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<title>A small molecule pan-inhibitor of Ras-superfamily GTPases with high efficacy towards Rab7 - 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="A small molecule pan-inhibitor of Ras-superfamily GTPases with high efficacy towards Rab7" /><meta name="citation_publisher" content="National Center for Biotechnology Information (US)" /><meta name="citation_date" content="2013/03/07" /><meta name="citation_author" content="Lin Hong" /><meta name="citation_author" content="Peter Simons" /><meta name="citation_author" content="Anna Waller" /><meta name="citation_author" content="Juan Strouse" /><meta name="citation_author" content="Zurab Surviladze" /><meta name="citation_author" content="Oleg Ursu" /><meta name="citation_author" content="Cristian Bologa" /><meta name="citation_author" content="Kristine Gouveia" /><meta name="citation_author" content="Jacob O. Agola" /><meta name="citation_author" content="Soumik BasuRay" /><meta name="citation_author" content="Angela Wandinger-Ness" /><meta name="citation_author" content="Larry Sklar" /><meta name="citation_author" content="Denise S. Simpson" /><meta name="citation_author" content="Chad E. Schroeder" /><meta name="citation_author" content="Jennifer E. Golden" /><meta name="citation_author" content="Jeffrey Aubé" /><meta name="citation_pmid" content="23762935" /><meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK143553/" /><link rel="schema.DC" href="http://purl.org/DC/elements/1.0/" /><meta name="DC.Title" content="A small molecule pan-inhibitor of Ras-superfamily GTPases with high efficacy towards Rab7" /><meta name="DC.Type" content="Text" /><meta name="DC.Publisher" content="National Center for Biotechnology Information (US)" /><meta name="DC.Contributor" content="Lin Hong" /><meta name="DC.Contributor" content="Peter Simons" /><meta name="DC.Contributor" content="Anna Waller" /><meta name="DC.Contributor" content="Juan Strouse" /><meta name="DC.Contributor" content="Zurab Surviladze" /><meta name="DC.Contributor" content="Oleg Ursu" /><meta name="DC.Contributor" content="Cristian Bologa" /><meta name="DC.Contributor" content="Kristine Gouveia" /><meta name="DC.Contributor" content="Jacob O. Agola" /><meta name="DC.Contributor" content="Soumik BasuRay" /><meta name="DC.Contributor" content="Angela Wandinger-Ness" /><meta name="DC.Contributor" content="Larry Sklar" /><meta name="DC.Contributor" content="Denise S. Simpson" /><meta name="DC.Contributor" content="Chad E. Schroeder" /><meta name="DC.Contributor" content="Jennifer E. Golden" /><meta name="DC.Contributor" content="Jeffrey Aubé" /><meta name="DC.Date" content="2013/03/07" /><meta name="DC.Identifier" content="https://www.ncbi.nlm.nih.gov/books/NBK143553/" /><meta name="description" content="Low molecular weight guanine triphosphate hydrolases (GTPases) are GTP-binding enzymes that play pivotal roles in cell biology. Grouped into three subfamilies which are designated by function, Ras, Rho and Rab GTPases are involved in signal transduction, cytoskeleton modulation, and macromolecule cargo transport and degradation, respectively. Mutation and aberrant gene expression levels have been linked to human diseases including cancer, immunodeficiencies, and neurological disorders. A high through-put screen of the Molecular Libraries Small Molecule Repository (MLSMR) identified a compound, ML282, which potently inhibits GTPases from all three subfamilies. Importantly, this represents the discovery of the first reported compound to inhibit Rab GTPases, especially Rab7, the mutation of which is a causal factor in a heritable neuropathy called Charcot-Marie-Tooth Type 2B disease. ML282 inhibits Rab7 with an average EC50 = 53.2 ± 0.35 nM and with high response, as compared to other GTPases in the panel. The subsequent structure activity relationships (SAR) and secondary assays demonstrate its use as a molecular probe for both biochemical and cellular studies." /><meta name="og:title" content="A small molecule pan-inhibitor of Ras-superfamily GTPases with high efficacy towards Rab7" /><meta name="og:type" content="book" /><meta name="og:description" content="Low molecular weight guanine triphosphate hydrolases (GTPases) are GTP-binding enzymes that play pivotal roles in cell biology. Grouped into three subfamilies which are designated by function, Ras, Rho and Rab GTPases are involved in signal transduction, cytoskeleton modulation, and macromolecule cargo