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<meta name="ncbi_db" content="books" /><meta name="ncbi_pdid" content="book-part" /><meta name="ncbi_acc" content="NBK143539" /><meta name="ncbi_domain" content="mlprobe" /><meta name="ncbi_report" content="record" /><meta name="ncbi_type" content="fulltext" /><meta name="ncbi_objectid" content="" /><meta name="ncbi_pcid" content="/NBK143539/" /><meta name="ncbi_pagename" content="Discovery and Characterization of a Selective Activator of the G-Protein Activated Inward-Rectifying Potassium (GIRK) Channel - Probe Reports from the NIH Molecular Libraries Program - NCBI Bookshelf" /><meta name="ncbi_bookparttype" content="chapter" /><meta name="ncbi_app" content="bookshelf" />
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<title>Discovery and Characterization of a Selective Activator of the G-Protein Activated Inward-Rectifying Potassium (GIRK) Channel - Probe Reports from the NIH Molecular Libraries Program - NCBI Bookshelf</title>
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<meta name="robots" content="INDEX,FOLLOW,NOARCHIVE" /><meta name="citation_inbook_title" content="Probe Reports from the NIH Molecular Libraries Program [Internet]" /><meta name="citation_title" content="Discovery and Characterization of a Selective Activator of the G-Protein Activated Inward-Rectifying Potassium (GIRK) Channel" /><meta name="citation_publisher" content="National Center for Biotechnology Information (US)" /><meta name="citation_date" content="2013/03/14" /><meta name="citation_author" content="Emily Days" /><meta name="citation_author" content="Kristian Kaufmann" /><meta name="citation_author" content="Ian Romaine" /><meta name="citation_author" content="Colleen Niswender" /><meta name="citation_author" content="Michelle Lewis" /><meta name="citation_author" content="Thomas Utley" /><meta name="citation_author" content="Yu Du" /><meta name="citation_author" content="Gregory Sliwoski" /><meta name="citation_author" content="Ryan Morrison" /><meta name="citation_author" content="Eric S. Dawson" /><meta name="citation_author" content="Julie L. Engers" /><meta name="citation_author" content="Jerod Denton" /><meta name="citation_author" content="J. Scott Daniels" /><meta name="citation_author" content="Gary A. Sulikowski" /><meta name="citation_author" content="Craig W. Lindsley" /><meta name="citation_author" content="C. David Weaver" /><meta name="citation_pmid" content="23762945" /><meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK143539/" /><link rel="schema.DC" href="http://purl.org/DC/elements/1.0/" /><meta name="DC.Title" content="Discovery and Characterization of a Selective Activator of the G-Protein Activated Inward-Rectifying Potassium (GIRK) Channel" /><meta name="DC.Type" content="Text" /><meta name="DC.Publisher" content="National Center for Biotechnology Information (US)" /><meta name="DC.Contributor" content="Emily Days" /><meta name="DC.Contributor" content="Kristian Kaufmann" /><meta name="DC.Contributor" content="Ian Romaine" /><meta name="DC.Contributor" content="Colleen Niswender" /><meta name="DC.Contributor" content="Michelle Lewis" /><meta name="DC.Contributor" content="Thomas Utley" /><meta name="DC.Contributor" content="Yu Du" /><meta name="DC.Contributor" content="Gregory Sliwoski" /><meta name="DC.Contributor" content="Ryan Morrison" /><meta name="DC.Contributor" content="Eric S. Dawson" /><meta name="DC.Contributor" content="Julie L. Engers" /><meta name="DC.Contributor" content="Jerod Denton" /><meta name="DC.Contributor" content="J. Scott Daniels" /><meta name="DC.Contributor" content="Gary A. Sulikowski" /><meta name="DC.Contributor" content="Craig W. Lindsley" /><meta name="DC.Contributor" content="C. David Weaver" /><meta name="DC.Date" content="2013/03/14" /><meta name="DC.Identifier" content="https://www.ncbi.nlm.nih.gov/books/NBK143539/" /><meta name="description" content="We have developed the first potent, subtype-selective small molecule activator of a G-protein activated inward-rectifying potassium (GIRK) channel. ML297 is potent (EC50 = 160 nM) and as efficacious as activation of GIRK via a Gi/o-coupled receptor (GPCR). ML297 shows a preference for the GIRK1/GIRK2 subunit combination compared to GIRK1/GIRK4 and is inactive on GIRK2/GIRK3 and a number of other potassium channels. This represents a major advance in this field, as the only other known small molecule activators of GIRK channels are simple alcohols and the natural product, naringin, all of which are very low potency and non-selective with respect to GIRK subtype. ML297 possesses favorable physiochemical and dystrophia myotonica protein kinase (DMPK) properties (ML297 is centrally penetrant, affording good CNS exposure in rats), making it a useful tool to selectively probe GIRK1-containing GIRK function in vitro and in vivo which will allow the role of GIRK1-containing GIRKs to be studied in numerous normal and pathophysiological conditions. These properties make ML297 the first and only molecule of its type to selectively probe GIRK1-containing GIRKs and will for the first time allow the potential therapeutic utility of GIRK as a target for numerous important therapeutic indications to be examined." /><meta name="og:title" content="Discovery and Characterization of a Selective Activator of the G-Protein Activated Inward-Rectifying Potassium (GIRK) Channel" /><meta name="og:type" content="book" /><meta name="og:description" content="We have developed the first potent, subtype-selective small molecule activator of a G-protein activated inward-rectifying potassium (GIRK) channel. ML297 is potent (EC50 = 160 nM) and as efficacious as activation of GIRK via a Gi/o-coupled receptor (GPCR). ML297 shows a preference for the GIRK1/GIRK2 subunit combination compared