">Copyright Notice</a></div></div><h3>Publisher</h3><p>National Center for Biotechnology Information (US), Bethesda (MD)</p><h3>NLM Citation</h3><p>Manka J, Zhou Y, Chun A, et al. Identification of a Selective Allosteric Agonist of mGlu5. 2011 Dec 16 [Updated 2013 Mar 7]. In: Probe Reports from the NIH Molecular Libraries Program [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2010-. <span class="bk_cite_avail"></span></p></div><div class="small-screen-prev"><a href="/books/n/mlprobe/ml275/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M75,30 c-80,60 -80,0 0,60 c-30,-60 -30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Prev</text></svg></a></div><div class="small-screen-next"><a href="/books/n/mlprobe/ml269/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M25,30c80,60 80,0 0,60 c30,-60 30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Next</text></svg></a></div></article><article data-type="fig" id="figobml273fu1"><div id="ml273.fu1" class="figure"><div class="graphic"><img data-src="/books/NBK143559/bin/ml273fu1.jpg" alt="Image ml273fu1" /></div></div></article><article data-type="table-wrap" id="figobml273tu1"><div id="ml273.tu1" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK143559/table/ml273.tu1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml273.tu1_lrgtbl__"><table><thead><tr><th id="hd_h_ml273.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CID/ML#</th><th id="hd_h_ml273.tu1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Target Name</th><th id="hd_h_ml273.tu1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Secondary Assay 1 EC<sub>50</sub> (nM) [SID, AID]</th><th id="hd_h_ml273.tu1_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Anti-target Name(s) secondary assays 2–9</th><th id="hd_h_ml273.tu1_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Fold-Shift [SID, AIDs]</th><th id="hd_h_ml273.tu1_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Fold Selective</th><th id="hd_h_ml273.tu1_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Secondary Assay 11 Name: radioligand binding IC50 (nM) [SID, AID]</th></tr></thead><tbody><tr><td headers="hd_h_ml273.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CID 53384845/<a href="/pcsubstance/?term=ML273[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML273</a></td><td headers="hd_h_ml273.tu1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">mGlu<sub>5</sub> PAM</td><td headers="hd_h_ml273.tu1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">9.4 nM [<a href="https://pubchem.ncbi.nlm.nih.gov/substance/125311644" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 125311644</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588721" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 588721</a>]</td><td headers="hd_h_ml273.tu1_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">mGlu<sub>1</sub>,<sub>2–4</sub>,<sub>6–8</sub></td><td headers="hd_h_ml273.tu1_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">all receptors inactive, fold-shift <1.5 @ 10 μM [<a href="https://pubchem.ncbi.nlm.nih.gov/substance/125311644" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 125311644</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588736" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 588736</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588733" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 588733</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588728" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 588728</a>,<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588734" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 588734</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588735" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 588735</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588730" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 588730</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588737" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 588737</a>,<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588731" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 588731</a>,</td><td headers="hd_h_ml273.tu1_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">>800</td><td headers="hd_h_ml273.tu1_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">7.3 nM [<a href="https://pubchem.ncbi.nlm.nih.gov/substance/125311644" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 125311644</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588710" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 588710</a>]</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobml273tu2"><div id="ml273.tu2" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK143559/table/ml273.tu2/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml273.tu2_lrgtbl__"><table><thead><tr><th id="hd_h_ml273.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">AID</th><th id="hd_h_ml273.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Name</th></tr></thead><tbody><tr><td headers="hd_h_ml273.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588715" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 588715</a></td><td headers="hd_h_ml273.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Secondary kinetic rat mGlu5 calcium Fluorescence Assay Description using Fluo-4 AM Dye</td></tr><tr><td headers="hd_h_ml273.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588736" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 588736</a></td><td headers="hd_h_ml273.