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<title>Identification of a novel, small molecule activator of KCNQ1 channels - 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="Identification of a novel, small molecule activator of KCNQ1 channels" /><meta name="citation_publisher" content="National Center for Biotechnology Information (US)" /><meta name="citation_date" content="2013/03/07" /><meta name="citation_author" content="Haibo Yu" /><meta name="citation_author" content="Zhihong Lin" /><meta name="citation_author" content="Kaiping Xu" /><meta name="citation_author" content="Xiaofang Huang" /><meta name="citation_author" content="Shunyou Long" /><meta name="citation_author" content="Meng Wu" /><meta name="citation_author" content="Owen B. McManus" /><meta name="citation_author" content="Julie Le Engers" /><meta name="citation_author" content="Margrith E. Mattmann" /><meta name="citation_author" content="Darren W. Engers" /><meta name="citation_author" content="Uyen M. Le" /><meta name="citation_author" content="Craig W. Lindsley" /><meta name="citation_author" content="Corey R. Hopkins" /><meta name="citation_author" content="Min Li" /><meta name="citation_pmid" content="23762928" /><meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK143558/" /><link rel="schema.DC" href="http://purl.org/DC/elements/1.0/" /><meta name="DC.Title" content="Identification of a novel, small molecule activator of KCNQ1 channels" /><meta name="DC.Type" content="Text" /><meta name="DC.Publisher" content="National Center for Biotechnology Information (US)" /><meta name="DC.Contributor" content="Haibo Yu" /><meta name="DC.Contributor" content="Zhihong Lin" /><meta name="DC.Contributor" content="Kaiping Xu" /><meta name="DC.Contributor" content="Xiaofang Huang" /><meta name="DC.Contributor" content="Shunyou Long" /><meta name="DC.Contributor" content="Meng Wu" /><meta name="DC.Contributor" content="Owen B. McManus" /><meta name="DC.Contributor" content="Julie Le Engers" /><meta name="DC.Contributor" content="Margrith E. Mattmann" /><meta name="DC.Contributor" content="Darren W. Engers" /><meta name="DC.Contributor" content="Uyen M. Le" /><meta name="DC.Contributor" content="Craig W. Lindsley" /><meta name="DC.Contributor" content="Corey R. Hopkins" /><meta name="DC.Contributor" content="Min Li" /><meta name="DC.Date" content="2013/03/07" /><meta name="DC.Identifier" content="https://www.ncbi.nlm.nih.gov/books/NBK143558/" /><meta name="description" content="KCNQ voltage-gated potassium channels are involved in regulating excitability, action potential duration and transport processes in a variety of cell types. A high throughput fluorescent screen based depolarization-triggered thallium influx through KCNQ1 channels was developed and used to screen the Molecular Libraries Probe Production Centers Network (MLPCN) library to identify activators of KCNQ1 channels. Identified hits were characterized using IonWorks automated electrophysiology. An initial racemic hit (EC50 = 1.7 μM) served as a starting point for optimization studies of newly synthesized compounds. ML277 was identified as a potent (EC50 = 0.26 μM) activator of KCNQ1 channels with more than 100-fold selectivity for activation of KCNQ1 channels compared with closely related KCNQ2 and KCNQ4 channels and with distantly related hERG potassium channels. ML277 provides a novel and selective chemical probe to investigate the role of KCNQ1 channels." /><meta name="og:title" content="Identification of a novel, small molecule activator of KCNQ1 channels" /><meta name="og:type" content="book" /><meta name="og:description" content="KCNQ voltage-gated potassium channels are involved in regulating excitability, action potential duration and transport processes in a variety of cell types. A high throughput fluorescent screen based depolarization-triggered thallium influx through KCNQ1 channels was developed and used to screen the Molecular Libraries Probe Production Centers Network (MLPCN) library to identify activators of KCNQ1 channels. Identified hits were characterized using IonWorks automated electrophysiology. An initial racemic hit (EC50 = 1.7 μM) served as a starting point for optimization studies of newly synthesized compounds. ML277 was identified as a potent (EC50 = 0.26 μM) activator of KCNQ1 channels with more than 100-fold selectivity for activation of KCNQ1 channels compared with closely related KCNQ2 and KCNQ4 channels and with distantly related hERG potassium channels. 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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="#__NBK143558_dtls__">Show details</a><div style="display:none" class="ui-widget" id="__NBK143558_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/ml278/" title="Previous page in this title">< Prev</a><a class="active page_link next" href="/books/n/mlprobe/ml276/" 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="_NBK143558_"><span class="title" itemprop="name">Identification of a novel, small molecule activator of KCNQ1 channels</span></h1><p class="contrib-group"><span itemprop="author">Haibo Yu</span>, <span itemprop="author">Zhihong Lin</span>, <span itemprop="author">Kaiping Xu</span>, <span itemprop="author">Xiaofang Huang</span>, <span itemprop="author">Shunyou Long</span>, <span itemprop="author">Meng Wu</span>, <span itemprop="author">Owen B. McManus</span>, <span itemprop="author">Julie Le Engers</span>, <span itemprop="author">Margrith E. Mattmann</span>, <span itemprop="author">Darren W. Engers</span>, <span itemprop="author">Uyen M. Le</span>, <span itemprop="author">Craig W. Lindsley</span>, <span itemprop="author">Corey R. Hopkins</span>, and <span itemprop="author">Min Li</span>.