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<script type="text/javascript" src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.boots.min.js"> </script><title>Discovery of a potent, selective and in vivo active mGluR4 positive allosteric modulator - 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="Discovery of a potent, selective and in vivo active mGluR4 positive allosteric modulator">
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<meta name="citation_publisher" content="National Center for Biotechnology Information (US)">
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<meta name="citation_date" content="2010/10/20">
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<meta name="citation_author" content="Corey R Hopkins">
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<meta name="citation_author" content="Colleen M Niswender">
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<meta name="citation_author" content="L Michelle Lewis">
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<meta name="citation_author" content="C David Weaver">
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<meta name="citation_author" content="Craig W Lindsley">
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<meta name="DC.Title" content="Discovery of a potent, selective and in vivo active mGluR4 positive allosteric modulator">
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<meta name="DC.Contributor" content="Corey R Hopkins">
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<meta name="DC.Contributor" content="Colleen M Niswender">
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<meta name="DC.Contributor" content="L Michelle Lewis">
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<meta name="DC.Contributor" content="C David Weaver">
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<meta name="DC.Contributor" content="Craig W Lindsley">
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<meta name="DC.Date" content="2010/10/20">
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<meta name="description" content="Among the 8 cloned metabotropic glutamate receptors (mGluRs), the group III receptors (4,6,7,8) have thus far received the least attention in terms of their therapeutic potential. This can be attributed to the paucity of available selective ligands for these targets. However, recently, there have been numerous reports detailing the potential benefits of mGluR4 activation in several disease models, most notably for their role in modulating neurotransmission in the basal ganglia, a mechanism that is expected to provide palliative benefit for the treatment of Parkinson's disease (PD). In addition, recent reports also have detailed the neuroprotective effects of an mGluR4 positive allosteric modulator (PAM) in cultured neurons and in vivo. ML128 (CID-44191096) is a highly optimized mGluR4 in vitro and in vivo probe and now represents the most potent and selective of mGluR4 PAM identified to date. Furthermore, ML128 is only mGluR4 PAM that is centrally penetrant upon systemic dosing, while also displaying excellent pharmacokinetics and anti-Parkinsonian activity in a preclinical rodent model of PD.">
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<meta name="og:description" content="Among the 8 cloned metabotropic glutamate receptors (mGluRs), the group III receptors (4,6,7,8) have thus far received the least attention in terms of their therapeutic potential. This can be attributed to the paucity of available selective ligands for these targets. However, recently, there have been numerous reports detailing the potential benefits of mGluR4 activation in several disease models, most notably for their role in modulating neurotransmission in the basal ganglia, a mechanism that is expected to provide palliative benefit for the treatment of Parkinson's disease (PD). In addition, recent reports also have detailed the neuroprotective effects of an mGluR4 positive allosteric modulator (PAM) in cultured neurons and in vivo. ML128 (CID-44191096) is a highly optimized mGluR4 in vitro and in vivo probe and now represents the most potent and selective of mGluR4 PAM identified to date. Furthermore, ML128 is only mGluR4 PAM that is centrally penetrant upon systemic dosing, while also displaying excellent pharmacokinetics and anti-Parkinsonian activity in a preclinical rodent model of PD.">
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id="jr-fip-info-p"><a id="jr-fip-prev" class="wsprkl btn" title="Jump to previuos match">◀</a><button id="jr-fip-matches">no matches yet</button><a id="jr-fip-next" class="wsprkl btn" title="Jump to next match">▶</a></nav></nav></div><div id="jr-epub-interstitial" class="hidden"></div><div id="jr-content"><article data-type="main"><div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><div class="fm-sec"><h1 id="_NBK50684_"><span class="title" itemprop="name">Discovery of a potent, selective and <i>in vivo</i> active mGluR4 positive allosteric modulator</span></h1><p class="contribs">Hopkins CR, Niswender CM, Lewis LM, et al.</p><p class="fm-aai"><a href="#_NBK50684_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>Among the 8 cloned metabotropic glutamate receptors (mGluRs), the group III receptors (4,6,7,8) have thus far received the least attention in terms of their therapeutic potential. This can be attributed to the paucity of available selective ligands for these targets. However, recently, there have been numerous reports detailing the potential benefits of mGluR4 activation in several disease models, most notably for their role in modulating neurotransmission in the basal ganglia, a mechanism that is expected to provide palliative benefit for the treatment of Parkinson's disease (PD). In addition, recent reports also have detailed the neuroprotective effects of an mGluR4 positive allosteric modulator (PAM) in cultured neurons and in vivo. ML128 (CID-44191096) is a highly optimized mGluR4 in vitro and in vivo probe and now represents the most potent and selective of mGluR4 PAM identified to date. Furthermore, ML128 is only mGluR4 PAM that is centrally penetrant upon systemic dosing, while also displaying excellent pharmacokinetics and anti-Parkinsonian activity in a preclinical rodent model of PD.</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">AID-2437</a></p><div id="ml128.s2"><h2 id="_ml128_s2_">Probe Structure & Characteristics</h2><p><i>N</i>-(4-chloro-3-methoxyphenyl)picolinamide</p><p>MW = 262.6, ClogP = 2.81, tPSA = 50</p><div id="ml128.fu1" class="figure"><div class="graphic"><img src="/books/NBK50684/bin/ml128fu1.jpg" alt="Image ml128fu1" /></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml128tu1"><a href="/books/NBK50684/table/ml128.tu1/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figml128tu1" rid-ob="figobml128tu1"><img class="small-thumb" src="/books/NBK50684/table/ml128.tu1/?report=thumb" src-large="/books/NBK50684/table/ml128.tu1/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ml128.tu1"><a href="/books/NBK50684/table/ml128.tu1/?report=objectonly" target="object" rid-ob="figobml128tu1">Table</a></h4></div></div></div><div id="ml128.s3"><h2 id="_ml128_s3_">Recommendations for the scientific use of this probe</h2><p>This probe (CID 44191096) can be used to investigate the role of selective allosteric activation of mGluR4 <i>in vitro</i> and <i>in vivo</i>. CID 44191096 is the most potent (EC<sub>50</sub> = 240 nM, 28-fold shift) and selective (>30 μM vs. mGluRs 1,2,3,5,7,8 and >10 μM vs. MDS Pharma Panel of 68 GPCRs, ion channels and transporters) mGluR4 positive allosteric modulator (PAM) disclosed to date, and the only mGluR4 PAM that is centrally penetrant upon systemic dosing. CID 44191096 displays excellent pharmacokinetics and anti-Parkinsonian activity in a preclinical rodent model of Parkinson’s disease.</p><div id="ml128.s4"><h3>Specific Aim</h3><p>To identify small molecule positive allosteric modulators (PAMs) of mGluR8 and/or other group III mGluRs. Probe candidates will be highly selective versus the other seven mGluRs, and ideally be suitable for both <i>in vitro</i> and <i>in vivo</i> studies.</p></div><div id="ml128.s5"><h3>Significance</h3><p>The metabotropic glutamate receptors (mGluRs) are members of the GPCR family C, characterized by
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a large extracellular amino-terminal binding domain (agonist binding site) along with a
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seven-transmembrane spanning (7TM) domain which is the binding site for most known mGluR allosteric
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modulators. (<a class="bibr" href="#ml128.r1" rid="ml128.r1 ml128.r2 ml128.r3">1–3</a>) The eight
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cloned mGluRs have been assigned to three groups (group I: mGluRs 1 and 5, group II: mGluRs 2 and 3,
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and group III: mGluRs 4,6,7,8) based on their structural similarity, ligand specificity, and
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preferred coupling mechanisms. (<a class="bibr" href="#ml128.r4" rid="ml128.r4">4</a>) Among the mGluRs, the
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group III receptors have thus far received less attention in terms of their therapeutic potential
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because of the paucity of selective ligands. However, recently there have been numerous reports
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detailing the potential benefits of mGluR4 activation in several disease models, most notably rodent
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models of Parkinson’s disease. (<a class="bibr" href="#ml128.r5" rid="ml128.r5">5</a>,<a class="bibr" href="#ml128.r6" rid="ml128.r6">6</a>) Parkinson’s disease (PD) is caused by the death of
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dopamine neurons in the basal ganglia and results in motor symptoms such as tremor and bradykinesia.