transport and degradation, respectively. Mutation and aberrant gene expression levels have been linked to human diseases including cancer, immunodeficiencies, and neurological disorders. A high through-put screen of the Molecular Libraries Small Molecule Repository (MLSMR) identified a compound, ML282, which potently inhibits GTPases from all three subfamilies. Importantly, this represents the discovery of the first reported compound to inhibit Rab GTPases, especially Rab7, the mutation of which is a causal factor in a heritable neuropathy called Charcot-Marie-Tooth Type 2B disease. ML282 inhibits Rab7 with an average EC50 = 53.2 ± 0.35 nM and with high response, as compared to other GTPases in the panel. The subsequent structure activity relationships (SAR) and secondary assays demonstrate its use as a molecular probe for both biochemical and cellular studies." /><meta name="og:url" content="https://www.ncbi.nlm.nih.gov/books/NBK143553/" /><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/ml282/" /><link rel="canonical" href="https://www.ncbi.nlm.nih.gov/books/NBK143553/" /><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="/core/mathjax/2.7.9/MathJax.js?config=/corehtml/pmc/js/mathjax-config-classic.3.4.js"></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="#__NBK143553_dtls__">Show details</a><div style="display:none" class="ui-widget" id="__NBK143553_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/ml283/" title="Previous page in this title">< Prev</a><a class="active page_link next" href="/books/n/mlprobe/ml281/" 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="_NBK143553_"><span class="title" itemprop="name">A small molecule pan-inhibitor of Ras-superfamily GTPases with high efficacy towards Rab7</span></h1><p class="contrib-group"><span itemprop="author">Lin Hong</span>, <span itemprop="author">Peter Simons</span>, <span itemprop="author">Anna Waller</span>, <span itemprop="author">Juan Strouse</span>, <span itemprop="author">Zurab Surviladze</span>, <span itemprop="author">Oleg Ursu</span>, <span itemprop="author">Cristian Bologa</span>, <span itemprop="author">Kristine Gouveia</span>, <span itemprop="author">Jacob O. Agola</span>, <span itemprop="author">Soumik BasuRay</span>, <span itemprop="author">Angela Wandinger-Ness</span>, <span itemprop="author">Larry Sklar</span>, <span itemprop="author">Denise S. Simpson</span>, <span itemprop="author">Chad E. Schroeder</span>, <span itemprop="author">Jennifer E. Golden</span>, and <span itemprop="author">Jeffrey Aubé</span>.</p><a data-jig="ncbitoggler" href="#__NBK143553_ai__" style="border:0;text-decoration:none">Author Information and Affiliations</a><div style="display:none" class="ui-widget" id="__NBK143553_ai__"><p class="contrib-group"><h4>Authors</h4><span itemprop="author">Lin Hong</span>,<sup>1,2</sup> <span itemprop="author">Peter Simons</span>,<sup>1,2</sup> <span itemprop="author">Anna Waller</span>,<sup>1,2</sup> <span itemprop="author">Juan Strouse</span>,<sup>1,2</sup> <span itemprop="author">Zurab Surviladze</span>,<sup>1,2</sup> <span itemprop="author">Oleg Ursu</span>,<sup>3</sup> <span itemprop="author">Cristian Bologa</span>,<sup>3</sup> <span itemprop="author">Kristine Gouveia</span>,<sup>2</sup> <span itemprop="author">Jacob O. Agola</span>,<sup>4</sup> <span itemprop="author">Soumik BasuRay</span>,<sup>4</sup> <span itemprop="author">Angela Wandinger-Ness</span>,<sup>4</sup> <span itemprop="author">Larry Sklar</span>,<sup>1,2</sup><sup>,7</sup> <span itemprop="author">Denise S. Simpson</span>,<sup>5</sup> <span itemprop="author">Chad E. Schroeder</span>,<sup>5</sup> <span itemprop="author">Jennifer E. Golden</span>,<sup>5</sup> and <span itemprop="author">Jeffrey Aubé</span><sup>5,6</sup>.</p><h4>Affiliations</h4><div class="affiliation"><sup>1</sup>
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Department of Cytometry, University of New Mexico, Albuquerque, NM</div><div class="affiliation"><sup>2</sup>
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Univeristy of New Mexico Center for Molecular Discovery, Albuquerque, NM</div><div class="affiliation"><sup>3</sup>
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Division of Biocomputing, University of New Mexico, Albuquerque, NM</div><div class="affiliation"><sup>4</sup>
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Department of Cell Biology, University of New Mexico, Albuquerque, NM</div><div class="affiliation"><sup>5</sup>