</p><a data-jig="ncbitoggler" href="#__NBK143558_ai__" style="border:0;text-decoration:none">Author Information and Affiliations</a><div style="display:none" class="ui-widget" id="__NBK143558_ai__"><p class="contrib-group"><h4>Authors</h4><span itemprop="author">Haibo Yu</span>,<sup>1</sup> <span itemprop="author">Zhihong Lin</span>,<sup>1</sup> <span itemprop="author">Kaiping Xu</span>,<sup>1</sup> <span itemprop="author">Xiaofang Huang</span>,<sup>1</sup> <span itemprop="author">Shunyou Long</span>,<sup>1</sup> <span itemprop="author">Meng Wu</span>,<sup>1</sup> <span itemprop="author">Owen B. McManus</span>,<sup>1</sup> <span itemprop="author">Julie Le Engers</span>,<sup>2</sup> <span itemprop="author">Margrith E. Mattmann</span>,<sup>2</sup> <span itemprop="author">Darren W. Engers</span>,<sup>2</sup> <span itemprop="author">Uyen M. Le</span>,<sup>2</sup> <span itemprop="author">Craig W. Lindsley</span>,<sup>2</sup> <span itemprop="author">Corey R. Hopkins</span>,<sup>2</sup> and <span itemprop="author">Min Li</span><sup>1</sup>.</p><h4>Affiliations</h4><div class="affiliation"><sup>1</sup>
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Johns Hopkins Ion Channel Center</div><div class="affiliation"><sup>2</sup>
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Vanderbilt Specialized Chemistry Center for Accelerated Probe Development</div></div><p class="small">Received: <span itemprop="datePublished">December 16, 2011</span>; Last Update: <span itemprop="dateModified">March 7, 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>KCNQ voltage-gated potassium channels are involved in regulating excitability, action potential
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duration and transport processes in a variety of cell types. A high throughput fluorescent screen
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based depolarization-triggered thallium influx through KCNQ1 channels was developed and used to
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screen the Molecular Libraries Probe Production Centers Network (MLPCN) library to identify activators of KCNQ1 channels. Identified hits were characterized using IonWorks automated electrophysiology. An initial racemic hit (EC<sub>50</sub> = 1.7 μM) served as a starting point for optimization studies of newly synthesized compounds. <a href="/pcsubstance/?term=ML277[synonym]" ref="pagearea=abstract&targetsite=entrez&targetcat=term&targettype=pubchem">ML277</a> was identified as a potent (EC<sub>50</sub> = 0.26 μM) activator of KCNQ1 channels with more than 100-fold selectivity for activation of KCNQ1 channels compared with closely related KCNQ2 and KCNQ4 channels and with distantly related hERG potassium channels. <a href="/pcsubstance/?term=ML277[synonym]" ref="pagearea=abstract&targetsite=entrez&targetcat=term&targettype=pubchem">ML277</a> provides a novel and selective chemical probe to investigate the role of KCNQ1 channels.</p></div><div class="h2"></div><p><b>Assigned Assay Grant #:</b> 1 R03 MH090837-01</p><p><b>Screening Center Name & PI</b>: Johns Hopkins Ion Channel Center, Min Li</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> Meng Wu, Johns Hopkins University School of Medicine</p><p>PubChem Summary Bioassay Identifier (<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2699" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2699</a>)</p><div id="ml277.s1"><h2 id="_ml277_s1_">Probe Structure & Characteristics</h2><div id="ml277.fu1" class="figure bk_fig"><div class="graphic"><img src="/books/NBK143558/bin/ml277fu1.jpg" alt="ML277." /></div><h3><span class="title">ML277</span></h3></div><div id="ml277.tu1" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK143558/table/ml277.tu1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml277.tu1_lrgtbl__"><table><thead><tr><th id="hd_h_ml277.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CID/ML#</th><th id="hd_h_ml277.tu1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Target Name</th><th id="hd_h_ml277.tu1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">EC<sub>50</sub> (nM) [SID, AID]</th><th id="hd_h_ml277.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_ml277.tu1_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">EC<sub>50</sub> (μM) [SID, AID]</th><th id="hd_h_ml277.tu1_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Fold Selective</th><th id="hd_h_ml277.tu1_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Secondary Assay(s) Name: EC<sub>50</sub> (nM) [SID, AID]</th></tr></thead><tbody><tr><td headers="hd_h_ml277.