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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="bibr" href="#ml128.r7" rid="ml128.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>. (<a class="bibr" href="#ml128.r8" rid="ml128.r8">8</a>,<a class="bibr" href="#ml128.r9" rid="ml128.r9">9</a>) 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/NBK50684/figure/ml128.f1/?report=objectonly" target="object" rid-figpopup="figml128f1" rid-ob="figobml128f1">Figure 1</a>). (<a class="bibr" href="#ml128.r8" rid="ml128.r8">8</a>,<a class="bibr" href="#ml128.r10" rid="ml128.r10">10</a>,<a class="bibr" href="#ml128.r11" rid="ml128.r11">11</a>) 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. (<a class="bibr" href="#ml128.r10" rid="ml128.r10">10</a>,<a class="bibr" href="#ml128.r11" rid="ml128.r11">11</a>) 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="figml128f1" co-legend-rid="figlgndml128f1"><a href="/books/NBK50684/figure/ml128.f1/?report=objectonly" target="object" title="Figure 1" class="img_link icnblk_img figpopup" rid-figpopup="figml128f1" rid-ob="figobml128f1"><img class="small-thumb" src="/books/NBK50684/bin/ml128f1.gif" src-large="/books/NBK50684/bin/ml128f1.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="figlgndml128f1"><h4 id="ml128.f1"><a href="/books/NBK50684/figure/ml128.f1/?report=objectonly" target="object" rid-ob="figobml128f1">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></div><div id="ml128.s6"><h3>Rationale</h3><p>In the present study, we developed and implemented a fluorescence-based calcium assay for
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high-throughput screening (HTS) of chemical libraries for novel modulators of mGluR8 function, and
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developed the appropriate counter screens within the mGluR family to identify other selective mGluR
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ligands as well. (<a class="bibr" href="#ml128.r12" rid="ml128.r12">12</a>)</p></div></div><div id="ml128.s7"><h2 id="_ml128_s7_">Screening Center Information: Assay Implementation and Screening</h2><div id="ml128.s8"><h3>PubChem Bioassay Name</h3><p>A direct assay for HTS of G<sub>i</sub>/G<sub>o</sub>-linked GPCRs: mGluR8 as the prototype</p></div><div id="ml128.s9"><h3>List of PubChem bioassay identifiers generated for this screening project (AIDs)</h3><p><b><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/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>,
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<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/2180" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-2180</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2179" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-2179</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2437" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-2437</a></b></p></div><div id="ml128.s10"><h3>PubChem Primary Assay Description</h3><p>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 x 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></div><div id="ml128.s11"><h3>Summary of Screen</h3><p>The initial mGluR screens were performed during the pilot phase, 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 85240633 (<a href="https://pubchem.ncbi.nlm.nih.gov/substance/308065" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID-308065</a>) that was devoid of activity at mGluR8.</p></div><div id="ml128.s12"><h3>Chemical Probe Lead Optimization</h3><p>Optimization efforts focused on our one mGluR4 PAM lead (CID 308065), which was comparable to (-)-PHCCC in terms of potency (EC<sub>50</sub>~ 5 μM, 135% Glu Max, 5-fold shift), but with a molecular weight of only 250 and ligand efficiency (LE) of 0.33 (<a class="figpopup" href="/books/NBK50684/figure/ml128.f2/?report=objectonly" target="object" rid-figpopup="figml128f2" rid-ob="figobml128f2">Figure 2</a>). CID 308065 represented a very attractive starting point for lead optimization in that small libraries could be rapidly prepared to survey the Western amide moiety and the Eastern aniline moiety employing simple amide coupling or acylation chemistry with a diverse array of commercially available building blocks. Our goal was to develop a best-in-class mGluR4 PAM (EC<sub>50</sub> < 500 nM, fold-shift >10) with selectivity versus the other 7 mGluRs and ideally centrally penetrant to enable the study of selective mGluR4 activation <i>in vivo</i> and advance the field.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml128f2" co-legend-rid="figlgndml128f2"><a href="/books/NBK50684/figure/ml128.f2/?report=objectonly" target="object" title="Figure 2" class="img_link icnblk_img figpopup" rid-figpopup="figml128f2" rid-ob="figobml128f2"><img class="small-thumb" src="/books/NBK50684/bin/ml128f2.gif" src-large="/books/NBK50684/bin/ml128f2.jpg" alt="Figure 2. Strucutre of mGluR4 PAM hit CID 308065 and SAR plan." /></a><div class="icnblk_cntnt" id="figlgndml128f2"><h4 id="ml128.f2"><a href="/books/NBK50684/figure/ml128.f2/?report=objectonly" target="object" rid-ob="figobml128f2">Figure 2</a></h4><p class="float-caption no_bottom_margin">Strucutre of mGluR4 PAM hit CID 308065 and SAR plan. </p></div></div><p>Our first library (<a class="figpopup" href="/books/NBK50684/table/ml128.t1/?report=objectonly" target="object" rid-figpopup="figml128t1" rid-ob="figobml128t1">Table 1</a>) maintained the Eastern
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3,4-dichloroaniline moiety and surveyed alternative amide moieties (heteroaryl, aryl and
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cycloalkyl). Like many allosteric ligands, SAR was shallow, with few actives from this effort. A
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5-bromofuran (CID 836051) showed slight improvement in potency, but the corresponding 5-phenyl congener was inactive. The majority of other groups explored (aryl, heteroaryl and cycloalkly) possessed EC<sub>50</sub>s >10 μM. Two exceptions were a 2-pyridyl amide, CID 4644726 (EC<sub>50</sub> = 1.4 μM, 80% Glu Max) and a pyrimidine amide CID 44191096 (EC<sub>50</sub> = 2.8 μM, 83% Glu Max). Based on the potency and physiochemical properties imparted by the 2-pyridyl amide, we next held this moiety constant, and surveyed alterative anilines and heterocyclic amines with diverse substiutents (<a class="figpopup" href="/books/NBK50684/table/ml128.t2/?report=objectonly" target="object" rid-figpopup="figml128t2" rid-ob="figobml128t2">Table 2</a>). (<a class="bibr" href="#ml128.r13" rid="ml128.r13">13</a>)</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml128t1"><a href="/books/NBK50684/table/ml128.t1/?report=objectonly" target="object" title="Table 1" class="img_link icnblk_img figpopup" rid-figpopup="figml128t1" rid-ob="figobml128t1"><img class="small-thumb" src="/books/NBK50684/table/ml128.t1/?report=thumb" src-large="/books/NBK50684/table/ml128.t1/?report=previmg" alt="Table 1. SAR of the Western Amide Moiety." /></a><div class="icnblk_cntnt"><h4 id="ml128.t1"><a href="/books/NBK50684/table/ml128.t1/?report=objectonly" target="object" rid-ob="figobml128t1">Table 1</a></h4><p class="float-caption no_bottom_margin">SAR of the Western Amide Moiety. </p></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml128t2"><a href="/books/NBK50684/table/ml128.t2/?report=objectonly" target="object" title="Table 2" class="img_link icnblk_img figpopup" rid-figpopup="figml128t2" rid-ob="figobml128t2"><img class="small-thumb" src="/books/NBK50684/table/ml128.t2/?report=thumb" src-large="/books/NBK50684/table/ml128.t2/?report=previmg" alt="Table 2. SAR of the Eastern aniline." /></a><div class="icnblk_cntnt"><h4 id="ml128.t2"><a href="/books/NBK50684/table/ml128.t2/?report=objectonly" target="object" rid-ob="figobml128t2">Table 2</a></h4><p class="float-caption no_bottom_margin">SAR of the Eastern aniline. </p></div></div><p>This second generation library exploring alternatives for the Western 2-furyl amide was more
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productive. Multiple halo- and or alkoxy-substituted benzamides afforded potent mGluR4 PAMs with
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submicromolar EC<sub>50</sub>s, Glu Max values over 200% and fold-shifts of >30 for both