to GIRK1/GIRK4 and is inactive on GIRK2/GIRK3 and a number of other potassium channels. This represents a major advance in this field, as the only other known small molecule activators of GIRK channels are simple alcohols and the natural product, naringin, all of which are very low potency and non-selective with respect to GIRK subtype. ML297 possesses favorable physiochemical and dystrophia myotonica protein kinase (DMPK) properties (ML297 is centrally penetrant, affording good CNS exposure in rats), making it a useful tool to selectively probe GIRK1-containing GIRK function in vitro and in vivo which will allow the role of GIRK1-containing GIRKs to be studied in numerous normal and pathophysiological conditions. These properties make ML297 the first and only molecule of its type to selectively probe GIRK1-containing GIRKs and will for the first time allow the potential therapeutic utility of GIRK as a target for numerous important therapeutic indications to be examined." /><meta name="og:url" content="https://www.ncbi.nlm.nih.gov/books/NBK143539/" /><meta name="og:site_name" content="NCBI Bookshelf" /><meta name="og:image" content="https://www.ncbi.nlm.nih.gov/corehtml/pmc/pmcgifs/bookshelf/thumbs/th-mlprobe-lrg.png" /><meta name="twitter:card" content="summary" /><meta name="twitter:site" content="@ncbibooks" /><meta name="bk-non-canon-loc" content="/books/n/mlprobe/ml297/" /><link rel="canonical" href="https://www.ncbi.nlm.nih.gov/books/NBK143539/" /><link rel="stylesheet" href="/corehtml/pmc/css/figpopup.css" type="text/css" media="screen" /><link rel="stylesheet" href="/corehtml/pmc/css/bookshelf/2.26/css/books.min.css" type="text/css" /><link rel="stylesheet" href="/corehtml/pmc/css/bookshelf/2.26/css/books_print.min.css" type="text/css" media="print" /><style type="text/css">p a.figpopup{display:inline !important} .bk_tt {font-family: monospace} .first-line-outdent .bk_ref {display: inline} .body-content h2, .body-content .h2 {border-bottom: 1px solid #97B0C8} .body-content h2.inline {border-bottom: none} a.page-toc-label , .jig-ncbismoothscroll a {text-decoration:none;border:0 !important} .temp-labeled-list .graphic {display:inline-block !important} .temp-labeled-list img{width:100%}</style><script type="text/javascript" src="/corehtml/pmc/js/jquery.hoverIntent.min.js"> </script><script type="text/javascript" src="/corehtml/pmc/js/common.min.js?_=3.18"> </script><script type="text/javascript" src="/corehtml/pmc/js/large-obj-scrollbars.min.js"> </script><script type="text/javascript">window.name="mainwindow";</script><script type="text/javascript" src="/corehtml/pmc/js/bookshelf/2.26/book-toc.min.js"> </script><script type="text/javascript" src="/corehtml/pmc/js/bookshelf/2.26/books.min.js"> </script><meta name="book-collection" content="NONE" />
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<div class="pre-content"><div><div class="bk_prnt"><p class="small">NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.</p><p>Probe Reports from the NIH Molecular Libraries Program [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2010-. </p></div><div class="iconblock clearfix whole_rhythm no_top_margin bk_noprnt"><a class="img_link icnblk_img" title="Table of Contents Page" href="/books/n/mlprobe/"><img class="source-thumb" src="/corehtml/pmc/pmcgifs/bookshelf/thumbs/th-mlprobe-lrg.png" alt="Cover of Probe Reports from the NIH Molecular Libraries Program" height="100px" width="80px" /></a><div class="icnblk_cntnt eight_col"><h2>Probe Reports from the NIH Molecular Libraries Program [Internet].</h2><a data-jig="ncbitoggler" href="#__NBK143539_dtls__">Show details</a><div style="display:none" class="ui-widget" id="__NBK143539_dtls__"><div>Bethesda (MD): National Center for Biotechnology Information (US); 2010-.</div></div><div class="half_rhythm"><ul class="inline_list"><li style="margin-right:1em"><a class="bk_cntns" href="/books/n/mlprobe/">Contents</a></li></ul></div><div class="bk_noprnt"><form method="get" action="/books/n/mlprobe/" id="bk_srch"><div class="bk_search"><label for="bk_term" class="offscreen_noflow">Search term</label><input type="text" title="Search this book" id="bk_term" name="term" value="" data-jig="ncbiclearbutton" /> <input type="submit" class="jig-ncbibutton" value="Search this book" submit="false" style="padding: 0.1em 0.4em;" /></div></form></div></div><div class="icnblk_cntnt two_col"><div class="pagination bk_noprnt"><a class="active page_link prev" href="/books/n/mlprobe/ml298/" title="Previous page in this title">< Prev</a><a class="active page_link next" href="/books/n/mlprobe/ml296/" title="Next page in this title">Next ></a></div></div></div></div></div>
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<div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><h1 id="_NBK143539_"><span class="title" itemprop="name">Discovery and Characterization of a Selective Activator of the G-Protein Activated Inward-Rectifying Potassium (GIRK) Channel</span></h1><p class="contrib-group"><span itemprop="author">Emily Days</span>, <span itemprop="author">Kristian Kaufmann</span>, <span itemprop="author">Ian Romaine</span>, <span itemprop="author">Colleen Niswender</span>, <span itemprop="author">Michelle Lewis</span>, <span itemprop="author">Thomas Utley</span>, <span itemprop="author">Yu Du</span>, <span itemprop="author">Gregory Sliwoski</span>, <span itemprop="author">Ryan Morrison</span>, <span itemprop="author">Eric S. Dawson</span>, <span itemprop="author">Julie L. Engers</span>, <span itemprop="author">Jerod Denton</span>, <span itemprop="author">J. Scott Daniels</span>, <span itemprop="author">Gary A. Sulikowski</span>, <span itemprop="author">Craig W. Lindsley</span>, and <span itemprop="author">C. David Weaver</span>.