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CID 53347901/<a href="/pcsubstance/?term=ML277[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML277</a></td><td headers="hd_h_ml277.tu1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">KCNQ1</td><td headers="hd_h_ml277.tu1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">261 [<a href="https://pubchem.ncbi.nlm.nih.gov/substance/125081894" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 125081894</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588673" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 588673</a>]</td><td headers="hd_h_ml277.tu1_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">KCNQ2</td><td headers="hd_h_ml277.tu1_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">>30 [<a href="https://pubchem.ncbi.nlm.nih.gov/substance/125081894" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 125081894</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/493009" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 493009</a>]</td><td headers="hd_h_ml277.tu1_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">>100</td><td headers="hd_h_ml277.tu1_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">KCNQ2 Manual EP: ~300 [<a href="https://pubchem.ncbi.nlm.nih.gov/substance/125081894" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 125081894</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/602120" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 602120</a>]</td></tr></tbody></table></div></div></div><div id="ml277.s2"><h2 id="_ml277_s2_">1. Recommendations for Scientific Use of the Probe</h2><p>Human genetic studies have identified a link between expression of certain KCNQ1 alleles and susceptibility to diabetes [<a class="bk_pop" href="#ml277.r1">1</a>], pancreatic insulin secretion [<a class="bk_pop" href="#ml277.r2">2</a>], and insulin signaling[<a class="bk_pop" href="#ml277.r3">3</a>]. <a href="/pcsubstance/?term=ML277[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML277</a> would provide a novel pharmacological tool to investigate the role of KCNQ1 channels in insulin secretion from human pancreatic islets or islets from other species that express a similar set of channels in islets. <a href="/pcsubstance/?term=ML277[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML277</a> offers a complementary tool to use of nonselective KCNQ1 inhibitors. Additional pharmacological characterization of the effects of <a href="/pcsubstance/?term=ML277[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML277</a> on islet ion channels would be a prerequisite to these studies. KCNQ1 is also expressed in some epithelial tissues plays a role in salt, glucose, and vitamin transport [<a class="bk_pop" href="#ml277.r4">4</a>]. <a href="/pcsubstance/?term=ML277[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML277</a> may provide a new pharmacological probe to investigate the role of these channels in fluid and salt transport. Co-assembly of KCNQ1 and KCNE1 forms the I<i><sub>ks</sub></i> current, which regulates action potential duration. Characterization of the effects of <a href="/pcsubstance/?term=ML277[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML277</a> on KCNQ1/E1 and KCNQ1/KCNEx channels would provide a possible additional tool for investigation of the roles of KCNQ1 channels in a variety of tissues.</p></div><div id="ml277.s3"><h2 id="_ml277_s3_">2. Materials and Methods</h2><ul><li class="half_rhythm"><div>CHO-KCNQ1, Parental CHO, CHO-KCNQ2 and CHO-KCNQ1/KCNE1 cell lines</div></li><li class="half_rhythm"><div>FluxOR dye kit (Invitrogen, <a href="/nuccore/682550" class="bk_tag" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=nuccore">F10017</a>)</div></li><li class="half_rhythm"><div>BD Biocoat, Poly-D-Lysine coated, black/clear bottom 384-well assay plates</div></li><li class="half_rhythm"><div>Hamamatsu FDSS 6000 fluorescent plate reader</div></li><li class="half_rhythm"><div>Population Patch Clamp patch plates from Molecular Devices</div></li></ul><div id="ml277.s4"><h3>2.1. Assays</h3><ul><li class="half_rhythm"><div>Summary <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2699" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2699</a>: Summary of assays for compounds that potentiate/activate KCNQ1 potassium channels</div></li><li class="half_rhythm"><div><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2648" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 2648</a>: Primary cell-based high-throughput screening assay for identification of compounds that potentiate/activate KCNQ1 potassium channels</div></li><li class="half_rhythm"><div><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/493006" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 493006</a>: Counter screen assay of the parental CHO cells for identification of compounds that potentiate KCNQ1 potassium channels</div></li><li class="half_rhythm"><div><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/493007" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 493007</a>: Validation assay for identification of compounds that potentiate KCNQ1 potassium channels</div></li><li class="half_rhythm"><div><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/493009" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 493009</a>: Specificity screen assay against KCNQ2 for identification of compounds that potentiate KCNQ1 potassium channels</div></li><li class="half_rhythm"><div><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/493184" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 493184</a>: Secondary automated electrophysiology assay of compounds that potentiate KCNQ1 potassium channels</div></li><li class="half_rhythm"><div><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/493186" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 493186</a>: Specificity screen assay against KCNQ1/E1 for identification of compounds that potentiate KCNQ1 potassium channels</div></li><li class="half_rhythm"><div><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588673" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 588673</a>: SAR analysis for compounds that activate KCNQ1 potassium channels in the KCNQ1 expressing cells on automated patch clamp</div></li><li