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human and rat. Multiple analogs represented a significant improvement over (-)-PHCCC. The most potent analogs, CID 44191096, CID 44189740 and CID 42644786 were selective for mGluR4 (>30 μM versus mGluRs 1,2,3,5,7,8). CID 44191096 and CID 44189740 met MLPCN probe criteria with mGluR4 PAM EC<sub>50</sub>s of 240 nM/110 nM (human/rat) and 340 nM/80 nM (human/rat), respectively. Both provided high efficacy (>100% Glu Max for rat and >200% Glu Max for human) and fold-shifts in the 20 to 40-fold range. Both are orders of magnitude better than the gold standard mGluR4 probe, (-)-PHCCC. <a class="figpopup" href="/books/NBK50684/figure/ml128.f3/?report=objectonly" target="object" rid-figpopup="figml128f3" rid-ob="figobml128f3">Figure 3A</a> demonstrates that CID 44191096 is in fact a positive allosteric modulator, having no effect on mGluR4 activation alone, but in the presence of an EC<sub>20</sub> concentration of glutamate affords a dose-dependent increase in mGluR4 activation. The left-ward fold-shift (<a class="figpopup" href="/books/NBK50684/figure/ml128.f3/?report=objectonly" target="object" rid-figpopup="figml128f3" rid-ob="figobml128f3">Figure 3B</a>) of a fixed 30 μM concentration of CID 44191096 is ~33-fold. (<a class="bibr" href="#ml128.r13" rid="ml128.r13">13</a>)</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml128f3" co-legend-rid="figlgndml128f3"><a href="/books/NBK50684/figure/ml128.f3/?report=objectonly" target="object" title="Figure 3" class="img_link icnblk_img figpopup" rid-figpopup="figml128f3" rid-ob="figobml128f3"><img class="small-thumb" src="/books/NBK50684/bin/ml128f3.gif" src-large="/books/NBK50684/bin/ml128f3.jpg" alt="Figure 3. Potency and efficacy of the novel mGluR4 PAM, CID 44191096." /></a><div class="icnblk_cntnt" id="figlgndml128f3"><h4 id="ml128.f3"><a href="/books/NBK50684/figure/ml128.f3/?report=objectonly" target="object" rid-ob="figobml128f3">Figure 3</a></h4><p class="float-caption no_bottom_margin">Potency and efficacy of the novel mGluR4 PAM, CID 44191096. (a) CID 44191096 was
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added in progressively higher concentrations to cell co-expressing human mGluR4 and the chimeric G protein Gqi5 (white boxes). After a 2.5 minute incubation period, an EC20 <a href="/books/NBK50684/figure/ml128.f3/?report=objectonly" target="object" rid-ob="figobml128f3">(more...)</a></p></div></div><p>While CID 44191096 will advance the field in terms of both <i>in vitro</i> molecular
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pharmacology and electrophysiology studies, we were compelled to go deeper and determine if CID
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44191096 would be suitable for <i>in vivo</i> studies. At this point, the Lead Profiling
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Screen (68 GPCRs, ion channels and transporters) from MDS Pharma was performed on CID 44191096 to determine a broader ancillary pharmacology profile for this MLPCN probe. In addition to selectivity versus the mGluR family, CID 44191096 possessed clean ancillary pharmacology, displaying no significant activity (no inhibition >50% at 10 μM for any GPCR, ion cannel or transporter targets in the 68 target Lead Profiling Screen). (<a class="bibr" href="#ml128.r13" rid="ml128.r13">13</a>)</p></div><div id="ml128.s13"><h3>In vitro and in vivo DMPK</h3><p>Based on these data, we evaluated CID 44191096 and several other potent analogs in a panel of in
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vitro Drug Metabolism assays such as microsomal stability and plasma protein binding (<a class="figpopup" href="/books/NBK50684/table/ml128.t3/?report=objectonly" target="object" rid-figpopup="figml128t3" rid-ob="figobml128t3">Table 3</a>). In both human and rat liver microsomes (modeling PhI oxidative metabolism), the compounds displayed poor to moderate stability – not unexpected due to the amide moiety in the face of microsomal amidases. CID 44191096 in particular displayed poor metabolic stability in both human and rat liver microsomes (5.3% and 1.8%, respectively, after 30 minute incubation). Despite the poor <i>in vitro</i> stability, CID 44191096 was then dosed i.p. at 10 mg/kg as a microsuspension in 10% Tween-80 to male rats. Plasma and brain samples were taken at 0.5, 1 and 8 hours after administration and levels of CID 44191096 were determined. CID 44191096 had reasonable PK, but excitingly, was centrally penetrant. The AUC<sub>brain</sub>/AUC<sub>plasma</sub> ratio was found to be 4.1, making CID 44191096 the first mGluR4 PAM with central levels after systemic dosing.(<a class="bibr" href="#ml128.r13" rid="ml128.r13">13</a>)</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml128t3"><a href="/books/NBK50684/table/ml128.t3/?report=objectonly" target="object" title="Table 3" class="img_link icnblk_img figpopup" rid-figpopup="figml128t3" rid-ob="figobml128t3"><img class="small-thumb" src="/books/NBK50684/table/ml128.t3/?report=thumb" src-large="/books/NBK50684/table/ml128.t3/?report=previmg" alt="Table 3. In vitro Drug Metabolism evaluation." /></a><div class="icnblk_cntnt"><h4 id="ml128.t3"><a href="/books/NBK50684/table/ml128.t3/?report=objectonly" target="object" rid-ob="figobml128t3">Table 3</a></h4><p class="float-caption no_bottom_margin">In vitro Drug Metabolism evaluation. </p></div></div></div><div id="ml128.s14"><h3><i>In vivo</i> efficacy in a preclinical model of Parkinson’s disease (PD)</h3><p>Based on the potency, efficacy and PK of CID 44191096, we evaluated CID 44191096 in a preclinical
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model of PD – haloperidol-induced catalepsy. (<a class="bibr" href="#ml128.r14" rid="ml128.r14">14</a>)
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In this model, rats are injected with haloperidol, a dopamine antagonist to induce catalepsy, and
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then our mGluR4 PAM (CID 44191096) is administered. Latency to withdrawal is then evaluated at four doses (3, 10, 30 and 56.6 mg/kg) of CID 85240643 and two time points (90 and 120 minutes) relative to an Adenosine A2A receptor antagonist positive control (<a class="figpopup" href="/books/NBK50684/figure/ml128.f4/?report=objectonly" target="object" rid-figpopup="figml128f4" rid-ob="figobml128f4">Figure 4</a>). (<a class="bibr" href="#ml128.r14" rid="ml128.r14">14</a>) At 56.6 mg/kg, CID 44191096 was as effective as a gold standard A2A antagonist at the same dose. Thus, CID 44191096 is the first mGluR4 PAM to show efficacy in a preclinical PD model upon systemic dosing. CID 44191096 would therefore be a useful <i>in vivo</i> tool to the scientific community to study the role of selective mGluR4 activation <i>in vivo</i>.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml128f4" co-legend-rid="figlgndml128f4"><a href="/books/NBK50684/figure/ml128.f4/?report=objectonly" target="object" title="Figure 4" class="img_link icnblk_img figpopup" rid-figpopup="figml128f4" rid-ob="figobml128f4"><img class="small-thumb" src="/books/NBK50684/bin/ml128f4.gif" src-large="/books/NBK50684/bin/ml128f4.jpg" alt="Figure 4. Effect of CID 44191096 on haloperidol(0.75 mg/kg)-induced catalepsy relative to A2A receptor antagonist positive control." /></a><div class="icnblk_cntnt" id="figlgndml128f4"><h4 id="ml128.f4"><a href="/books/NBK50684/figure/ml128.f4/?report=objectonly" target="object" rid-ob="figobml128f4">Figure 4</a></h4><p class="float-caption no_bottom_margin">Effect of CID 44191096 on haloperidol(0.75 mg/kg)-induced catalepsy relative to A2A receptor antagonist positive control. </p></div></div></div><div id="ml128.s15"><h3>Solubility</h3><p>~ 100 μM in DMSO. Homogeneous/microsuspension at 10 mg/mL in : 10% Tween-80, and 40% PEG-400.</p></div><div id="ml128.s16"><h3>Synthetic procedure and Spectral data for CID 44191096</h3><div id="ml128.fu2" class="figure"><div class="graphic"><img src="/books/NBK50684/bin/ml128fu32.jpg" alt="Image ml128fu32" /></div></div><div id="ml128.s17"><h4>General Procedures for Library Amide Synthesis (Route I)</h4><p>A solution of the appropriate carboxylic acid (1.0 equivalent) in dry 1,4-dioxane (1.0M) at room temperature was charged with HOBt (1.0 equivalent), DIEA (2.0 equivalents) and EDCI (1.5 equivalents). After 15 min, the appropriate aniline (1.0 equivalent) was added and the heterogeneous mixture was heated to 50 °C. After 12 h, the rxn was transferred to DCM:water (1:1). The organic layer was separated and sequentially washed with water (2 x), and passed through a Phase seperator. After concentration, the desired analogs were purified by mass-directed preparative HPLC.</p></div><div id="ml128.s18"><h4>General Procedures for Library Amide Synthesis (Route II)</h4><p>To a solution of the appropriate aniline in DMF:DIEA (4:1) (1 mL, 0.1 M). The appropriate acid chloride (0.1 mmol, 1.0 equivalent) was added and after 12 h at rt, the desired analogs were directly purified by mass-guided preparative HPLC.</p></div><div id="ml128.s19"><h4><i>N</i>-(4-chloro-3-methoxyphenyl)picolinamide (CID 44191096) [<a href="/pcsubstance/?term=ML128[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML128</a>]</h4><p>Following the general procedure above (<b>Route I</b>), <b>CID 44191096</b> was