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University of Kansas Specialized Chemistry Center, Lawrence, KS</div><div class="affiliation"><sup>6</sup>
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Department of Medicinal Chemistry, University of Kansas, Lawrence, KS</div><div class="affiliation">
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<sup>7</sup> Corresponding author’s email:
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<a href="mailto:dev@null" data-email="ude.mnu.dulas@ralksl" class="oemail">ude.mnu.dulas@ralksl</a></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>Low molecular weight guanine triphosphate hydrolases (GTPases) are GTP-binding enzymes that play pivotal roles in cell biology. Grouped into three subfamilies which are designated by function, Ras, Rho and Rab GTPases are involved in signal transduction, cytoskeleton modulation, and macromolecule cargo transport and degradation, respectively. Mutation and aberrant gene expression levels have been linked to human diseases including cancer, immunodeficiencies, and neurological disorders. A high through-put screen of the Molecular Libraries Small Molecule Repository (MLSMR) identified a compound, <a href="/pcsubstance/?term=ML282[synonym]" ref="pagearea=abstract&targetsite=entrez&targetcat=term&targettype=pubchem">ML282</a>, which potently inhibits GTPases from all three subfamilies. Importantly, this represents the discovery of the first reported compound to inhibit Rab GTPases, especially Rab7, the mutation of which is a causal factor in a heritable neuropathy called Charcot-Marie-Tooth Type 2B disease. <a href="/pcsubstance/?term=ML282[synonym]" ref="pagearea=abstract&targetsite=entrez&targetcat=term&targettype=pubchem">ML282</a> inhibits Rab7 with an average EC<sub>50</sub> = 53.2 ± 0.35 nM and with high response, as compared to other GTPases in the panel. The subsequent structure activity relationships (SAR) and secondary assays demonstrate its use as a molecular probe for both biochemical and cellular studies.</p></div><div class="h2"></div><p><b>Assigned Assay Grant #:</b> MH081231-01</p><p><b>Screening Center Name & PI:</b> UNM Center for Molecular Discovery, Larry Sklar</p><p><b>Chemistry Center Name & PI:</b> University of Kansas Specialized Chemistry Center, Jeffrey Aubé</p><p><b>Assay Submitter & Institution:</b> Angela Wandinger-Ness, UNM</p><p><b>PubChem Summary Bioassay Identifier (AID):</b>
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<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1772" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1772</a></p><div id="ml282.s1"><h2 id="_ml282_s1_">Probe Structure & Characteristics</h2><div id="ml282.fu1" class="figure"><div class="graphic"><img src="/books/NBK143553/bin/ml282fu1.jpg" alt="Image ml282fu1" /></div></div><div id="ml282.t1" class="table"><h3><span class="label">Table 1</span><span class="title">Probe ML282 Assay Data Summary</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK143553/table/ml282.t1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml282.t1_lrgtbl__"><table class="no_margin"><thead><tr><th id="hd_h_ml282.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID/ML#</th><th id="hd_h_ml282.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Target Name</th><th id="hd_h_ml282.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">EC<sub>50</sub> (nM) [SID]<sup><a class="bk_pop" href="#ml282.tfn1">a</a></sup></th><th id="hd_h_ml282.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Anti-target Name(s)</th><th id="hd_h_ml282.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">EC<sub>50</sub> (μM) [SID, AID]<sup><a class="bk_pop" href="#ml282.tfn1">a</a></sup></th><th id="hd_h_ml282.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Fold Selective</th><th id="hd_h_ml282.t1_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Secondary Assay(s) Name: EC<sub>50</sub> (nM) [SID, AID]<sup><a class="bk_pop" href="#ml282.tfn1">a</a></sup><sup>,</sup><sup><a class="bk_pop" href="#ml282.tfn6">f</a></sup></th><th id="hd_h_ml282.t1_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Secondary Assay(s) Name: EC<sub>50</sub> (nM) [SID, AID]<sup><a class="bk_pop" href="#ml282.tfn1">a</a></sup>,<sup>g</sup></th><th id="hd_h_ml282.t1_1_1_1_9" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Secondary Assay(s) Name: EC<sub>50</sub> (nM) [SID, AID]<sup><a class="bk_pop" href="#ml282.tfn1">a</a></sup></th></tr></thead><tbody><tr><td headers="hd_h_ml282.t1_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">CID 1067700/<a href="/pcsubstance/?term=ML282[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML282</a></td><td headers="hd_h_ml282.t1_1_1_1_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">Rab7</td><td headers="hd_h_ml282.