class="half_rhythm"><div><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/602121" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 602121</a>: SAR analysis for compounds that activate KCNQ1 potassium channels in the KCNQ1 expressing cells on automated patch clamp 2</div></li><li class="half_rhythm"><div><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/602120" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 602120</a>: Manual patch clamp assay to confirm a potent KCNQ1 activator</div></li></ul></div><div id="ml277.s5"><h3>2.2. Probe Chemical Characterization</h3><p>Probe compound <a href="/pcsubstance/?term=ML277[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML277</a> (CID 53347901, <a href="https://pubchem.ncbi.nlm.nih.gov/substance/125081894" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 125081894</a>) was prepared according to the scheme in <a class="figpopup" href="/books/NBK143558/figure/ml277.f1/?report=objectonly" target="object" rid-figpopup="figml277f1" rid-ob="figobml277f1">Figure 1</a> and provided the following characterization data: <sup>1</sup>H NMR: (400 MHz, CDCl<sub>3</sub>) δ (ppm): 9.98 ( br s, 1H), 7.81 (m, 4H), 7.39 (d, <i>J</i> = 8.1 Hz, 2H), 7.05 (s, 1H), 6.98 (dt, <i>J</i> = 2.6, 8.9 Hz, 2H), 4.75 (d, <i>J</i> = 4.8 Hz, 1H), 4.08 (dd, <i>J</i> = 2.2, 14.7 Hz, 1H), 3.88 (s, 3H), 3.14 (td, <i>J</i> = 2.4, 14 Hz, 1H), 2.48 (s, 3H), 2.33 (d, <i>J</i> = 14 Hz, 1H), 1.63-1.12 (m, 6H); <sup>13</sup>C NMR: (400 MHz, CDCl<sub>3</sub>) δ (ppm): 168.06, 159.55, 156.86, 149.71, 144.18, 136.77, 130.11, 127.33, 127.19, 126.93, 114.05, 105.90, 56.21, 55.28, 43.94, 23.54, 23.07, 21.55, 19.75. LCMS: R<sub>T</sub> = 0.845 min., <i>m</i>/<i>z</i> = 472.1 [M + H]<sup>+</sup> (>99% @ 215 and 254 nm).</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml277f1" co-legend-rid="figlgndml277f1"><a href="/books/NBK143558/figure/ml277.f1/?report=objectonly" target="object" title="Figure 1" class="img_link icnblk_img figpopup" rid-figpopup="figml277f1" rid-ob="figobml277f1"><img class="small-thumb" src="/books/NBK143558/bin/ml277f1.gif" src-large="/books/NBK143558/bin/ml277f1.jpg" alt="Figure 1. Preparation of probe compound ML277." /></a><div class="icnblk_cntnt" id="figlgndml277f1"><h4 id="ml277.f1"><a href="/books/NBK143558/figure/ml277.f1/?report=objectonly" target="object" rid-ob="figobml277f1">Figure 1</a></h4><p class="float-caption no_bottom_margin">Preparation of probe compound ML277. </p></div></div><p><b>Solubility:</b> Powder samples were diluted to 10 mM solution at Analiza. The solubility as determined in PBS buffer is shown in <a class="figpopup" href="/books/NBK143558/table/ml277.t1/?report=objectonly" target="object" rid-figpopup="figml277t1" rid-ob="figobml277t1">Table 1</a>. Kinetic solubility measurements are performed after 18 hours. The stability data shown in <a class="figpopup" href="/books/NBK143558/table/ml277.t1/?report=objectonly" target="object" rid-figpopup="figml277t1" rid-ob="figobml277t1">Table 1</a> suggests that <a href="/pcsubstance/?term=ML277[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML277</a> is soluble for up to 90 minutes. These results suggest that <a href="/pcsubstance/?term=ML277[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML277</a> display adequate solubility for <i>in vitro</i> experiments in which <a href="/pcsubstance/?term=ML277[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML277</a> is tested less than one hour after preparation.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml277t1"><a href="/books/NBK143558/table/ml277.t1/?report=objectonly" target="object" title="Table 1" class="img_link icnblk_img figpopup" rid-figpopup="figml277t1" rid-ob="figobml277t1"><img class="small-thumb" src="/books/NBK143558/table/ml277.t1/?report=thumb" src-large="/books/NBK143558/table/ml277.t1/?report=previmg" alt="Table 1. Solubility as determined in PBS buffer." /></a><div class="icnblk_cntnt"><h4 id="ml277.t1"><a href="/books/NBK143558/table/ml277.t1/?report=objectonly" target="object" rid-ob="figobml277t1">Table 1</a></h4><p class="float-caption no_bottom_margin">Solubility as determined in PBS buffer. </p></div></div><p><b>Stability:</b> Stability was determined for <a href="/pcsubstance/?term=ML277[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML277</a> at 23° C in PBS (no antioxidants or other protectorants and DMSO concentration below 0.1%) and is shown in <a class="figpopup" href="/books/NBK143558/table/ml277.t2/?report=objectonly" target="object" rid-figpopup="figml277t2" rid-ob="figobml277t2">Table 2</a>. <a href="/pcsubstance/?term=ML277[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML277</a> is stable up to 90 min.; however, since there is a significant time gap between the 90 min. and 24 hour measurement, it is difficult to state the half-life of the molecule. <a href="/pcsubstance/?term=ML277[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML277</a> shows significant instability at the 24 and 48 hour time points, which may result from chemical instability or low solubility.