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obtained as a white solid (49%): Rf = 0.33 (33% EtOAc/hexanes); Analytical
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LCMS: single peak (214 nm), RT = 3.130 min; 1H NMR (400 MHz, DMSO-<i>d6</i>) δ 10.76 (br s, 1H), 8.76 (d, J = 4.8 Hz, 1H), 8.17 (d, J = 8.0 Hz, 1H), 8.09 (ddd, J = 7.6, 7.6, 1.6 Hz, 1H), 7.85 (d, J = 2.0 Hz, 1H), 7.70 (m, 1H), 7.63 (dd, J = 8.8, 2.4 Hz, 1H), 7.40 (d, j = 8.8 Hz, 1H), 3.87 (s, 3H); HRMS, calc’d for C<sub>13</sub>H<sub>1</sub>2N<sub>2</sub>O<sub>2</sub>Cl (M+H+): 263.0587, Found 269.0588.</p></div></div><div id="ml128.s20"><h3>MLS#s</h3><p>0022608909, 002608910, 002608911, 002608912, 002608913, 002608914 (probe, 500 mg)</p></div></div><div id="ml128.rl1"><h2 id="_ml128_rl1_">Bibliography</h2><dl class="temp-labeled-list"><dl class="bkr_refwrap"><dt>1.</dt><dd><div class="bk_ref" id="ml128.r1">Conn PJ, Pin J-P. <span><span class="ref-journal">Annu. 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></dl><dl class="bkr_refwrap"><dt>2.</dt><dd><div class="bk_ref" id="ml128.r2">Marino MJ, Conn PJ. <span><span class="ref-journal">Curr. Opin. Pharmacol. </span>2006;<span class="ref-vol">6 </span>(1):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></dl><dl class="bkr_refwrap"><dt>3.</dt><dd><div class="bk_ref" id="ml128.r3">Conn PJ, Christopoulos A, Lindsley CW. <span><span class="ref-journal">Nat Rev Drug Discovery. </span>2009;<span class="ref-vol">8</span>(1):41–54.</span> [<a href="/pmc/articles/PMC2907734/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2907734</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19116626" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19116626</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>4.</dt><dd><div class="bk_ref" id="ml128.r4">Schoepp DD, Jane DE, Monn JA. <span><span class="ref-journal">Neuropharmacology. </span>1999;<span class="ref-vol">38</span>(10):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></dl><dl class="bkr_refwrap"><dt>5.</dt><dd><div class="bk_ref" id="ml128.r5">Hopkins CR, Lindsley CW, Niswender CM. <span><span class="ref-journal">Future Med. Chem. </span>2009;<span class="ref-vol">1</span>:501–512.</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></dl><dl class="bkr_refwrap"><dt>6.</dt><dd><div class="bk_ref" id="ml128.r6">Hefti FF. <span class="ref-journal">Parkinson’s Disease Drug Discovery for Nervous System Diseases.</span> Wiley-Interscience; Hoboken, NJ: 2005. pp. 183–204.</div></dd></dl><dl class="bkr_refwrap"><dt>7.</dt><dd><div class="bk_ref" id="ml128.r7">Valenti O, Marino MJ, Wittmann M, Lis E, DiLella AG, Kinney GG, Conn PJ. <span><span class="ref-journal">J. Neurosci. </span>2003;<span class="ref-vol">23</span>(18):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></dl><dl class="bkr_refwrap"><dt>8.</dt><dd><div class="bk_ref" id="ml128.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. <span><span class="ref-journal">Neuropharmacology. </span>2003;<span class="ref-vol">45</span>(7):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></dl><dl class="bkr_refwrap"><dt>9.</dt><dd><div class="bk_ref" id="ml128.r9">Battaglia G, Busceti CL, Molinaro G, Giagioni F, Traficante A, Nicoletti F, Bruno V. <span><span class="ref-journal">J. Neurosci. </span>2006;<span class="ref-vol">26</span>(27):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></dl><dl class="bkr_refwrap"><dt>10.</dt><dd><div class="bk_ref" id="ml128.r10">Annoura H, Fukunaga A, Uesugi M. <span><span class="ref-journal">Bioorg. Med. Chem. Lett. </span>1996;<span class="ref-vol">6</span>(7):763–766.</span></div></dd></dl><dl class="bkr_refwrap"><dt>11.</dt><dd><div class="bk_ref" id="ml128.r11">Marino MJ, Williams DL Jr, O’Brien JA, Valenti O, McDonald TP, Clements MK, Wang R, DiLella AG, Kinney GG, Conn PJ. <span><span class="ref-journal">Proc. Natl. Acad. Sci. U.S.A. </span>2003;<span class="ref-vol">100</span>(23):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></dl><dl class="bkr_refwrap"><dt>12.</dt><dd><div class="bk_ref" id="ml128.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. <span><span class="ref-journal">Mol. Pharmacol. </span>2008;<span class="ref-vol">74</span>(5):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></dl><dl class="bkr_refwrap"><dt>13.</dt><dd><div class="bk_ref" id="ml128.r13">Engers DW, Niswender CM, Weaver CD, Jadhav S, Menon U, Conn PJ, Lindsley CW, Hopkins CR. <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><dl class="bkr_refwrap"><dt>14.</dt><dd><div class="bk_ref" id="ml128.r14">Varty GB, Hodgson RA, Pond AJ, Grzelak ME, Parker EM, Hunter JC. <span><span class="ref-journal">Psychopharmacology. </span>2008;<span class="ref-vol">200</span>(3):393–401.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/18594798" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18594798</span></a>]</div></dd></dl></dl></div><div id="ml128.app1"><h2 id="_ml128_app1_">APPENDIX I. Solubility, Stability and Reactivity data as determined by Absorption Systems</h2><div id="ml128.s21"><h3>Solubility</h3><p>Solubility in PBS (at pH = 7.4) for <a href="/pcsubstance/?term=ML128[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML128</a> was 6.38 μM.</p></div><div id="ml128.s22"><h3>Stability</h3><p>Stability (at room temperature = 23 °C) for <a href="/pcsubstance/?term=ML128[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML128</a> in PBS (no antioxidants or other protectorants and DMSO concentration below 0.1%) is shown in the table below. After 48 hours, the percent of parent compound remaining was 109%, but the assay variability over the course of the experiment ranged from a low of 85% (at 15 minutes) to a high of 130% (at 1 hour).</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml128tu2"><a href="/books/NBK50684/table/ml128.tu2/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figml128tu2" rid-ob="figobml128tu2"><img class="small-thumb" src="/books/NBK50684/table/ml128.tu2/?report=thumb" src-large="/books/NBK50684/table/ml128.tu2/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ml128.tu2"><a href="/books/NBK50684/table/ml128.tu2/?report=objectonly" target="object" rid-ob="figobml128tu2">Table</a></h4></div></div></div><div id="ml128.s23"><h3>Reactivity</h3><p>As assessed through a glutathione (GSH) trapping experiment in phosphate buffered saline (with a substrate concentration of typically 5–50 μM and a GSH concentration of 5 mM, at t = 60 minutes) <a href="/pcsubstance/?term=ML128[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML128</a> was found to not form any detectable GSH adducts.<sup><a href="#ml128.fn1">*</a></sup></p></div></div><div id="ml128.app2"><h2 id="_ml128_app2_">APPENDIX II. Liquid Chromatography-Mass Spectrometry (LCMS) and Nuclear Magnetic Resonance (NMR) as prepared by Vanderbilt Specialized Chemistry Center</h2><div id="ml128.fu3" class="figure"><div class="graphic"><img src="/books/NBK50684/bin/ml128fu33.jpg" alt="Image ml128fu33" /></div></div><div id="ml128.fu4" class="figure"><div class="graphic"><img src="/books/NBK50684/bin/ml128fu34.jpg" alt="Image ml128fu34" /></div></div><div id="ml128.fu5" class="figure"><div class="graphic"><img src="/books/NBK50684/bin/ml128fu35.jpg" alt="Image ml128fu35" /></div></div><div id="ml128.fu6" class="figure"><div class="graphic"><img src="/books/NBK50684/bin/ml128fu36.jpg" alt="Image ml128fu36" /></div></div><div id="ml128.fu7" class="figure"><div class="graphic"><img src="/books/NBK50684/bin/ml128fu37.jpg" alt="Image ml128fu37" /></div></div><div id="ml128.fu8" class="figure"><div class="graphic"><img src="/books/NBK50684/bin/ml128fu38.jpg" alt="Image ml128fu38" /></div></div></div><h2 id="NBK50684_footnotes">Footnotes</h2><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>*</dt><dd><div id="ml128.fn1"><p class="no_top_margin">Solubility (PBS at pH = 7.4), Stability and Reactivity experiments were conducted at Absorption Systems. For additional information see: <a href="https://www.absorption.com/site" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">https://www<wbr style="display:inline-block"></wbr>​.absorption.com/site</a></p></div></dd></dl></dl><div id="bk_toc_contnr"></div></div></div><div class="fm-sec"><h2 id="_NBK50684_pubdet_">Publication Details</h2><h3>Author Information and Affiliations</h3><p class="contrib-group"><h4>Authors</h4><span itemprop="author">Corey R Hopkins</span>, <span itemprop="author">Colleen M Niswender</span>, <span itemprop="author">L Michelle Lewis</span>, <span itemprop="author">C David Weaver</span>, and <span itemprop="author">Craig W Lindsley</span><sup>1</sup>.