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">53.2 ± 0.35 <sup><a class="bk_pop" href="#ml282.tfn2">b</a></sup></td><td headers="hd_h_ml282.t1_1_1_1_4" rowspan="22" colspan="1" style="text-align:center;vertical-align:middle;">Glutathione S-transferase</td><td headers="hd_h_ml282.t1_1_1_1_5" rowspan="22" colspan="1" style="text-align:center;vertical-align:middle;">>100<br /><br /><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/602137" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 602137</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/602145" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 602145</a></td><td headers="hd_h_ml282.t1_1_1_1_6" rowspan="22" colspan="1" style="text-align:center;vertical-align:middle;">>100</td><td headers="hd_h_ml282.t1_1_1_1_7" rowspan="22" colspan="1" style="text-align:center;vertical-align:middle;">Cellular viability of U937 cell line: not toxic<br /><br />EC<sub>50</sub> >20000<br /><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588369" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 588369</a></td><td headers="hd_h_ml282.t1_1_1_1_8" rowspan="22" colspan="1" style="text-align:center;vertical-align:middle;">VLA4 binding in U937 ΔST cell: active<br /><br />EC<sub>50</sub> ~50<br /><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/602148" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 602148</a></td><td headers="hd_h_ml282.t1_1_1_1_9" rowspan="22" colspan="1" style="text-align:center;vertical-align:middle;">EGFR degradation in SCC-12F cell: active<br />EC<sub>50</sub> < 10<br /><br /><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/602146" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 602146</a></td></tr><tr><td headers="hd_h_ml282.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">AIDs <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588394" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">588394</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588631" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">588631</a></td></tr><tr><td headers="hd_h_ml282.t1_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">CID 1067700/<a href="/pcsubstance/?term=ML282[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML282</a></td><td headers="hd_h_ml282.t1_1_1_1_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">Ras wild Type</td><td headers="hd_h_ml282.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">49.1 ± 1.41<sup><a class="bk_pop" href="#ml282.tfn2">b</a></sup></td></tr><tr><td headers="hd_h_ml282.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588388" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 588388</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588630" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">588630</a></td></tr><tr><td headers="hd_h_ml282.t1_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">CID 1067700/<a href="/pcsubstance/?term=ML282[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML282</a></td><td headers="hd_h_ml282.t1_1_1_1_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">Ras activated</td><td headers="hd_h_ml282.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">51.5 ± 2.83 <sup><a class="bk_pop" href="#ml282.tfn2">b</a></sup></td></tr><tr><td headers="hd_h_ml282.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588387" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 588387</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588628" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 588628</a></td></tr><tr><td headers="hd_h_ml282.t1_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">CID 1067700/<a href="/pcsubstance/?term=ML282[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML282</a></td><td headers="hd_h_ml282.t1_1_1_1_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">Cdc42 wild type</td><td headers="hd_h_ml282.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">130.0 ± 23.0 <sup><a class="bk_pop" href="#ml282.tfn2">b</a></sup></td></tr><tr><td headers="hd_h_ml282.