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml277t2"><a href="/books/NBK143558/table/ml277.t2/?report=objectonly" target="object" title="Table 2" class="img_link icnblk_img figpopup" rid-figpopup="figml277t2" rid-ob="figobml277t2"><img class="small-thumb" src="/books/NBK143558/table/ml277.t2/?report=thumb" src-large="/books/NBK143558/table/ml277.t2/?report=previmg" alt="Table 2. Stability as determined for ML277 at 23° C in PBS." /></a><div class="icnblk_cntnt"><h4 id="ml277.t2"><a href="/books/NBK143558/table/ml277.t2/?report=objectonly" target="object" rid-ob="figobml277t2">Table 2</a></h4><p class="float-caption no_bottom_margin">Stability as determined for ML277 at 23° C in PBS. </p></div></div><div id="ml277.fu2" class="figure"><div class="graphic"><img src="/books/NBK143558/bin/ml277fu2.jpg" alt="Image ml277fu2" /></div></div><p><b>Compounds added to the SMR collection (MLS#s):</b> MLS003875054 (<a href="/pcsubstance/?term=ML277[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML277</a>, CID 53347902, 20.1 mg); MLS003875049 (CID 53488270, 3.6 mg); MLS003875050 (CID 25541644, 5.1 mg); MLS003875051 (CID 2313552, 4.8 mg); MLS003875052 (CID 26915367, 4.8 mg); MLS003875053 (CID 25993147, 5.1 mg)</p></div><div id="ml277.s6"><h3>2.3. Probe Preparation</h3><p><b>(R)-N-(4-(4-methoxyphenyl)thiazol-2-yl)-1-tosylpiperidine-2-carboxamide (<a href="/pcsubstance/?term=ML277[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML277</a>, CID 53347902).</b> To a solution of 4-(4-methoxyphenyl)thiazol-2-amine, 2, in DMF (0.65 mmol, 0.4M) was added in order O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU; 0.72 mmol), N,N-Diisopropylethylamine (DIEA; 2 mmol), and (R)-1-(tert-butoxycarbonyl)piperidine-2-carboxylic acid, 1, (0.65 mmol). The mixture was stirred overnight at room temperature. The reaction mixture was dissolved in 5× volume H<sub>2</sub>O and extracted with dichloromethane (DCM), then concentrated in vacuo. The product was purified by column chromatography (ethyl acetate and hexanes, ramp to 50% ethyl acetate).</p><p>The Boc-protected intermediate was subsequently dissolved in minimal DCM. To this was added equivolume TFA and the deprotection proceeded at room temperature for 2 hours, at which time the reaction mixture was concentrated in vacuo.</p><p>The final compound was afforded by dissolving the deprotected intermediate (0.57 mmol) in DCM (0.1 M). To this solution was added triethylamine (1.14 mmol) and p-Toluenesulfonyl chloride (TsCl; 0.63 mmol). After stirring overnight at room temperature, the reaction mixture was washed with saturated sodium bicarbonate and brine, and passed through a phase separator. The mixture was concentrated in vacuo and purified by HPLC.</p></div></div><div id="ml277.s7"><h2 id="_ml277_s7_">3. Results</h2><div id="ml277.s8"><h3>3.1. Dose Response Curves for Probe</h3><p><a href="/pcsubstance/?term=ML277[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML277</a> displayed potent activation of KCNQ1 channels in automated electrophysiology experiments using IonWorks instruments. The protocol used to evaluate activation of KCNQ1 channels is shown in <a class="figpopup" href="/books/NBK143558/figure/ml277.f2/?report=objectonly" target="object" rid-figpopup="figml277f2" rid-ob="figobml277f2">Figure 2A</a>. Currents from a representative well (<a class="figpopup" href="/books/NBK143558/figure/ml277.f2/?report=objectonly" target="object" rid-figpopup="figml277f2" rid-ob="figobml277f2">Figure 2A</a>) were significantly increased by 0.3 μM <a href="/pcsubstance/?term=ML277[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML277</a>. In dose-response experiments (<a class="figpopup" href="/books/NBK143558/figure/ml277.f2/?report=objectonly" target="object" rid-figpopup="figml277f2" rid-ob="figobml277f2">Figure 2B</a>) <a href="/pcsubstance/?term=ML277[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML277</a> displayed an EC<sub>50</sub> value of 260 nM and produced a 266% enhancement of KCNQ1 current amplitudes at +40 mV.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml277f2" co-legend-rid="figlgndml277f2"><a href="/books/NBK143558/figure/ml277.f2/?report=objectonly" target="object" title="Figure 2" class="img_link icnblk_img figpopup" rid-figpopup="figml277f2" rid-ob="figobml277f2"><img class="small-thumb" src="/books/NBK143558/bin/ml277f2.gif" src-large="/books/NBK143558/bin/ml277f2.jpg" alt="Figure 2. Enhancement of KCNQ1 currents by ML277 on IonWorks Quattro." /></a><div class="icnblk_cntnt" id="figlgndml277f2"><h4 id="ml277.f2"><a href="/books/NBK143558/figure/ml277.f2/?report=objectonly" target="object" rid-ob="figobml277f2">Figure 2</a></h4><p class="float-caption no_bottom_margin">Enhancement of KCNQ1 currents by ML277 on IonWorks Quattro. A) KCNQ1 currents from a single well in the absence and presence of 0.1 μM ML277 are shown. B) ML277 activated KCNQ1 currents in a dose-dependent manner with EC<sub>50</sub> value of 260 nM, a 266% <a href="/books/NBK143558/figure/ml277.f2/?report=objectonly" target="object" rid-ob="figobml277f2">(more...)</a></p></div></div><div id="ml277.s9"><h4>Scaffold/Moiety Chemical Liabilities</h4><p>No chemical liabilities for the probe molecule have been identified at the present time.</p></div></div><div id="ml277.s10"><h3>3.2. Cellular Activity</h3><p>The primary HTS assay and all secondary assays are cell-based assays, indicating that <a href="/pcsubstance/?term=ML277[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML277</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.</p></div><div id="ml277.s11"><h3>3.3. Profiling Assays</h3><p><a href="/pcsubstance/?term=ML277[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML277</a> (CID 53347901) is a newly synthesized compound and has not been tested in assays performed within the MLPCN network.