</p><h4>Contact</h4><div class="affiliation"><sup>1</sup> <span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ude.tlibrednav@yelsdnil.giarc" class="oemail">ude.tlibrednav@yelsdnil.giarc</a></div><h3>Publication History</h3><p class="small">Received: <span itemprop="datePublished">December 18, 2009</span>; Last Update: <span itemprop="dateModified">October 20, 2010</span>.</p><h3>Copyright</h3><div><div class="half_rhythm"><a href="/books/about/copyright/">Copyright Notice</a></div></div><h3>Publisher</h3><p>National Center for Biotechnology Information (US), Bethesda (MD)</p><h3>NLM Citation</h3><p>Hopkins CR, Niswender CM, Lewis LM, et al. Discovery of a potent, selective and in vivo active mGluR4 positive allosteric modulator. 2009 Dec 18 [Updated 2010 Oct 20]. 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/ml129/?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/ml127/?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="figobml128fu1"><div id="ml128.fu1" class="figure"><div class="graphic"><img data-src="/books/NBK50684/bin/ml128fu1.jpg" alt="Image ml128fu1" /></div></div></article><article data-type="table-wrap" id="figobml128tu1"><div id="ml128.tu1" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK50684/table/ml128.tu1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml128.tu1_lrgtbl__"><table><thead><tr><th id="hd_h_ml128.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">CID/ML#</th><th id="hd_h_ml128.tu1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Target Name</th><th id="hd_h_ml128.tu1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">IC50/EC50 (nM) [SID, AID]</th><th id="hd_h_ml128.tu1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Anti-target Name(s)</th><th id="hd_h_ml128.tu1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">IC50/EC50 (μM) [SID, AID]</th><th id="hd_h_ml128.tu1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Selectivity</th><th id="hd_h_ml128.tu1_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Secondary Assay(s) Name: IC50/EC50 (nM) [SID, AID]</th></tr></thead><tbody><tr><td headers="hd_h_ml128.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">CID 44191096 <a href="/pcsubstance/?term=ML128[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML128</a></td><td headers="hd_h_ml128.tu1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">mGluR4</td><td headers="hd_h_ml128.tu1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">240 (hm) 110 (rat) [<a href="https://pubchem.ncbi.nlm.nih.gov/substance/85240643" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID-85240643</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/2197" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-2197</a>]</td><td headers="hd_h_ml128.tu1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">mGluRs 1,2,3,5,7, 8 PanLabs</td><td headers="hd_h_ml128.tu1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">> 10 μM [<a href="https://pubchem.ncbi.nlm.nih.gov/substance/85240643" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID-85240643</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/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>]</td><td headers="hd_h_ml128.tu1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">>50</td><td headers="hd_h_ml128.tu1_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Fold-Shift 28x(hm), 35x(rat)<br /><br />[<a href="https://pubchem.ncbi.nlm.nih.gov/substance/85240643" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID-85240643</a>,
|
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<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2179" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-2179</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2180" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-2180</a>]</td></tr></tbody></table></div></div></article><article data-type="fig" id="figobml128f1"><div id="ml128.f1" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK50684/bin/ml128f1.jpg" alt="Figure 1. (-)-PHCCC, the prototypical mGluR4 PAM - weak, non-selective, poor physiochemical properties and no CNS penetration." /></div><h3><span class="label">Figure 1</span><span class="title">(-)-PHCCC, the prototypical mGluR4 PAM - weak, non-selective, poor physiochemical properties and no CNS penetration</span></h3></div></article><article data-type="fig" id="figobml128f2"><div id="ml128.f2" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK50684/bin/ml128f2.jpg" alt="Figure 2. Strucutre of mGluR4 PAM hit CID 308065 and SAR plan." /></div><h3><span class="label">Figure 2</span><span class="title">Strucutre of mGluR4 PAM hit CID 308065 and SAR plan</span></h3></div></article><article data-type="table-wrap" id="figobml128t1"><div id="ml128.t1" class="table"><h3><span class="label">Table 1</span><span class="title">SAR of the Western Amide Moiety</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK50684/table/ml128.t1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml128.t1_lrgtbl__"><table class="no_margin"><thead><tr><th id="hd_h_ml128.t1_1_1_1_1" colspan="5" rowspan="1" style="text-align:center;vertical-align:bottom;"><div class="graphic"><img src="/books/NBK50684/bin/ml128fu2.jpg" alt="Image ml128fu2.jpg" /></div><span class="hr"></span></th></tr><tr><th headers="hd_h_ml128.t1_1_1_1_1" id="hd_h_ml128.t1_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">SID (CID)</th><th headers="hd_h_ml128.t1_1_1_1_1" id="hd_h_ml128.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">R</th><th headers="hd_h_ml128.t1_1_1_1_1" id="hd_h_ml128.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">EC<sub>50</sub> (μM)<sup>a</sup> (hmGl uR4)</th><th headers="hd_h_ml128.t1_1_1_1_1" id="hd_h_ml128.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">Glu Max (h)<sup>a</sup></th><th headers="hd_h_ml128.t1_1_1_1_1" id="hd_h_ml128.t1_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">LE</th></tr></thead><tbody><tr><td headers="hd_h_ml128.t1_1_1_1_1 hd_h_ml128.t1_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>85240633 (CID 308065)</b></td><td headers="hd_h_ml128.t1_1_1_1_1 hd_h_ml128.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50684/bin/ml128fu3.jpg" alt="Image ml128fu3.jpg" /></div></td><td headers="hd_h_ml128.t1_1_1_1_1 hd_h_ml128.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>>5</b></td><td headers="hd_h_ml128.t1_1_1_1_1 hd_h_ml128.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>135±5</b></td><td headers="hd_h_ml128.t1_1_1_1_1 hd_h_ml128.t1_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.33</td></tr><tr><td headers="hd_h_ml128.t1_1_1_1_1 hd_h_ml128.t1_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>85240633 (CID 836051)</b></td><td headers="hd_h_ml128.t1_1_1_1_1 hd_h_ml128.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50684/bin/ml128fu4.jpg" alt="Image ml128fu4.jpg" /></div></td><td headers="hd_h_ml128.t1_1_1_1_1 hd_h_ml128.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4.1</td><td headers="hd_h_ml128.t1_1_1_1_1 hd_h_ml128.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">62</td><td headers="hd_h_ml128.t1_1_1_1_1 hd_h_ml128.t1_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.32</td></tr><tr><td headers="hd_h_ml128.t1_1_1_1_1 hd_h_ml128.t1_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>85240635 (CID 44191097)</b></td><td headers="hd_h_ml128.t1_1_1_1_1 hd_h_ml128.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50684/bin/ml128fu5.jpg" alt="Image ml128fu5.jpg" /></div></td><td headers="hd_h_ml128.t1_1_1_1_1 hd_h_ml128.