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588385" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 588385</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588626" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 588626</a></td></tr><tr><td headers="hd_h_ml282.t1_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">CID 1067700/<a href="/pcsubstance/?term=ML282[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML282</a></td><td headers="hd_h_ml282.t1_1_1_1_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">Cdc42 activated</td><td headers="hd_h_ml282.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">91.0 ± 4.0 <sup><a class="bk_pop" href="#ml282.tfn2">b</a></sup></td></tr><tr><td headers="hd_h_ml282.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588384" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 588384</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588624" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 588624</a></td></tr><tr><td headers="hd_h_ml282.t1_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">CID 1067700/<a href="/pcsubstance/?term=ML282[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML282</a></td><td headers="hd_h_ml282.t1_1_1_1_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">Rho wild type</td><td headers="hd_h_ml282.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">79.5 ± 3.54 <sup><a class="bk_pop" href="#ml282.tfn3">c</a></sup></td></tr><tr><td headers="hd_h_ml282.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">AIDs <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588479" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">588479</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588622" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 588622</a></td></tr><tr><td headers="hd_h_ml282.t1_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">CID 1067700/<a href="/pcsubstance/?term=ML282[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML282</a></td><td headers="hd_h_ml282.t1_1_1_1_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">Rac1 wild type</td><td headers="hd_h_ml282.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">62.1 ± 32.5 <sup><a class="bk_pop" href="#ml282.tfn3">c</a></sup></td></tr><tr><td headers="hd_h_ml282.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">AIDs <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588479" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">588479</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588622" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 588622</a></td></tr><tr><td headers="hd_h_ml282.t1_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">CID 1067700/<a href="/pcsubstance/?term=ML282[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML282</a></td><td headers="hd_h_ml282.t1_1_1_1_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">Rac1 activated</td><td headers="hd_h_ml282.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">76.5 ± 24.7 <sup><a class="bk_pop" href="#ml282.tfn3">c</a></sup></td></tr><tr><td headers="hd_h_ml282.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">AIDs <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588479" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">588479</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588622" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 588622</a></td></tr><tr><td headers="hd_h_ml282.t1_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">CID 1067700/<a href="/pcsubstance/?term=ML282[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML282</a></td><td headers="hd_h_ml282.t1_1_1_1_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">Rab7</td><td headers="hd_h_ml282.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">37.9 ± 10.0 <sup><a class="bk_pop" href="#ml282.tfn4">d</a></sup></td></tr><tr><td headers="hd_h_ml282.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">AIDs <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588479" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">588479</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588622" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 588622</a></td></tr><tr><td headers="hd_h_ml282.t1_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">CID 1067700/<a href="/pcsubstance/?term=ML282[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML282</a></td><td headers="hd_h_ml282.t1_1_1_1_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">Cdc42 wild type</td><td headers="hd_h_ml282.