</p><p>The selectivity profile of <a href="/pcsubstance/?term=ML277[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML277</a> was examined in Ricerca’s (formerly MDS Pharma’s) Lead Profiling Screen (binding assay panel of 68 GPCRs, ion channels and transporters screened at 10 μM), and was found to bind with only 6 of the 68 assays conducted (no inhibition of radio ligand binding > 50% at 10 μM) (<a class="figpopup" href="/books/NBK143558/table/ml277.t3/?report=objectonly" target="object" rid-figpopup="figml277t3" rid-ob="figobml277t3">Table 3</a>). <a href="/pcsubstance/?term=ML277[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML277</a> did have activity against several targets (see <a class="figpopup" href="/books/NBK143558/table/ml277.t1/?report=objectonly" target="object" rid-figpopup="figml277t1" rid-ob="figobml277t1">Table 1</a>); however, it should be pointed out that these are only single-point values and that functional selectivity may be significantly better than suggested by these “% activities.” This is highlighted by the fact that <a href="/pcsubstance/?term=ML277[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML277</a> was shown to have 80% inhibition @ 10 μM against the hERG channel. However, further profiling studies at Johns Hopkins University showed that in a functional assay <a href="/pcsubstance/?term=ML277[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML277</a> had no activity against hERG up to 30 μM. In addition, <a href="/pcsubstance/?term=ML277[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML277</a> was shown to weakly inhibit the Calcium L-Type channel (~55% at 10 μM); this will be further evaluated in the extended probe phase. These discrepancies are not uncommon and as such, these binding activities only point to receptors to be evaluated.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml277t3"><a href="/books/NBK143558/table/ml277.t3/?report=objectonly" target="object" title="Table 3" class="img_link icnblk_img figpopup" rid-figpopup="figml277t3" rid-ob="figobml277t3"><img class="small-thumb" src="/books/NBK143558/table/ml277.t3/?report=thumb" src-large="/books/NBK143558/table/ml277.t3/?report=previmg" alt="Table 3. Ricerca Profiling of SID 125081894/VU0458298-1." /></a><div class="icnblk_cntnt"><h4 id="ml277.t3"><a href="/books/NBK143558/table/ml277.t3/?report=objectonly" target="object" rid-ob="figobml277t3">Table 3</a></h4><p class="float-caption no_bottom_margin">Ricerca Profiling of SID 125081894/VU0458298-1. </p></div></div><p><a href="/pcsubstance/?term=ML277[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML277</a> selectivity for blocking KCNQ channel family members was examined using automated electrophysiology as described in <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/493009" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 493009</a>. <a href="/pcsubstance/?term=ML277[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML277</a> caused no significant changes (<25% up to 30 μM) in the amplitudes of KCNQ2 or KCNQ4 currents indicating greater than 100-fold selectivity for activation of KCNQ1 channels compared with KCNQ2 and KCNQ4 channels. In addition, <a href="/pcsubstance/?term=ML277[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML277</a> produced no significant block of hERG potassium channels up to 30 μM indicating more than 100-fold selectivity for KCNQ1 compared with hERG. The recombinant cells expressing other KCNQ and hERG channels were made from the same parental CHO-K1 cells used to express KCNQ1, which indicates that the compound <a href="/pcsubstance/?term=ML277[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML277</a> doesn’t affect endogenous channels or membrane properties of the host CHO-K1 cells.</p><div id="ml277.t4" class="table"><h3><span class="label">Table 4</span><span class="title">Effects of ML277 on activation of KCNQ2, KCNQ4 and inhibition of hERG channels</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK143558/table/ml277.t4/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml277.t4_lrgtbl__"><table class="no_margin"><thead><tr><th id="hd_h_ml277.t4_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Cmpd</th><th id="hd_h_ml277.t4_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">KCNQ1 (EC<sub>50</sub>)</th><th id="hd_h_ml277.t4_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">KCNQ2 (μM)</th><th id="hd_h_ml277.t4_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">KCNQ4 (μM)</th><th id="hd_h_ml277.t4_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">hERG (μM)</th></tr></thead><tbody><tr><td headers="hd_h_ml277.t4_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"><a href="/pcsubstance/?term=ML277[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML277</a></td><td headers="hd_h_ml277.t4_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">261 nM</td><td headers="hd_h_ml277.t4_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">>30</td><td headers="hd_h_ml277.t4_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">>30</td><td headers="hd_h_ml277.t4_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">>30</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div id="ml277.tfn1"><p class="no_margin">EC<sub>50</sub> values are plotted for KCNQ1, KCNQ2 and KCNQ4 channels. IC<sub>50</sub> value is given for hERG.