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>10</td><td headers="hd_h_ml128.t1_1_1_1_1 hd_h_ml128.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"></td><td headers="hd_h_ml128.t1_1_1_1_1 hd_h_ml128.t1_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ml128.t1_1_1_1_1 hd_h_ml128.t1_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>85240636 (CID 869104)</b></td><td headers="hd_h_ml128.t1_1_1_1_1 hd_h_ml128.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50684/bin/ml128fu6.jpg" alt="Image ml128fu6.jpg" /></div></td><td headers="hd_h_ml128.t1_1_1_1_1 hd_h_ml128.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>10</td><td headers="hd_h_ml128.t1_1_1_1_1 hd_h_ml128.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"></td><td headers="hd_h_ml128.t1_1_1_1_1 hd_h_ml128.t1_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ml128.t1_1_1_1_1 hd_h_ml128.t1_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>85240640 (CID 2318321)</b></td><td headers="hd_h_ml128.t1_1_1_1_1 hd_h_ml128.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50684/bin/ml128fu7.jpg" alt="Image ml128fu7.jpg" /></div></td><td headers="hd_h_ml128.t1_1_1_1_1 hd_h_ml128.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>10</td><td headers="hd_h_ml128.t1_1_1_1_1 hd_h_ml128.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"></td><td headers="hd_h_ml128.t1_1_1_1_1 hd_h_ml128.t1_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ml128.t1_1_1_1_1 hd_h_ml128.t1_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>85240641 (CID 44191098)</b></td><td headers="hd_h_ml128.t1_1_1_1_1 hd_h_ml128.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50684/bin/ml128fu8.jpg" alt="Image ml128fu8.jpg" /></div></td><td headers="hd_h_ml128.t1_1_1_1_1 hd_h_ml128.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>10</td><td headers="hd_h_ml128.t1_1_1_1_1 hd_h_ml128.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"></td><td headers="hd_h_ml128.t1_1_1_1_1 hd_h_ml128.t1_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ml128.t1_1_1_1_1 hd_h_ml128.t1_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>85240639 (CID 30268259)</b></td><td headers="hd_h_ml128.t1_1_1_1_1 hd_h_ml128.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50684/bin/ml128fu9.jpg" alt="Image ml128fu9.jpg" /></div></td><td headers="hd_h_ml128.t1_1_1_1_1 hd_h_ml128.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>10</td><td headers="hd_h_ml128.t1_1_1_1_1 hd_h_ml128.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"></td><td headers="hd_h_ml128.t1_1_1_1_1 hd_h_ml128.t1_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ml128.t1_1_1_1_1 hd_h_ml128.t1_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>85240631 (CID 140002)</b></td><td headers="hd_h_ml128.t1_1_1_1_1 hd_h_ml128.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50684/bin/ml128fu10.jpg" alt="Image ml128fu10.jpg" /></div></td><td headers="hd_h_ml128.t1_1_1_1_1 hd_h_ml128.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>10</td><td headers="hd_h_ml128.t1_1_1_1_1 hd_h_ml128.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"></td><td headers="hd_h_ml128.t1_1_1_1_1 hd_h_ml128.t1_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ml128.t1_1_1_1_1 hd_h_ml128.t1_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>85240632 (CID 82516 )</b></td><td headers="hd_h_ml128.t1_1_1_1_1 hd_h_ml128.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50684/bin/ml128fu11.jpg" alt="Image ml128fu11.jpg" /></div></td><td headers="hd_h_ml128.t1_1_1_1_1 hd_h_ml128.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>10</td><td headers="hd_h_ml128.t1_1_1_1_1 hd_h_ml128.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"></td><td headers="hd_h_ml128.t1_1_1_1_1 hd_h_ml128.t1_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ml128.t1_1_1_1_1 hd_h_ml128.t1_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>85240642 (CID 4644726)</b></td><td headers="hd_h_ml128.t1_1_1_1_1 hd_h_ml128.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50684/bin/ml128fu12.jpg" alt="Image ml128fu12.jpg" /></div></td><td headers="hd_h_ml128.t1_1_1_1_1 hd_h_ml128.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>1.4±0.1</b></td><td headers="hd_h_ml128.t1_1_1_1_1 hd_h_ml128.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>80±9</b></td><td headers="hd_h_ml128.t1_1_1_1_1 hd_h_ml128.t1_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>0.34</b></td></tr><tr><td headers="hd_h_ml128.t1_1_1_1_1 hd_h_ml128.t1_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>85240637 (CID 871161)</b></td><td headers="hd_h_ml128.t1_1_1_1_1 hd_h_ml128.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50684/bin/ml128fu13.jpg" alt="Image ml128fu13.jpg" /></div></td><td headers="hd_h_ml128.t1_1_1_1_1 hd_h_ml128.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>10</td><td headers="hd_h_ml128.t1_1_1_1_1 hd_h_ml128.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"></td><td headers="hd_h_ml128.t1_1_1_1_1 hd_h_ml128.t1_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"></td></tr><tr><td headers="hd_h_ml128.t1_1_1_1_1 hd_h_ml128.t1_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>85240638 (CID 44191099)</b></td><td headers="hd_h_ml128.t1_1_1_1_1 hd_h_ml128.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><div class="graphic"><img src="/books/NBK50684/bin/ml128fu14.jpg" alt="Image ml128fu14.jpg" /></div></td><td headers="hd_h_ml128.t1_1_1_1_1 hd_h_ml128.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>2.8±0.2</b></td><td headers="hd_h_ml128.t1_1_1_1_1 hd_h_ml128.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>83±10</b></td><td headers="hd_h_ml128.t1_1_1_1_1 hd_h_ml128.t1_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><b>0.33</b></td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>a</dt><dd><div id="ml128.tfn1"><p class="no_margin">EC<sub>50</sub> and GluMax are the average of at least three independent determinations performed in triplicate.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobml128t2"><div id="ml128.t2" class="table"><h3><span class="label">Table 2</span><span class="title">SAR of the Eastern aniline</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK50684/table/ml128.t2/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml128.t2_lrgtbl__"><table class="no_margin"><thead><tr><th id="hd_h_ml128.t2_1_1_1_1" colspan="6" rowspan="1" style="text-align:center;vertical-align:bottom;"><div class="graphic"><img src="/books/NBK50684/bin/ml128fu15.jpg" alt="Image ml128fu15.jpg" /></div><span class="hr"></span></th></tr><tr><th headers="hd_h_ml128.t2_1_1_1_1" id="hd_h_ml128.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">SID (CID)</th><th headers="hd_h_ml128.t2_1_1_1_1" id="hd_h_ml128.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">R</th><th headers="hd_h_ml128.t2_1_1_1_1" id="hd_h_ml128.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">EC<sub>50</sub> (μM) (h/r)<sup>a</sup></th><th headers="hd_h_ml128.t2_1_1_1_1" id="hd_h_ml128.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">GluMax (h/r)<sup>a</sup></th><th headers="hd_h_ml128.t2_1_1_1_1" id="hd_h_ml128.