</p><a data-jig="ncbitoggler" href="#__NBK143539_ai__" style="border:0;text-decoration:none">Author Information and Affiliations</a><div style="display:none" class="ui-widget" id="__NBK143539_ai__"><p class="contrib-group"><h4>Authors</h4><span itemprop="author">Emily Days</span>, <span itemprop="author">Kristian Kaufmann</span>, <span itemprop="author">Ian Romaine</span>, <span itemprop="author">Colleen Niswender</span>, <span itemprop="author">Michelle Lewis</span>, <span itemprop="author">Thomas Utley</span>, <span itemprop="author">Yu Du</span>, <span itemprop="author">Gregory Sliwoski</span>, <span itemprop="author">Ryan Morrison</span>, <span itemprop="author">Eric S. Dawson</span>, <span itemprop="author">Julie L. Engers</span>, <span itemprop="author">Jerod Denton</span>, <span itemprop="author">J. Scott Daniels</span>, <span itemprop="author">Gary A. Sulikowski</span>, <span itemprop="author">Craig W. Lindsley</span>,<sup><img src="/corehtml/pmc/pmcgifs/corrauth.gif" alt="corresponding author" /></sup> and <span itemprop="author">C. David Weaver</span>.</p><h4>Affiliations</h4><div class="affiliation"><sup><img src="/corehtml/pmc/pmcgifs/corrauth.gif" alt="corresponding author" /></sup>
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<span class="before-email-separator"></span><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="ude.tlibrednav@yelsdnil.giarc" class="oemail">ude.tlibrednav@yelsdnil.giarc</a></div></div><p class="small">Received: <span itemprop="datePublished">April 6, 2012</span>; Last Update: <span itemprop="dateModified">March 14, 2013</span>.</p></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="_abs_rndgid_" itemprop="description"><p>We have developed the first potent, subtype-selective small molecule activator of a G-protein activated inward-rectifying potassium (GIRK) channel. <a href="/pcsubstance/?term=ML297[synonym]" ref="pagearea=abstract&targetsite=entrez&targetcat=term&targettype=pubchem">ML297</a> is potent (EC<sub>50</sub> = 160 nM) and as efficacious as activation of GIRK via a G<sub>i/o</sub>-coupled receptor (GPCR). <a href="/pcsubstance/?term=ML297[synonym]" ref="pagearea=abstract&targetsite=entrez&targetcat=term&targettype=pubchem">ML297</a> shows a preference for the GIRK1/GIRK2 subunit combination compared to GIRK1/GIRK4 and is inactive on GIRK2/GIRK3 and a number of other potassium channels. This represents a major advance in this field, as the only other known small molecule activators of GIRK channels are simple alcohols and the natural product, naringin, all of which are very low potency and non-selective with respect to GIRK subtype. <a href="/pcsubstance/?term=ML297[synonym]" ref="pagearea=abstract&targetsite=entrez&targetcat=term&targettype=pubchem">ML297</a> possesses favorable physiochemical and dystrophia myotonica protein kinase (DMPK) properties (<a href="/pcsubstance/?term=ML297[synonym]" ref="pagearea=abstract&targetsite=entrez&targetcat=term&targettype=pubchem">ML297</a> is centrally penetrant, affording good CNS exposure in rats), making it a useful tool to selectively probe GIRK1-containing GIRK function <i>in vitro</i> and <i>in vivo</i> which will allow the role of GIRK1-containing GIRKs to be studied in numerous normal and pathophysiological conditions. These properties make <a href="/pcsubstance/?term=ML297[synonym]" ref="pagearea=abstract&targetsite=entrez&targetcat=term&targettype=pubchem">ML297</a> the first and only molecule of its type to selectively probe GIRK1-containing GIRKs and will for the first time allow the potential therapeutic utility of GIRK as a target for numerous important therapeutic indications to be examined.</p></div><div class="h2"></div><p><b>Assigned Assay Grant #:</b> RO3 MH076398-01</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, Craig W. Lindsley</p><p><b>Assay Submitter & Institution:</b> C. David Weaver, Vanderbilt University</p><p><b>PubChem Summary Bioassay Identifier (AID):</b>
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<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/504480" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">504480</a></p><div id="ml297.s1"><h2 id="_ml297_s1_">Probe Structure & Characteristics</h2><div id="ml297.fu1" class="figure bk_fig"><div class="graphic"><img src="/books/NBK143539/bin/ml297fu1.jpg" alt="ML297." /></div><h3><span class="title">ML297</span></h3></div><div id="ml297.tu1" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK143539/table/ml297.tu1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml297.tu1_lrgtbl__"><table><thead><tr><th id="hd_h_ml297.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CID/ML#</th><th id="hd_h_ml297.tu1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Target Name</th><th id="hd_h_ml297.tu1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">IC<sub>50</sub>/(nM) [SID, AID]</th><th id="hd_h_ml297.tu1_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Anti-target Name(s)</th><th id="hd_h_ml297.tu1_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">IC<sub>50</sub> (μM) [SID, AID]</th><th id="hd_h_ml297.tu1_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Fold Selective</th><th id="hd_h_ml297.tu1_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Secondary Assay(s) Name: IC<sub>50</sub>/EC<sub>50</sub> (nM) [SID, AID]</th></tr></thead><tbody><tr><td headers="hd_h_ml297.