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">64.5 ± 28.3 <sup><a class="bk_pop" href="#ml282.tfn3">c</a></sup></td></tr><tr><td headers="hd_h_ml282.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">AIDs <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588479" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">588479</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588622" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 588622</a></td></tr><tr><td headers="hd_h_ml282.t1_1_1_1_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">CID 1067700/<a href="/pcsubstance/?term=ML282[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML282</a></td><td headers="hd_h_ml282.t1_1_1_1_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">Cdc42 activated</td><td headers="hd_h_ml282.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">129.0 ± 30.0 <sup><a class="bk_pop" href="#ml282.tfn5">e</a></sup></td></tr><tr><td headers="hd_h_ml282.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">AIDs <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588479" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">588479</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588622" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 588622</a></td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt>a</dt><dd><div id="ml282.tfn1"><p class="no_margin">Reported data is an average of the EC<sub>50</sub> values from two separate lots of <a href="/pcsubstance/?term=ML282[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML282</a> (SIDs <a href="https://pubchem.ncbi.nlm.nih.gov/substance/57578339" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">57578339</a> and <a href="https://pubchem.ncbi.nlm.nih.gov/substance/85747738" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">85747738</a>) unless otherwise noted</p></div></dd><dt>b</dt><dd><div id="ml282.tfn2"><p class="no_margin">Reported dose response data was obtained with 100nM GTP, 1mM EDTA and is an average of the EC<sub>50</sub> values from two separate lots of <a href="/pcsubstance/?term=ML282[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML282</a> (<a href="https://pubchem.ncbi.nlm.nih.gov/substance/57578339" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 57578339</a> and <a href="https://pubchem.ncbi.nlm.nih.gov/substance/85747738" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 85747738</a> reported.</p></div></dd><dt>c</dt><dd><div id="ml282.tfn3"><p class="no_margin">Reported dose response data was obtained with 1nM GTP, 1mM Mg<sup>2+</sup> and is an average of the EC<sub>50</sub> values from two separate lots of <a href="/pcsubstance/?term=ML282[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML282</a> (<a href="https://pubchem.ncbi.nlm.nih.gov/substance/57578339" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 57578339</a> and <a href="https://pubchem.ncbi.nlm.nih.gov/substance/85747738" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 85747738</a> reported.</p></div></dd><dt>d</dt><dd><div id="ml282.tfn4"><p class="no_margin">Reported dose response data was obtained with 1nM GTP, 1mM Mg<sup>2+</sup> and represents only <a href="https://pubchem.ncbi.nlm.nih.gov/substance/85747738" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 85747738</a></p></div></dd><dt>e</dt><dd><div id="ml282.tfn5"><p class="no_margin">Reported dose response data was obtained with 1nM GTP, 1mM Mg<sup>2+</sup> and represents only <a href="https://pubchem.ncbi.nlm.nih.gov/substance/57578339" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 57578339</a></p></div></dd><dt>f</dt><dd><div id="ml282.tfn6"><p class="no_margin">Reported in <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588369" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 588369</a> and <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588410" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 588410</a> for respective <a href="https://pubchem.ncbi.nlm.nih.gov/substance/57578339" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 57578339</a> and <a href="https://pubchem.ncbi.nlm.nih.gov/substance/85747738" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 85747738</a>.