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Secondary mGlu1 Selectivity Assay</td></tr><tr><td headers="hd_h_ml273.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588733" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 588733</a></td><td headers="hd_h_ml273.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Secondary mGlu2 Selectivity Assay</td></tr><tr><td headers="hd_h_ml273.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588728" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 588728</a></td><td headers="hd_h_ml273.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Secondary mGlu3 Selectivity Assay</td></tr><tr><td headers="hd_h_ml273.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588734" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 588734</a></td><td headers="hd_h_ml273.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Secondary mGlu4 Selectivity Assay</td></tr><tr><td headers="hd_h_ml273.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588735" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 588735</a></td><td headers="hd_h_ml273.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Secondary rat mGlu5 Fold-Shift Assay Using High Expressing Cell Line</td></tr><tr><td headers="hd_h_ml273.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588730" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 588730</a></td><td headers="hd_h_ml273.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Secondary mGlu6 Selectivity Assay</td></tr><tr><td headers="hd_h_ml273.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588731" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 588731</a></td><td headers="hd_h_ml273.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Secondary mGlu7 Selectivity Assay</td></tr><tr><td headers="hd_h_ml273.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588732" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 588732</a></td><td headers="hd_h_ml273.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Secondary mGlu8 Selectivity Assay</td></tr><tr><td headers="hd_h_ml273.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588737" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 588737</a></td><td headers="hd_h_ml273.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Secondary human mGlu5 Fold-Shift Assay Using Low Expressing Cell Line</td></tr><tr><td headers="hd_h_ml273.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588710" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 588710</a></td><td headers="hd_h_ml273.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Secondary mGlu5 [3H]MethoxyPEPy Radioligand Binding Assay</td></tr><tr><td headers="hd_h_ml273.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588753" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 588753</a></td><td headers="hd_h_ml273.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Secondary Ricerca Lead Profiler Binding Assay</td></tr></tbody></table></div></div></article><article data-type="fig" id="figobml273f1"><div id="ml273.f1" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK143559/bin/ml273f1.jpg" alt="Figure 1. (R)-5-((3-fluorophenyl)ethynyl)-N-(3-hydroxy-3-methylbutan-2-yl)picolinamide." /></div><h3><span class="label">Figure 1</span><span class="title">(<i>R</i>)-5-((3-fluorophenyl)ethynyl)-N-(3-hydroxy-3-methylbutan-2-yl)picolinamide</span></h3></div></article><article data-type="fig" id="figobml273fu2"><div id="ml273.fu2" class="figure"><div class="graphic"><img data-src="/books/NBK143559/bin/ml273fu2.jpg" alt="Image ml273fu2" /></div></div></article><article data-type="fig" id="figobml273fu3"><div id="ml273.fu3" class="figure"><div class="graphic"><img data-src="/books/NBK143559/bin/ml273fu3.jpg" alt="Image ml273fu3" /></div></div></article><article data-type="fig" id="figobml273f2"><div id="ml273.f2" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK143559/bin/ml273f2.jpg" alt="Figure 2. ML254 (SID 125305189) [3H]methoxyPEPy binding curve." /></div><h3><span class="label">Figure 2</span><span class="title">ML254 (SID 125305189) [3H]methoxyPEPy binding curve</span></h3></div></article><article data-type="table-wrap" id="figobml273t1"><div id="ml273.t1" class="table"><h3><span class="label">Table 1</span><span class="title">Orthosteric-based mGlu agonists based upon glutamate</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK143559/table/ml273.t1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml273.t1_lrgtbl__"><table class="no_margin"><thead><tr><th id="hd_h_ml273.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Orthosteric Agonist<sup>*</sup></th><th id="hd_h_ml273.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Structure</th><th id="hd_h_ml273.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">mGlu<sub>1</sub> EC<sub>50</sub></th><th id="hd_h_ml273.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">mGlu<sub>5</sub> EC<sub>50</sub></th><th id="hd_h_ml273.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Group I selective?</th></tr></thead><tbody><tr><td headers="hd_h_ml273.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Glutamate</td><td headers="hd_h_ml273.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143559/bin/ml273fu4.jpg" alt="Image ml273fu4.jpg" /></div></td><td headers="hd_h_ml273.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">9–13</td><td headers="hd_h_ml273.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">3–10</td><td headers="hd_h_ml273.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">All</td></tr><tr><td headers="hd_h_ml273.