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CID 56642816/<a href="/pcsubstance/?term=ML297[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML297</a></td><td headers="hd_h_ml297.tu1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">GIRK 1/2<br />(Thallium flux)</td><td headers="hd_h_ml297.tu1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">160 nM, 122% [<a href="https://pubchem.ncbi.nlm.nih.gov/substance/134418959" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 134418959</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/623869" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 623869</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/623952" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 623952</a>]</td><td headers="hd_h_ml297.tu1_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">GIRK 2/3 (Thallium flux)</td><td headers="hd_h_ml297.tu1_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">>30,000 nM [<a href="https://pubchem.ncbi.nlm.nih.gov/substance/134418959" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 134418959</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/623975" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 623975</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/623983" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 623983</a>]</td><td headers="hd_h_ml297.tu1_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">>200</td><td headers="hd_h_ml297.tu1_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Electophysiology GIRK1/GIRK2 = 540 nM, 94.5%, GIRK2/GIRK3 >30,000 nM<br />[<a href="https://pubchem.ncbi.nlm.nih.gov/substance/134418959" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 134418959</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/623974" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 623974</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/623976" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 623976</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/623977" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 623977</a>]</td></tr></tbody></table></div></div></div><div id="ml297.s2"><h2 id="_ml297_s2_">1. Recommendations for Scientific Use of the Probe</h2><p><a href="/pcsubstance/?term=ML297[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML297</a> (CID 56642816) is the first potent, small molecule activator of GIRK1/GIRK2 (EC<sub>50</sub> = 160 nM) with ~8-fold selectivity versus GIRK1/GIRK4 and no activity at GIRK2/GIRK3 or a number of other potassium channels (K<sub>ir</sub>2.1, K<sub>v</sub>7.4, hERG). <a href="/pcsubstance/?term=ML297[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML297</a> can be used both <i>in vitro</i> and <i>in vivo</i> to study the role of selective activation of GIRK1/GIRK2 in a manner previously unavailable with the classical tool compound ethanol. Moreover, <a href="/pcsubstance/?term=ML297[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML297</a> possess an attractive <i>in vitro</i> and <i>in vivo</i> DMPK profile, ancillary pharmacology (no activity at 10 μM in the Ricerca Panel) and affords good CNS exposure. As there are no other potent and effective small molecule GIRK activators, <a href="/pcsubstance/?term=ML297[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML297</a> will be a useful <i>in vitro</i> and <i>in vivo</i> probe to study subtype selective GIRK activation, to probe GIRK’s role in cellular communication and stimulus secretion coupling in neuron preparations and brain slices, as well as to help establish potential utility for GIRK as a target for a wide variety of important therapeutic indications.</p></div><div id="ml297.s3"><h2 id="_ml297_s3_">2. Materials and Methods</h2><div id="ml297.s4"><h3>2.1. Assays</h3><ul><li class="half_rhythm"><div><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/504480" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 504480</a>: Assay for HTS of Gi/Go-linked GPCRs using mGluR8: Summary (mGlu8_Summary)</div></li><li class="half_rhythm"><div><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/488969" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 488969</a>: Assay for HTS of Gi/Go-linked GPCRs using mGluR8: Primary Screening (mGlu8_Primary)</div></li><li class="half_rhythm"><div><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/623911" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 623911</a>: hGIRK1/2_mGlu8_WaveformData (GIRK1/2_Confirmatory)</div></li><li class="half_rhythm"><div><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/623869" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 623869</a>: rmGlu8_Gqi9_Counterscreen</div></li><li class="half_rhythm"><div><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/623868" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 623868</a>: mGlu8_nonGIRK_Counterscreen</div></li><li class="half_rhythm"><div><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/623909" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 623909</a>: rmGlu8_hGIRK ½_CRC (GIRK_Confirmatory_CRC) - Dry powderReorder</div></li><li class="half_rhythm"><div><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/623952" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 623952</a>: hGIRK_1/2_Thallium_Flux_minus_mGlu8 - Dry powder reorder</div></li><li class="half_rhythm"><div><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/624042" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 624042</a>: rmGlu8_hGIRK1/2_PTX</div></li><li class="half_rhythm"><div><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/623977" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 623977</a>: human_GIRK ½_Voltage_clamp (GIRK1_2_Confirmatory_EP)</div></li><li class="half_rhythm"><div><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/623976" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 623976</a>: human_GIRK ¼_Voltage_clamp (GIRK1_4_Confirmatory_EP)</div></li><li class="half_rhythm"><div><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/623974" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 623974</a>: human_GIRK 2/3_Voltage_clamp (GIRK2/3_Confirmatory_EP)</div></li><li class="half_rhythm"><div><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/623975" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 