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">FS (h/r)<sup>a</sup></th><th headers="hd_h_ml128.t2_1_1_1_1" id="hd_h_ml128.t2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">LE</th></tr></thead><tbody><tr><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>85240644 (CID 42644786)</b></td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><div class="graphic"><img src="/books/NBK50684/bin/ml128fu16.jpg" alt="Image ml128fu16.jpg" /></div></td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.78±0.09/0.37±0.11</td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">207±14/107±5</td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">17.5±0.6/26.7±6.0</td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.34</td></tr><tr><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>85240643 (CID 44191096)</b></td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><div class="graphic"><img src="/books/NBK50684/bin/ml128fu17.jpg" alt="Image ml128fu17.jpg" /></div></td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>0.24±0.04/0.11±0.03</b></td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>182±14/109±3</b></td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>28.1±3.5/35.3±2.8</b></td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.37</td></tr><tr><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>85240647 (CID 44189740)</b></td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><div class="graphic"><img src="/books/NBK50684/bin/ml128fu18.jpg" alt="Image ml128fu18.jpg" /></div></td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>0.34±0.08/0.08±0.02</b></td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>235±18/113±4</b></td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>27.8±2.6/44.4±3.0</b></td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.34</td></tr><tr><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>85240646 (CID 38032499)</b></td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><div class="graphic"><img src="/books/NBK50684/bin/ml128fu19.jpg" alt="Image ml128fu19.jpg" /></div></td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">>5/>5</td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">132±8/75±8</td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">nd</td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.27</td></tr><tr><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>85240645 (CID 2306530)</b></td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><div class="graphic"><img src="/books/NBK50684/bin/ml128fu20.jpg" alt="Image ml128fu20.jpg" /></div></td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">>5/1.8±0.39</td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">150±9/81±4</td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">5.7±0.4/7.6±0.6</td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.28</td></tr><tr><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>85240648 (CID 44191178)</b></td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><div class="graphic"><img src="/books/NBK50684/bin/ml128fu21.jpg" alt="Image ml128fu21.jpg" /></div></td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.56±0.03/0.21±0.05</td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">178±10/121±1</td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">16.8±1.2/35.3±4.5</td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.35</td></tr><tr><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>85240649 (CID 2447227)</b></td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><div class="graphic"><img src="/books/NBK50684/bin/ml128fu22.jpg" alt="Image ml128fu22.jpg" /></div></td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">>5/2.4±0.62</td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">164±5/102±1</td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">nd</td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.28</td></tr><tr><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>85240650 (CID 738280)</b></td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><div class="graphic"><img src="/books/NBK50684/bin/ml128fu23.jpg" alt="Image ml128fu23.jpg" /></div></td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">>10/0.5±0.3</td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">90±9/50±8</td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">nd</td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.28</td></tr><tr><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>85240651 (CID 2442621)</b></td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><div class="graphic"><img src="/books/NBK50684/bin/ml128fu24.jpg" alt="Image ml128fu24.jpg" /></div></td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">1.1±0.2/0.74±0.15</td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">161±6/108±2</td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">7.2±1.7/12.0±2.7</td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.33</td></tr><tr><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>85240655 (CID 836002)</b></td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><div class="graphic"><img src="/books/NBK50684/bin/ml128fu25.jpg" alt="Image ml128fu25.jpg" /></div></td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">1.1±0.2/0.29±0.08</td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">227±17/124±2</td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">18.1±1.7/31.4±4.0</td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.37</td></tr><tr><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>85240652 (CID 44191179)</b></td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><div class="graphic"><img src="/books/NBK50684/bin/ml128fu26.jpg" alt="Image ml128fu26.jpg" /></div></td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">>10/>10</td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">nd</td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">nd</td></tr><tr><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>85240653 (CID 8403638)</b></td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><div class="graphic"><img src="/books/NBK50684/bin/ml128fu27.jpg" alt="Image ml128fu27.jpg" /></div></td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2.1±0.1/1.7±0.3</td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">47±8/41±9</td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">1.8±0.2/2.1±0.4</td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.28</td></tr><tr><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>85240654 (CID 44191180)</b></td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><div class="graphic"><img src="/books/NBK50684/bin/ml128fu28.jpg" alt="Image ml128fu28.jpg" /></div></td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">1.5±0.04/1.0±0.1</td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">54±6/42±8</td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2.1±0.1/2.7±0.2</td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.29</td></tr><tr><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>85240658 (CID 44189736)</b></td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><div class="graphic"><img src="/books/NBK50684/bin/ml128fu29.jpg" alt="Image ml128fu29.jpg" /></div></td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">>5/nd</td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">95/nd</td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">nd</td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">nd</td></tr><tr><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>85240657 (CID 44189737)</b></td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><div class="graphic"><img src="/books/NBK50684/bin/ml128fu30.jpg" alt="Image ml128fu30.jpg" /></div></td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">>10/>10</td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">nd</td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">nd</td></tr><tr><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>85240656 (CID 44189738)</b></td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><div class="graphic"><img src="/books/NBK50684/bin/ml128fu31.jpg" alt="Image ml128fu31.jpg" /></div></td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">>10/>10</td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">nd</td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">nd</td></tr><tr><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">(−)-PHCCC</td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">See <a class="figpopup" href="/books/NBK50684/figure/ml128.f1/?report=objectonly" target="object" rid-figpopup="figml128f1" rid-ob="figobml128f1">Figure 1</a></td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">>5/2.03±0.52</td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">251±13/88±4</td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">7.0±0.2/8.8±1.0</td><td headers="hd_h_ml128.t2_1_1_1_1 hd_h_ml128.t2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"></td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>a</dt><dd><div id="ml128.tfn2"><p class="no_margin">EC<sub>50</sub>, GluMax and FS are the average of at least three independent determinations performed in triplicate.</p></div></dd></dl></dl></div></div></div></article><article data-type="fig" id="figobml128f3"><div id="ml128.f3" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK50684/bin/ml128f3.jpg" alt="Figure 3. Potency and efficacy of the novel mGluR4 PAM, CID 44191096." /></div><h3><span class="label">Figure 3</span><span class="title">Potency and efficacy of the novel mGluR4 PAM, CID 44191096</span></h3><div class="caption"><p>(a) CID 44191096 was