</p></div></dd></dl></div></div></div></div><div id="ml282.s2"><h2 id="_ml282_s2_">1. Recommendations for Scientific Use of the Probe</h2><p><u>Limitations in the current state of the art being addressed by the probe:</u> This is a first-in-class probe that inhibits guanine nucleotide binding. Currently, there no reported compounds that are active against Rab family GTPases, and selective inhibitors of other GTPases are rare. The first reported GTPase inhibitors were discovered using cellular assays in which the anchoring of GTPase to membranes was blocked. Since the localization of GTPase to membranes is mediated through farnesyltransferase and prenyltransferase, the lipid transferase turned out to be the true target. However, since lipid transferases have a broad range of substrates, these inhibitors lack specificity and have been disappointing in clinical trials [<a class="bk_pop" href="#ml282.r1">1</a>]. Selective and direct GTPase inhibitors, though rare, are possible. Previously, our team identified and reported <a href="/pcsubstance/?term=ML141[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML141</a>, a probe that specifically inhibits Cdc42 and its active mutant by blocking nucleotide binding [<a class="bk_pop" href="#ml282.r2">2</a>]. Brefeldin A, a fungal metabolite, has been determined to promote the formation of an inactive complex of Arf and Arf GEF, thus blocking Arf activation [<a class="bk_pop" href="#ml282.r3">3</a>–<a class="bk_pop" href="#ml282.r4">4</a>]. These compounds have activities in the micromolar range and are specific towards a single GTPase. Through virtual screening, a compound has been discovered to specifically inhibit Rac1 [<a class="bk_pop" href="#ml282.r5">5</a>]. Compared to the compounds mentioned above, probe <a href="/pcsubstance/?term=ML282[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML282</a> has an improved activity of about 100-fold and shows inhibition towards all of the GTPases tested to date.</p><p><u>Use of the probe and relevant biology to which the probe can be applied:</u> As a non-selective, Ras-family GTPase inhibitor, <a href="/pcsubstance/?term=ML282[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML282</a> will serve several purposes. It will be a useful control compound for identifying specific GTPase inhibitors, analogous to the pan-kinase inhibitor, staurosporine, used in kinase inhibitor screening campaigns being conducted across academia and industry. Secondly, since the functions of subfamily GTPases often overlap, <a href="/pcsubstance/?term=ML282[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML282</a> could block these collective functions, thereby facilitating the discovery of new biological targets other than a GTPase that play a role in a particular biological process. Thirdly, the combined use of a selective and pan-inhibitor will help to define the function of individual GTPases. For instance, if the phenotypes of filopodia formation are the same for cells treated with either a Cdc42-specific inhibitor or the pan-inhibitor, it can be inferred that Cdc42 is exclusively accountable for filopodia formation. Lastly, <a href="/pcsubstance/?term=ML282[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML282</a> is the only reported small molecule compound that shows inhibitory activity for against Rab GTPases, including Rab7. For Rab7-related diseases, <a href="/pcsubstance/?term=ML282[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML282</a> provides a starting point for medicinal chemistry to develop Rab7 specific inhibitors.</p></div><div id="ml282.s3"><h2 id="_ml282_s3_">2. Materials and Methods</h2><div id="ml282.s4"><h3>Materials and Instrumentation</h3><p>GST-tagged GTPases were from Cytoskeleton (Denver, CO) and Rab7 was purified by the assay provider. BODIPY (4,4-difluoro-4-bora-3a,4a-diaza-s-indacene or dipyrromethene boron difluoride) nucleotide analogues (BODIPY FL GTP 2′-(or 3′)-O-[N-(2-aminoethyl)urethane] G-35778 and BODIPY FL GDP 2′-(or-3′)-O-[N-(2-aminoethyl)urethane], G-22360) were from Invitrogen Molecular Probes (Carlsbad, CA). 2-(benzoylcarbamothioylamino)-5, 5-dimethyl-4, 7- dihydrothieno[2,3-c]pyran-3-carboxylic acid (CID 1067700) was from ChemDiv and from University of Kansas Specialized Chemistry Center, which also supplied analogs to CID 1067700. Detergents Nonidet P-40 and Tween 20 were from Sigma (St. Louis, MO) and Bio-Rad (Hercules, CA), respectively. Precision Plus Protein™ Standards were also purchased from Bio-Rad. For cell permeabilization, CelLytic™M Cell Lysis Reagent, Protein Inhibitor Cocktail for Mammalian Cells and phenylmethanesulfonyl fluoride were from Sigma. BCA protein assay kit was from Thermo Fisher Scientific (Waltham, MA). EGF Receptor Rabbit mAb was from Cell Signaling (Danvers, MA). Anti-actin antibody produced in rabbit was from Sigma. Stabilized goat anti-rabbit IgG with peroxidase conjugated and SuperSignal West Dura were from Thermo Fisher Scientific. Recombinant human epidermal growth factor, EGF, was purchased from Invitrogen. Cycloheximide was from Sigma. The sequences of peptide LDV, FITC-LDV, and <i>N</i>-formyl peptide have been described before [<a class="bk_pop" href="#ml282.r6">6</a>] and are products of Biogen Idec (San Diego, CA).