623975</a>: human_GIRK 1/4_ThalliumFlux (GIRK1/4_ThalliumFlux_CRC)</div></li><li class="half_rhythm"><div><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/623983" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 623983</a>: human_GIRK 2/3_ThalliumFlux (GIRK2_3_ThalliumFlux_CRC)</div></li><li class="half_rhythm"><div><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/623984" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 623984</a>: human_Kir2.1_ThalliumFlux (hKir2.1_ThalliumFlux_CRC)</div></li><li class="half_rhythm"><div><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/623986" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 623986</a>: human_KV7.4_ThalliumFlux (hKV7.4_ThalliumFlux_CRC)</div></li><li class="half_rhythm"><div><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/623988" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 623988</a>: human_hERG_kV11.1_ThalliumFlux (hERG_ThalliumFlux_CRC)</div></li><li class="half_rhythm"><div><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/623932" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 623932</a>: <a href="/pcsubstance/?term=ML297[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML297</a> Competition in Radioligand Binding assays (Ricerca)</div></li></ul></div><div id="ml297.s5"><h3>2.2. Probe Chemical Characterization</h3><p>Probe compound <a href="/pcsubstance/?term=ML297[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML297</a> (CID 56642816, <a href="https://pubchem.ncbi.nlm.nih.gov/substance/134418959" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 134418959</a>) was prepared according to the scheme in <a class="figpopup" href="/books/NBK143539/figure/ml297.f1/?report=objectonly" target="object" rid-figpopup="figml297f1" rid-ob="figobml297f1">Figure 1</a>. and had the following characterization. <b>1-(3,4-difluorophenyl)-3-(3-methyl-1-phenyl-1<i>H</i>-pyrazol-5-yl)urea</b>– To a solution of 3-methyl-1-phenyl-1<i>H</i>-pyrazol-5-amine (500 mg, 2.9 mmol) in 11.5 ml of CH<sub>2</sub>Cl<sub>2</sub> was added 3,4-difluorophenylisocyanate (0.68 ml, 5.8 mmol). After 16 h the reaction was concentrated and the residue was purified by column chromatography with MeOH/CH<sub>2</sub>Cl<sub>2</sub> to afford 418 mg (65%) of the desired product. <sup>1</sup>H NMR (MeOD) δ 7.50 (m, 6H), 7.13 (dd, J = 19.2, 9.6 Hz, 1H), 6.98 (m, 1H), 6.35 (s, 1H), 2.27 (s, 3H); <sup>13</sup>C NMR (MeOD) δ 152.3, 149.8 (dd, J = 13.2, 242.9 Hz), 149.1, 145.8 (dd, J = 12.8, 240.4 Hz), 137.7 (d, 13.1 Hz), 135.6 (dd, J = 2.9, 9.0 Hz), 129.2, 128.1, 125.0, 116.7 (d, J = 18.1), 114.5 (dd, 3.6, 5.7 Hz), 107.9 (d, J = 21.8 Hz), 98.4, 12.2; <sup>19</sup>F NMR (MeOD) δ −137.3 (d, J = 22.6 Hz), −145.9 (d, J = 22.6 Hz); HRMS calculated for C<sub>17</sub>H<sub>14</sub>F<sub>2</sub>N<sub>4</sub>O (M+H)<sup>+</sup><i>m/z</i>: 329.1214 Measured 329.1211 m/z.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml297f1" co-legend-rid="figlgndml297f1"><a href="/books/NBK143539/figure/ml297.f1/?report=objectonly" target="object" title="Figure 1" class="img_link icnblk_img figpopup" rid-figpopup="figml297f1" rid-ob="figobml297f1"><img class="small-thumb" src="/books/NBK143539/bin/ml297f1.gif" src-large="/books/NBK143539/bin/ml297f1.jpg" alt="Figure 1. Synthesis of ML297." /></a><div class="icnblk_cntnt" id="figlgndml297f1"><h4 id="ml297.f1"><a href="/books/NBK143539/figure/ml297.f1/?report=objectonly" target="object" rid-ob="figobml297f1">Figure 1</a></h4><p class="float-caption no_bottom_margin">Synthesis of ML297. </p></div></div><p><b>Solubility.</b> Solubility for <a href="/pcsubstance/?term=ML297[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML297</a> in PBS was determined to be 17.5 μM (5./7 μg/ml), which is >100-fold higher than the cellular EC<sub>50</sub> for GIRK1/GIRK2.<sup><a class="bk_pop" href="#ml297.r1">1</a></sup></p><p><b>GSH Conjugates.</b> No glutathione conjugates detected.<sup><a class="bk_pop" href="#ml297.r1">1</a></sup></p><p><b>Stability.</b> Stability was determined for <a href="/pcsubstance/?term=ML297[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML297</a> at 23 °C in PBS (no antioxidants or other protectorants and DMSO concentration below 0.1%). After 48 hours, ~100% of the initial concentration of <a href="/pcsubstance/?term=ML297[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML297</a> remained in solution. Thus, <a href="/pcsubstance/?term=ML297[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML297</a> is very stable <i>in vitro</i> in assay buffer as well as <i>in vivo</i> (<i>vide infra</i>).<sup><a class="bk_pop" href="#ml297.r1">1</a></sup></p><div id="ml297.t1" class="table"><h3><span class="label">Table 1</span><span class="title">Stability of ML297</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK143539/table/ml297.t1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml297.t1_lrgtbl__"><table class="no_top_margin"><thead><tr><th id="hd_h_ml297.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"></th><th id="hd_h_ml297.t1_1_1_1_2" colspan="6" rowspan="1" style="text-align:center;vertical-align:middle;">Percent Remaining (%)</th></tr><tr><th headers="hd_h_ml297.t1_1_1_1_1" id="hd_h_ml297.t1_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Compound</th><th headers="hd_h_ml297.t1_1_1_1_2" id="hd_h_ml297.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0 Min</th><th headers="hd_h_ml297.t1_1_1_1_2" id="hd_h_ml297.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">15 Min</th><th headers="hd_h_ml297.t1_1_1_1_2" id="hd_h_ml297.