</p></div></dd></dl></div></div></div></div></div><div id="ml277.s12"><h2 id="_ml277_s12_">4. Discussion</h2><div id="ml277.s13"><h3>4.1. Comparison to Existing Art and How the New Probe is an Improvement</h3><p>Few potent and selective KCNQ1 channels have been described in the scientific or patent literature (<a class="figpopup" href="/books/NBK143558/table/ml277.t5/?report=objectonly" target="object" rid-figpopup="figml277t5" rid-ob="figobml277t5">Table 5</a>). R-L3 (L-363,373) enhances KCNQ1 currents expressed in Xenopus oocytes [<a class="bk_pop" href="#ml277.r5">5</a>, <a class="bk_pop" href="#ml277.r6">6</a>] at micromolar concentrations, but selectivity data for this compound against other KCNQ isoforms are not available. In IonWorks automated electrophysiology experiments, R-L3 produced modest activation of KCNQ1 channels, displaying a 0.96 μM EC<sub>50</sub> value for channel activation and produced a 68% maximal increase in current magnitude. Zinc pyrithione (ZnPy) activates KCNQ1 channels (EC<sub>50</sub>=3.5 μM), but additionally activates KCNQ2, KCNQ4 and KCNQ5 channels[<a class="bk_pop" href="#ml277.r7">7</a>]. Phenyl boronic acid (PBA) modulated KCNQ1 channels with a complex phenotype with kinetically distinct inhibitory and stimulatory phases[<a class="bk_pop" href="#ml277.r8">8</a>]. The EC<sub>50</sub> for enhancement of KCNQ1 currents (0.1 mM) occurred at lower concentrations than for other KCNQ channels, but the low potency, complex time-course for modulation, and effects on other voltage-gated potassium channels will limit the use of this molecule in pharmacological experiments. Amato and colleagues [<a class="bk_pop" href="#ml277.r9">9</a>] describe a series of N-pyridyl benzamide analogues that activate KCNQ2/3 channels. A few of these compounds also activate KCNQ1 channels at micromolar concentrations, but show increased activity for KCNQ2/3 channels. As can be seen in <a class="figpopup" href="/books/NBK143558/table/ml277.t5/?report=objectonly" target="object" rid-figpopup="figml277t5" rid-ob="figobml277t5">Table 5</a>, these compounds are either weak KCNQ1 activators, display no selectivity for the KCNQ1 channel, or are chemical structures that cannot be used in a meaningful manner to determine channel function due to other reactive functional groups.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml277t5"><a href="/books/NBK143558/table/ml277.t5/?report=objectonly" target="object" title="Table 5" class="img_link icnblk_img figpopup" rid-figpopup="figml277t5" rid-ob="figobml277t5"><img class="small-thumb" src="/books/NBK143558/table/ml277.t5/?report=thumb" src-large="/books/NBK143558/table/ml277.t5/?report=previmg" alt="Table 5. Structures and activities of known KCNQ1 activators." /></a><div class="icnblk_cntnt"><h4 id="ml277.t5"><a href="/books/NBK143558/table/ml277.t5/?report=objectonly" target="object" rid-ob="figobml277t5">Table 5</a></h4><p class="float-caption no_bottom_margin">Structures and activities of known KCNQ1 activators. </p></div></div><p>Searches of the patent literature at USPTO.GOV and using Google Patents revealed few applications or issued US patents claiming compounds that activate KCNQ1 channels. US2011/0257146 claims ZnPy as a KCNQ1 activator, but this compound is also described in the scientific literature.</p></div></div><div id="ml277.s14"><h2 id="_ml277_s14_">5. References</h2><dl class="temp-labeled-list"><dt>1.</dt><dd><div class="bk_ref" id="ml277.r1">Yasuda K, et al. Variants in KCNQ1 are associated with susceptibility to type 2 diabetes mellitus. <span><span class="ref-journal">Nat Genet. </span>2008;<span class="ref-vol">40</span>(9):1092–7.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/18711367" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18711367</span></a>]</div></dd><dt>2.</dt><dd><div class="bk_ref" id="ml277.r2">Jonsson A, et al. A variant in the KCNQ1 gene predicts future type 2 diabetes and mediates impaired insulin secretion. <span><span class="ref-journal">Diabetes. </span>2009;<span class="ref-vol">58</span>(10):2409–13.</span> [<a href="/pmc/articles/PMC2750226/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2750226</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19584308" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19584308</span></a>]</div></dd><dt>3.</dt><dd><div class="bk_ref" id="ml277.r3">Boini KM, et al. Enhanced insulin sensitivity of gene-targeted mice lacking functional KCNQ1. <span><span class="ref-journal">Am J Physiol Regul Integr Comp Physiol. </span>2009;<span class="ref-vol">296</span>(6):R1695–701.</span> [<a href="/pmc/articles/PMC2692790/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2692790</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19369585" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19369585</span></a>]</div></dd><dt>4.</dt><dd><div class="bk_ref" id="ml277.r4">Vallon V, et al. KCNQ1-dependent transport in renal and gastrointestinal epithelia. <span><span class="ref-journal">Proc Natl Acad Sci U S A. </span>2005;<span class="ref-vol">102</span>(49):17864–9.</span> [<a href="/pmc/articles/PMC1308898/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1308898</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/16314573" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16314573</span></a>]</div></dd><dt>5.</dt><dd><div class="bk_ref" id="ml277.r5">Salata JJ, et al. A novel benzodiazepine that activates cardiac slow delayed rectifier K+ currents. <span><span class="ref-journal">Mol Pharmacol. </span>1998;<span class="ref-vol">54</span>(1):220–30.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/9658209" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9658209</span></a>]</div></dd><dt>6.