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added in progressively higher concentrations to cell co-expressing human mGluR4 and the chimeric G protein Gqi5 (white boxes). After a 2.5 minute incubation period, an EC20 concentration of glutamate was added (black boxes) and the change in fluorescence was monitored using a kinetic imaging plate reader. Data are three independent determinations performed in triplicate. (b) Either DMSO vehicle or a 30 μM concentration of CID 44191096 was incubated with human mGluR4/G<sub>qi5</sub> cells and 2.5 minutes later increasing concentrations of glutamate were added. In this experiment, performed in triplicate and representative of three independent determinations, CID 44191096 shifted the glutamate concentration-response curve 33 fold to the left</p></div></div></article><article data-type="table-wrap" id="figobml128t3"><div id="ml128.t3" class="table"><h3><span class="label">Table 3</span><span class="title">In vitro Drug Metabolism evaluation</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK50684/table/ml128.t3/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml128.t3_lrgtbl__"><table class="no_top_margin"><thead><tr><th id="hd_h_ml128.t3_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">SID (CID)</th><th id="hd_h_ml128.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">HLM (%remaining)</th><th id="hd_h_ml128.t3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">RLM (%remaining)</th><th id="hd_h_ml128.t3_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">PPB (h) (%free)</th><th id="hd_h_ml128.t3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">PPB (r) (%free)</th></tr></thead><tbody><tr><td headers="hd_h_ml128.t3_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>85240644 (CID 42644786)</b></td><td headers="hd_h_ml128.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">3.0</td><td headers="hd_h_ml128.t3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">6.3</td><td headers="hd_h_ml128.t3_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">5.1</td><td headers="hd_h_ml128.t3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">6.5</td></tr><tr><td headers="hd_h_ml128.t3_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>85240643 (CID 44191096)</b></td><td headers="hd_h_ml128.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">5.3</td><td headers="hd_h_ml128.t3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">1.8</td><td headers="hd_h_ml128.t3_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2.2</td><td headers="hd_h_ml128.t3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2.4</td></tr><tr><td headers="hd_h_ml128.t3_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>85240647 (CID 44189740)</b></td><td headers="hd_h_ml128.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2.4</td><td headers="hd_h_ml128.t3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">1.4</td><td headers="hd_h_ml128.t3_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">4.0</td><td headers="hd_h_ml128.t3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">5.8</td></tr><tr><td headers="hd_h_ml128.t3_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>85240646 (CID 38032499)</b></td><td headers="hd_h_ml128.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">22</td><td headers="hd_h_ml128.t3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">20</td><td headers="hd_h_ml128.t3_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.8</td><td headers="hd_h_ml128.t3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">1.6</td></tr><tr><td headers="hd_h_ml128.t3_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><b>85240645 (CID 2306530)</b></td><td headers="hd_h_ml128.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">26</td><td headers="hd_h_ml128.t3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">19</td><td headers="hd_h_ml128.t3_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">1.3</td><td headers="hd_h_ml128.t3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2.9</td></tr></tbody></table></div></div></article><article data-type="fig" id="figobml128f4"><div id="ml128.f4" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK50684/bin/ml128f4.jpg" alt="Figure 4. Effect of CID 44191096 on haloperidol(0.75 mg/kg)-induced catalepsy relative to A2A receptor antagonist positive control." /></div><h3><span class="label">Figure 4</span><span class="title">Effect of CID 44191096 on haloperidol(0.75 mg/kg)-induced catalepsy relative to A2A receptor antagonist positive control</span></h3></div></article><article data-type="fig" id="figobml128fu2"><div id="ml128.fu2" class="figure"><div class="graphic"><img data-src="/books/NBK50684/bin/ml128fu32.jpg" alt="Image ml128fu32" /></div></div></article><article data-type="table-wrap" id="figobml128tu2"><div id="ml128.tu2" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK50684/table/ml128.tu2/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml128.tu2_lrgtbl__"><table><thead><tr><th id="hd_h_ml128.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;"></th><th id="hd_h_ml128.tu2_1_1_1_2" colspan="7" rowspan="1" style="text-align:center;vertical-align:bottom;">Percent Remaining (%)</th></tr><tr><th headers="hd_h_ml128.tu2_1_1_1_1" id="hd_h_ml128.tu2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">Compound</th><th headers="hd_h_ml128.tu2_1_1_1_2" id="hd_h_ml128.tu2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">0 Min</th><th headers="hd_h_ml128.tu2_1_1_1_2" id="hd_h_ml128.tu2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">15 Min</th><th headers="hd_h_ml128.tu2_1_1_1_2" id="hd_h_ml128.tu2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">30 Min</th><th headers="hd_h_ml128.tu2_1_1_1_2" id="hd_h_ml128.tu2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">1 Hour</th><th headers="hd_h_ml128.tu2_1_1_1_2" id="hd_h_ml128.tu2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">2 Hour</th><th headers="hd_h_ml128.tu2_1_1_1_2" id="hd_h_ml128.tu2_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">24 Hour</th><th headers="hd_h_ml128.tu2_1_1_1_2" id="hd_h_ml128.tu2_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">48 Hour</th></tr></thead><tbody><tr><td headers="hd_h_ml128.tu2_1_1_1_1 hd_h_ml128.tu2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="/pcsubstance/?term=ML128[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML128</a></td><td headers="hd_h_ml128.tu2_1_1_1_2 hd_h_ml128.tu2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">100</td><td headers="hd_h_ml128.tu2_1_1_1_2 hd_h_ml128.tu2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">85</td><td headers="hd_h_ml128.tu2_1_1_1_2 hd_h_ml128.tu2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">92</td><td headers="hd_h_ml128.tu2_1_1_1_2 hd_h_ml128.tu2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">130</td><td headers="hd_h_ml128.tu2_1_1_1_2 hd_h_ml128.tu2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">100</td><td headers="hd_h_ml128.tu2_1_1_1_2 hd_h_ml128.tu2_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">95</td><td headers="hd_h_ml128.tu2_1_1_1_2 hd_h_ml128.tu2_1_1_2_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">109</td></tr></tbody></table></div></div></article><article data-type="fig" id="figobml128fu3"><div id="ml128.fu3" class="figure"><div class="graphic"><img data-src="/books/NBK50684/bin/ml128fu33.jpg" alt="Image ml128fu33" /></div></div></article><article data-type="fig" id="figobml128fu4"><div id="ml128.fu4" class="figure"><div class="graphic"><img data-src="/books/NBK50684/bin/ml128fu34.jpg" alt="Image ml128fu34" /></div></div></article><article data-type="fig" id="figobml128fu5"><div id="ml128.fu5" class="figure"><div class="graphic"><img data-src="/books/NBK50684/bin/ml128fu35.jpg" alt="Image ml128fu35" /></div></div></article><article data-type="fig" id="figobml128fu6"><div id="ml128.fu6" class="figure"><div class="graphic"><img data-src="/books/NBK50684/bin/ml128fu36.jpg" alt="Image ml128fu36" /></div></div></article><article data-type="fig" id="figobml128fu7"><div id="ml128.fu7" class="figure"><div class="graphic"><img data-src="/books/NBK50684/bin/ml128fu37.jpg" alt="Image ml128fu37" /></div></div></article><article data-type="fig" id="figobml128fu8"><div id="ml128.fu8" class="figure"><div class="graphic"><img data-src="/books/NBK50684/bin/ml128fu38.jpg" alt="Image ml128fu38" /></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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