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">30 Min</th><th headers="hd_h_ml297.t1_1_1_1_2" id="hd_h_ml297.t1_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">90 Min</th><th headers="hd_h_ml297.t1_1_1_1_2" id="hd_h_ml297.t1_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">24 Hour</th><th headers="hd_h_ml297.t1_1_1_1_2" id="hd_h_ml297.t1_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">48 Hour</th></tr></thead><tbody><tr><td headers="hd_h_ml297.t1_1_1_1_1 hd_h_ml297.t1_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="/pcsubstance/?term=ML297[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML297</a>, CID 56642816</td><td headers="hd_h_ml297.t1_1_1_1_2 hd_h_ml297.t1_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">100</td><td headers="hd_h_ml297.t1_1_1_1_2 hd_h_ml297.t1_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">101</td><td headers="hd_h_ml297.t1_1_1_1_2 hd_h_ml297.t1_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">101</td><td headers="hd_h_ml297.t1_1_1_1_2 hd_h_ml297.t1_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">100</td><td headers="hd_h_ml297.t1_1_1_1_2 hd_h_ml297.t1_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">103</td><td headers="hd_h_ml297.t1_1_1_1_2 hd_h_ml297.t1_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">106</td></tr></tbody></table></div></div><p><b>Compounds added to the SMR collection (MLS#s):</b> MLS004084519 (<a href="/pcsubstance/?term=ML297[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML297</a>, CID 56642816, 21.3 mg); MLS003871708 (CID 53384948, 6.7 mg); MLS003871709 (CID 2815115, 5.5 mg); MLS003871710 (CID 53384949, 5.1 mg); MLS003871711 (CID 11840791, 5.9 mg); MLS003871712 (CID 53384950, 6.1 mg).</p></div><div id="ml297.s6"><h3>2.3. Probe Preparation</h3><p>Probe compound <a href="/pcsubstance/?term=ML297[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML297</a> (CID 56642816, <a href="https://pubchem.ncbi.nlm.nih.gov/substance/134418959" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 134418959</a>) was prepared according to the scheme in <a class="figpopup" href="/books/NBK143539/figure/ml297.f2/?report=objectonly" target="object" rid-figpopup="figml297f2" rid-ob="figobml297f2">Figure 2</a> and had the following characterization: <b>1-(3,4-difluorophenyl)-3-(3-methyl-1-phenyl-1<i>H</i>-pyrazol-5-yl)urea</b>– To a solution of 3-methyl-1-phenyl-1<i>H</i>-pyrazol-5-amine (500 mg, 2.9 mmol) in 11.5 ml of CH<sub>2</sub>Cl<sub>2</sub> was added 3,4-difluorophenylisocyanate (0.68 ml, 5.8 mmol). After 16 h, the reaction was concentrated and the residue was purified by column chromatography with MeOH/CH<sub>2</sub>Cl<sub>2</sub> to afford 418 mg (65%) of <a href="/pcsubstance/?term=ML297[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML297</a>. <sup>1</sup>H NMR (MeOD) δ 7.50 (m, 6H), 7.13 (dd, J = 19.2, 9.6 Hz, 1H), 6.98 (m, 1H), 6.35 (s, 1H), 2.27 (s, 3H); <sup>13</sup>C NMR (MeOD) δ 152.3, 149.8 (dd, J = 13.2, 242.9 Hz), 149.1, 145.8 (dd, J = 12.8, 240.4 Hz), 137.7 (d, 13.1 Hz), 135.6 (dd, J = 2.9, 9.0 Hz), 129.2, 128.1, 125.0, 116.7 (d, J = 18.1), 114.5 (dd, 3.6, 5.7 Hz), 107.9 (d, J = 21.8 Hz), 98.4, 12.2; <sup>19</sup>F NMR (MeOD) δ −137.3 (d, J = 22.6 Hz), −145.9 (d, J = 22.6 Hz); HRMS calculated for C<sub>17</sub>H<sub>14</sub>F<sub>2</sub>N<sub>4</sub>O (M+H)<sup>+</sup><i>m/z</i>: 329.1214 Measured 329.1211 m/z.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml297f2" co-legend-rid="figlgndml297f2"><a href="/books/NBK143539/figure/ml297.f2/?report=objectonly" target="object" title="Figure 2" class="img_link icnblk_img figpopup" rid-figpopup="figml297f2" rid-ob="figobml297f2"><img class="small-thumb" src="/books/NBK143539/bin/ml297f2.gif" src-large="/books/NBK143539/bin/ml297f2.jpg" alt="Figure 2. Compound Preparation of Probe ML297." /></a><div class="icnblk_cntnt" id="figlgndml297f2"><h4 id="ml297.f2"><a href="/books/NBK143539/figure/ml297.f2/?report=objectonly" target="object" rid-ob="figobml297f2">Figure 2</a></h4><p class="float-caption no_bottom_margin">Compound Preparation of Probe ML297. </p></div></div></div></div><div id="ml297.s7"><h2 id="_ml297_s7_">3. Results</h2><div id="ml297.s8"><h3>3.1. Dose Response Curves for Probe</h3><p>In both thallium flux and voltage-clamp electrophysiology assays, <a href="/pcsubstance/?term=ML297[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML297</a> preferentially activates GIRK1/GIRK2 with an EC<sub>50</sub> of 160 nM (122.6% efficacy) in thallium flux and an EC<sub>50</sub> of 540 nM (94.5% efficacy) in voltage-clamp electrohysiology (<a class="figpopup" href="/books/NBK143539/figure/ml297.f3/?report=objectonly" target="object" rid-figpopup="figml297f3" rid-ob="figobml297f3">Figure 3</a>).</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml297f3" co-legend-rid="figlgndml297f3"><a href="/books/NBK143539/figure/ml297.f3/?report=objectonly" target="object" title="Figure 3" class="img_link icnblk_img figpopup" rid-figpopup="figml297f3" rid-ob="figobml297f3"><img class="small-thumb" src="/books/NBK143539/bin/ml297f3.gif" src-large="/books/NBK143539/bin/ml297f3.jpg" alt="Figure 3. Shown are fits to data obtained by performing thallium flux and voltage-clamp assays on Probe ML297 at varying concentrations with cells expressing GIRK1/GIRK2." /></a><div class="icnblk_cntnt" id="figlgndml297f3"><h4 id="ml297.f3"><a href="/books/NBK143539/figure/ml297.f3/?report=objectonly" target="object" rid-ob="figobml297f3">Figure 3</a></h4><p class="float-caption no_bottom_margin">Shown are fits to data obtained by performing thallium flux and voltage-clamp assays on Probe ML297 at varying concentrations with cells expressing GIRK1/GIRK2. A) For the thallium flux experiments (EC<sub>50</sub> = 160 nM, 122.6%), the curve was fit to triplicate <a href="/books/NBK143539/figure/ml297.f3/?report=objectonly" target="object" rid-ob="figobml297f3">(more...)