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Quisqualate</td><td headers="hd_h_ml273.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143559/bin/ml273fu5.jpg" alt="Image ml273fu5.jpg" /></div></td><td headers="hd_h_ml273.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.2–0.3</td><td headers="hd_h_ml273.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">0.03–0.3</td><td headers="hd_h_ml273.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Yes</td></tr><tr><td headers="hd_h_ml273.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Ibotenate</td><td headers="hd_h_ml273.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143559/bin/ml273fu6.jpg" alt="Image ml273fu6.jpg" /></div></td><td headers="hd_h_ml273.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">10–60</td><td headers="hd_h_ml273.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">2–10</td><td headers="hd_h_ml273.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">No-mGluR3</td></tr><tr><td headers="hd_h_ml273.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">1S, 3R-ACPD</td><td headers="hd_h_ml273.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143559/bin/ml273fu7.jpg" alt="Image ml273fu7.jpg" /></div></td><td headers="hd_h_ml273.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">10–80</td><td headers="hd_h_ml273.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">5–7</td><td headers="hd_h_ml273.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">No-mGluR2,3</td></tr><tr><td headers="hd_h_ml273.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">1S, 3S-ACPD</td><td headers="hd_h_ml273.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143559/bin/ml273fu8.jpg" alt="Image ml273fu8.jpg" /></div></td><td headers="hd_h_ml273.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">>300</td><td headers="hd_h_ml273.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">>300</td><td headers="hd_h_ml273.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">No-mGluR2 selective</td></tr><tr><td headers="hd_h_ml273.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">L-CCG-1</td><td headers="hd_h_ml273.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143559/bin/ml273fu9.jpg" alt="Image ml273fu9.jpg" /></div></td><td headers="hd_h_ml273.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">50</td><td headers="hd_h_ml273.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">ND</td><td headers="hd_h_ml273.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">No-mGluR2 selective</td></tr><tr><td headers="hd_h_ml273.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">3-HPG</td><td headers="hd_h_ml273.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143559/bin/ml273fu10.jpg" alt="Image ml273fu10.jpg" /></div></td><td headers="hd_h_ml273.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">68–100</td><td headers="hd_h_ml273.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">14–35</td><td headers="hd_h_ml273.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Yes</td></tr><tr><td headers="hd_h_ml273.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">3,5-DHPG</td><td headers="hd_h_ml273.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143559/bin/ml273fu11.jpg" alt="Image ml273fu11.jpg" /></div></td><td headers="hd_h_ml273.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">6.6</td><td headers="hd_h_ml273.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">2.0</td><td headers="hd_h_ml273.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Yes</td></tr><tr><td headers="hd_h_ml273.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">CHPG</td><td headers="hd_h_ml273.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143559/bin/ml273fu12.jpg" alt="Image ml273fu12.jpg" /></div></td><td headers="hd_h_ml273.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Ant.</td><td headers="hd_h_ml273.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">>300</td><td headers="hd_h_ml273.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">No-mGluR2 selective</td></tr><tr><td headers="hd_h_ml273.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">4C3HPG</td><td headers="hd_h_ml273.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143559/bin/ml273fu13.jpg" alt="Image ml273fu13.jpg" /></div></td><td headers="hd_h_ml273.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Inactive</td><td headers="hd_h_ml273.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">750</td><td headers="hd_h_ml273.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Yes-mGluR5 selective</td></tr><tr><td headers="hd_h_ml273.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">t-ADA</td><td headers="hd_h_ml273.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
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<div class="graphic"><img src="/books/NBK143559/bin/ml273fu14.jpg" alt="Image ml273fu14.jpg" /></div></td><td headers="hd_h_ml273.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">190</td><td headers="hd_h_ml273.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">30</td><td headers="hd_h_ml273.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Yes</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>*</dt><dd><div id="ml273.tfn5"><p class="no_margin">EC50 values reported in micromolar (mM)</p></div></dd></dl></dl></div></div></div></article></div><div id="jr-scripts"><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/libs.min.js"> </script><script src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.min.js"> </script></div></div>
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