</dt><dd><div class="bk_ref" id="ml277.r6">Seebohm G, et al. Pharmacological activation of normal and arrhythmia-associated mutant KCNQ1 potassium channels. <span><span class="ref-journal">Circ Res. </span>2003;<span class="ref-vol">93</span>(10):941–7.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/14576198" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 14576198</span></a>]</div></dd><dt>7.</dt><dd><div class="bk_ref" id="ml277.r7">Gao Z, et al. Desensitization of chemical activation by auxiliary subunits: convergence of molecular determinants critical for augmenting KCNQ1 potassium channels. <span><span class="ref-journal">J Biol Chem. </span>2008;<span class="ref-vol">283</span>(33):22649–58.</span> [<a href="/pmc/articles/PMC2504881/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2504881</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/18490447" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18490447</span></a>]</div></dd><dt>8.</dt><dd><div class="bk_ref" id="ml277.r8">Mruk K, Kobertz WR. Discovery of a novel activator of KCNQ1-KCNE1 K channel complexes. <span><span class="ref-journal">PLoS One. </span>2009;<span class="ref-vol">4</span>(1):e4236.</span> [<a href="/pmc/articles/PMC2617778/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2617778</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19156197" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19156197</span></a>]</div></dd><dt>9.</dt><dd><div class="bk_ref" id="ml277.r9">Amato G, et al. N-Pyridyl and Pyrimidine Benzamides as KCNQ2/Q3 Potassium Channel Openers for the Treatment of Epilepsy. <span><span class="ref-journal">ACS Medicinal Chemistry Letters. </span>2011;<span class="ref-vol">2</span>(6):481–484.</span> [<a href="/pmc/articles/PMC4018159/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4018159</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24900334" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 24900334</span></a>]</div></dd><dt>10.</dt><dd><div class="bk_ref" id="ml277.r10">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" ref="pagearea=cite-ref&targetsite=external&targetcat=link&targettype=uri">https://www<wbr style="display:inline-block"></wbr>.absorption.com</a></div></dd><dt>11.</dt><dd><div class="bk_ref" id="ml277.r11">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/NBK143558/?report=reader">PubReader</a></li><li><a href="/books/NBK143558/?report=printable">Print View</a></li><li><a data-jig="ncbidialog" href="#_ncbi_dlg_citbx_NBK143558" data-jigconfig="width:400,modal:true">Cite this Page</a><div id="_ncbi_dlg_citbx_NBK143558" style="display:none" title="Cite this Page"><div class="bk_tt">Yu H, Lin Z, Xu K, et al. Identification of a novel, small molecule activator of KCNQ1 channels. 2011 Dec 16 [Updated 2013 Mar 7]. In: Probe Reports from the NIH Molecular Libraries Program [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2010-. <span class="bk_cite_avail"></span></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="#ml277.s1" ref="log$=inpage&link_id=inpage">Probe Structure & Characteristics</a></li><li><a href="#ml277.s2" ref="log$=inpage&link_id=inpage">Recommendations for Scientific Use of the Probe</a></li><li><a href="#ml277.s3" ref="log$=inpage&link_id=inpage">Materials and Methods</a></li><li><a href="#ml277.s7" ref="log$=inpage&link_id=inpage">Results</a></li><li><a href="#ml277.s12" ref="log$=inpage&link_id=inpage">Discussion</a></li><li><a href="#ml277.s14" ref="log$=inpage&link_id=inpage">References</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Related information</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="discovery_db_links" id="Shutter"></a></div><div class="portlet_content"><ul><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=pmc&DbFrom=books&Cmd=Link&LinkName=books_pmc_refs&IdsFromResult=3036230" ref="log$=recordlinks">PMC</a><div class="brieflinkpop offscreen_noflow">PubMed Central citations</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=pcassay&DbFrom=books&Cmd=Link&LinkName=books_pcassay_probe&IdsFromResult=3036230" ref="log$=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=3036230" ref="log$=recordlinks">PubChem Substance</a><div class="brieflinkpop offscreen_noflow">Related PubChem Substances</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=pubmed&DbFrom=books&Cmd=Link&LinkName=books_pubmed_refs&IdsFromResult=3036230" ref="log$=recordlinks">PubMed</a><div class="brieflinkpop offscreen_noflow">Links to PubMed</div></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Similar articles in PubMed</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="PBooksDiscovery_RA" id="Shutter"></a></div><div class="portlet_content"><ul><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/22910039" ref="ordinalpos=1&linkpos=1&log$=relatedarticles&logdbfrom=pubmed">Identification of (R)-N-(4-(4-methoxyphenyl)thiazol-2-yl)-1-tosylpiperidine-2-carboxamide, ML277, as a novel, potent and selective K(v)7.1 (KCNQ1) potassium channel activator.</a><span class="source">[Bioorg Med Chem Lett. 2012]</span><div class="brieflinkpop offscreen_noflow">Identification of (R)-N-(4-(4-methoxyphenyl)thiazol-2-yl)-1-tosylpiperidine-2-carboxamide, ML277, as a novel, potent and selective K(v)7.1 (KCNQ1) potassium channel activator.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Mattmann ME, Yu H, Lin Z, Xu K, Huang X, Long S, Wu M, McManus OB, Engers DW, Le UM, et al. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">Bioorg Med Chem Lett. 2012 Sep 15; 22(18):5936-41. 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