</a></p></div></div></div><div id="ml297.s9"><h3>3.2. Cellular Activity</h3><p>The GIRK screening assays (both Tl<sup>+</sup> flux and EP) are cell-based assays, indicating that <a href="/pcsubstance/?term=ML297[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML297</a> can gain access to its molecular target when applied to cells. The compound did not exhibit acute toxicity in cell-based assays at concentrations up to 30 μM, and cyctotoxicity assays aimed at this parameter indicated <a href="/pcsubstance/?term=ML297[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML297</a> had no cyctotoxicity in native HEK293 cells.</p></div><div id="ml297.s10"><h3>3.3. Profiling Assays</h3><p>To more fully characterize this potent, subtype selective GIRK1/GIRK2 activator <a href="/pcsubstance/?term=ML297[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML297</a> was tested using Ricerca’s (formerly MDS Pharma’s) Lead Profiling Screen (binding assay panel of 68 GPCRs, ion channels and transporters screened at 10 μM).<sup><a class="bk_pop" href="#ml297.r2">2</a></sup> Included in the Ricerca screening panel are a number of ion channels (calcium channel, L-Type and N-Type; potassium channel [K<sub>ATP</sub>]; potassium channel [hERG]) and class A GPCRs (D<sub>1–5</sub>, H<sub>1–3</sub>, etc…). <a href="/pcsubstance/?term=ML297[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML297</a> was found to be completely clean, affording no inhibition of any of the 68 assays conducted (inhibition of radio ligand binding > 50% at 10 μM). In addition to the selectivity data presented for related potassium channels in <a class="figpopup" href="/books/NBK143539/table/ml297.t2/?report=objectonly" target="object" rid-figpopup="figml297t2" rid-ob="figobml297t2">Table 2</a>, <a href="/pcsubstance/?term=ML297[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML297</a> is an exquisite probe to study GIRK1/2 activation without known concern for ancillary activity. <a class="figpopup" href="/books/NBK143539/table/ml297.t2/?report=objectonly" target="object" rid-figpopup="figml297t2" rid-ob="figobml297t2">Table 2</a> highlights calculated properties for <a href="/pcsubstance/?term=ML297[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML297</a>, which compares favorably with the MDDR.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml297t2"><a href="/books/NBK143539/table/ml297.t2/?report=objectonly" target="object" title="Table 2" class="img_link icnblk_img figpopup" rid-figpopup="figml297t2" rid-ob="figobml297t2"><img class="small-thumb" src="/books/NBK143539/table/ml297.t2/?report=thumb" src-large="/books/NBK143539/table/ml297.t2/?report=previmg" alt="Table 2. Calculated Property Comparison with MDDR Compounds." /></a><div class="icnblk_cntnt"><h4 id="ml297.t2"><a href="/books/NBK143539/table/ml297.t2/?report=objectonly" target="object" rid-ob="figobml297t2">Table 2</a></h4><p class="float-caption no_bottom_margin">Calculated Property Comparison with MDDR Compounds. </p></div></div><p>In order to aid the wider community in the use <a href="/pcsubstance/?term=ML297[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML297</a>, we further profiled <a href="/pcsubstance/?term=ML297[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML297</a> in a battery of pharmacokinetic assays (<a class="figpopup" href="/books/NBK143539/table/ml297.t3/?report=objectonly" target="object" rid-figpopup="figml297t3" rid-ob="figobml297t3">Table 3</a>) including an assessment of intrinsic clearance (CL<sub>INT</sub>) in hepatic microsomes, allowing for the prediction of pertinent rat and human PK parameters (CL and <i>t</i><sub>1/2</sub>). <a href="/pcsubstance/?term=ML297[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML297</a> is predicted to have high clearance in rat (CL<sub>INT</sub> = 382.0 ml/min/kg, CL<sub>HEP</sub> = 59.2 ml/min/kg) and moderate clearance in human (CL<sub>INT</sub> = 43.0 ml/min/kg, CL<sub>HEP</sub> = 14.1 ml/min/kg), and possesses reasonable free fraction (~1–5% free in human and rat equilibrium dialysis plasma protein binding studies). Moreover, <a href="/pcsubstance/?term=ML297[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML297</a> has a variable CYP P450 profile, displaying weak inhibition of the four major CYPs (3A4 (>30 μM), 2D6 (17.6 μM), 2C9 (21.6 μM) and 1A2 (11.6 μM)).</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml297t3"><a href="/books/NBK143539/table/ml297.t3/?report=objectonly" target="object" title="Table 3" class="img_link icnblk_img figpopup" rid-figpopup="figml297t3" rid-ob="figobml297t3"><img class="small-thumb" src="/books/NBK143539/table/ml297.t3/?report=thumb" src-large="/books/NBK143539/table/ml297.t3/?report=previmg" alt="Table 3. In vitro DMPK Profile of ML297." /></a><div class="icnblk_cntnt"><h4 id="ml297.t3"><a href="/books/NBK143539/table/ml297.t3/?report=objectonly" target="object" rid-ob="figobml297t3">Table 3</a></h4><p class="float-caption no_bottom_margin"><i>In vitro</i> DMPK Profile of ML297. </p></div></div></div></div><div id="ml297.s11"><h2 id="_ml297_s11_">4. Discussion</h2><div id="ml297.s12"><h3>4.1. Comparison to Existing Art and How the New Probe is an Improvement</h3><p><a href="/pcsubstance/?term=ML297[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML297</a> (CID 56642816) is the first potent, small molecule activator of GIRK1/2 (EC<sub>50</sub> = 160 nM, 122%) with ~8-fold selectivity versus GIRK1/4 and no activity at GIRK2/3 or a number of other potassium channels (K<sub>ir</sub>2.1, K<sub>v</sub>7.4, hERG). <a href="/pcsubstance/?term=ML297[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML297</a> can be used both <i>in vitro</i> and <i>in vivo</i> to study the role of selective activation of GIRK1/2 in a manner previously unavailable with the classical tool compound ethanol. The only compounds that are known to activate GIRK are alcohols (e.g. ethanol) at concentrations of hundreds of millimolar and recently, the compound naringin has been identified as a GIRK activator. However, the reported EC<sub>50</sub> is in excess of 100 μM. Clearly, the potency of <a href="/pcsubstance/?term=ML297[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML297</a> coupled with the GIRK subtype selectivity make it far superior relative to the prior art of GIRK activators. Moreover, <a href="/pcsubstance/?term=ML297[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML297</a> possess an attractive <i>in vitro</i> and <i>in vivo</i> DMPK profile, ancillary pharmacology (no activity at 10 μM in the Ricerca Panel), and affords good CNS exposure (brian:plasma ratio of 0.3 when dosed orally at 10 mg/kg). As there are no small molecule GIRK activators, <a href="/pcsubstance/?term=ML297[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML297</a> will be a useful <i>in vitro</i> and <i>in vivo</i> probe to study subtype selective GIRK activation, to probe GIRK’s role in cellular communication and stimulus secretion coupling in neuron preparations and brain slices, as well as to help establish potential utility for GIRK as a target for a wide variety of important therapeutic indications. Finally, <a href="/pcsubstance/?term=ML297[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML297</a> is free from IP constraints, which will allow the MLPCN to freely provide this probe to the biomedical research community.</p></div></div><div id="ml297.s13"><h2 id="_ml297_s13_">5. References</h2><dl class="temp-labeled-list"><dt>1.</dt><dd><div class="bk_ref" id="ml297.r1">Solubility (PBS at pH = 7.4), Stability and Reactivity experiments were conducted at Analiza. For additional information see: <a href="http://analiza.com" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">http://analiza<wbr style="display:inline-block"></wbr>.com</a></div></dd><dt>2.</dt><dd><div class="bk_ref" id="ml297.r2">For information on the Ricerca Lead Profiling Screen see: <a href="https://www.eurofinspanlabs.com/Catalog" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">https://www<wbr style="display:inline-block"></wbr>.eurofinspanlabs.com/Catalog</a></div></dd></dl></div><div id="bk_toc_contnr"></div></div></div>
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<div xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Views</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="PDF_download" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="/books/NBK143539/?report=reader">PubReader</a></li><li><a href="/books/NBK143539/?report=printable">Print View</a></li><li><a data-jig="ncbidialog" href="#_ncbi_dlg_citbx_NBK143539" data-jigconfig="width:400,modal:true">Cite this Page</a><div id="_ncbi_dlg_citbx_NBK143539" style="display:none" title="Cite this Page"><div class="bk_tt">Days E, Kaufmann K, Romaine I, et al. Discovery and Characterization of a Selective Activator of the G-Protein Activated Inward-Rectifying Potassium (GIRK) Channel. 2012 Apr 6 [Updated 2013 Mar 14]. In: Probe Reports from the NIH Molecular Libraries Program [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2010-. <span class="bk_cite_avail"></span></div></div></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>In this Page</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="page-toc" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="#ml297.s1" ref="log$=inpage&link_id=inpage">Probe Structure & Characteristics</a></li><li><a href="#ml297.s2" ref="log$=inpage&link_id=inpage">Recommendations for Scientific Use of the Probe</a></li><li><a href="#ml297.s3" ref="log$=inpage&link_id=inpage">Materials and Methods</a></li><li><a href="#ml297.s7" ref="log$=inpage&link_id=inpage">Results</a></li><li><a href="#ml297.s11" ref="log$=inpage&link_id=inpage">Discussion</a></li><li><a href="#ml297.s13" ref="log$=inpage&link_id=inpage">References</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Related information</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="discovery_db_links" id="Shutter"></a></div><div class="portlet_content"><ul><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=pcassay&DbFrom=books&Cmd=Link&LinkName=books_pcassay_probe&IdsFromResult=3036062" ref="log$=recordlinks">PubChem BioAssay for Chemical Probe</a><div class="brieflinkpop offscreen_noflow">PubChem BioAssay records reporting screening data for the development of the chemical probe(s) described in this book chapter</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=pcsubstance&DbFrom=books&Cmd=Link&LinkName=books_pcsubstance&IdsFromResult=3036062" ref="log$=recordlinks">PubChem Substance</a><div class="brieflinkpop offscreen_noflow">Related PubChem Substances</div></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Similar articles in PubMed</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="PBooksDiscovery_RA" id="Shutter"></a></div><div class="portlet_content"><ul><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/30136838" ref="ordinalpos=1&linkpos=1&log$=relatedarticles&logdbfrom=pubmed">Discovery and Characterization of VU0529331, a Synthetic Small-Molecule Activator of Homomeric G Protein-Gated, Inwardly Rectifying, Potassium (GIRK) Channels.</a><span class="source">[ACS Chem Neurosci. 2019]</span><div class="brieflinkpop offscreen_noflow">Discovery and Characterization of VU0529331, a Synthetic Small-Molecule Activator of Homomeric G Protein-Gated, Inwardly Rectifying, Potassium (GIRK) Channels.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Kozek KA, Du Y, Sharma S, Prael FJ 3rd, Spitznagel BD, Kharade SV, Denton JS, Hopkins CR, Weaver CD. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">ACS Chem Neurosci. 2019 Jan 16; 10(1):358-370. 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