</p><p>The CyAn<sub>ADP</sub> flow instrument and Biomek FX are products of Beckman Coulter (Indianapolis, IN). Low volume transfers (100 nL) were done via pintool (V&P Scientific; San Diego, CA). FACScan flow instrument is from Becton Dickinson (Franklin Lakes, NJ). Cyto-Plex™ Microspheres (4.0 μm) are from Thermo Fisher Scientific. Quantum™ FITC-5MESF is from Bangs Laboratories, Inc (Fishers, IN). Countess Cell Counter is from Life Technologies (Carlsbad, CA). The HyperCyt system is from Intellicyt (Albuquerque, NM). ChemiDoc™ XRS+ molecular imager is from Bio-Rad. HyperView software (version 2.5.1, IntelliCyt) was modified to enable specialized analysis functions used in these studies.</p></div><div id="ml282.s5"><h3>Cell culture</h3><p>U937 ΔST cells (a gift from Dr. Eric Prossnitz, Dept. Cell Biology and Physiology, University of New Mexico, Albuquerque, NM) were grown at 37°C in a humidified incubator with 5% CO<sub>2</sub> and 95% air in RPMI 1640 supplemented with 2 mM L-glutamine, 100 units/mL penicillin, 100 μg/mL streptomycin, and 10% heat-inactivated fetal bovine serum. SCC-12F cells (a gift from Dr. Laurie Hudson, Dept. Pharmaceutical Sciences, University of New Mexico, College of Pharmacy, Albuquerque, NM) were grown in a 1:1 mixture of DMEM and nutrient mixture F-12 Ham’s medium supplemented with 10% fetal bovine serum. HeLa cells stably overexpressing Rab7 wild-type (a gift from Dr. Matthew Seaman, Dept. Clinical Biochemistry, Cambridge Institute for Medical Research, Cambridge, UK) were grown in MEM with 10% serum or MEM without serum during starvation.</p></div><div id="ml282.s6"><h3>2.1. Assays</h3><div id="ml282.s7"><h4>Dose-response inhibition</h4><p>The compound was serially diluted 3–fold and the resulting concentrations in the reactions ranged from 100 μM to 15 nM. The eight GTPases were grouped into two sets: Rab7, H-Ras wild type and its V12 mutant, and Cdc42 and its L61 mutant were assayed in a buffer containing 1 mM EDTA, while Rho, Rac1 and its L61 mutant, and Cdc42 and its L61 mutant were assayed in the same buffer but instead containing 1 mM Mg<sup>2+</sup> with Cdc42 and its mutant being tested in both buffers. Besides 1 mM EDTA or 1 mM Mg<sup>2+</sup>, the buffer contained 30 mM HEPES, pH 7.2, 40 mM KCl, 100 mM NaCl, 0.1% (v/v) NP-40 and 1% BSA. For each multiplex reaction, an extra set of beads was included to serve as scavengers to bind any proteins that dissociate from their assigned bead set and thereby reduce interference due to protein dissociation during the assay. As a control, GST-tagged GFP was bound to a set of glutathione beads in a separate reaction to make sure that the fluorescence drop observed in the assay reaction in the presence of a compound was not due to fluorescence quenching of GFP nor interference of GST-tagged protein binding to beads, but due to the bona fide inhibition of fluorescent nucleotide binding.</p><p>The assay protocol has been described previously [<a class="bk_pop" href="#ml282.r2">2</a>, <a class="bk_pop" href="#ml282.r7">7</a>]. Briefly, each individual GST-tagged enzyme was incubated with 4 μm glutathione-coated microsphere beads overnight with gentle rotation. The microsphere beads have different red fluorescence dyes incorporated and therefore could be separated by a flow cytometer. The unbound enzyme was removed by sufficient washing with the buffer. The bead sets were then combined and dispensed to 384-well plates at 5 μL/well. For one plate, 0.5 μg each of the enzymes and 4.0 ×10<sup>4</sup> of each bead were used. Then 100 nL compound was added using Biomek FX followed by the addition of 5 μL/well of BODIPY-FL-GTP (ribose-linked BODIPY). For assays carried out in EDTA-containing buffer, the final concentration of BODIPY-FL-GTP was 100 nM while in Mg buffer, the concentration of BODIPY-FL-GTP was 1 nM. The plate was incubated at 4 °C for 2 h with gentle rotation. The beads were aspirated and delivered with the HyperCyt® instrument and read on CyAnADP flow cytometer. Forward scatter and side scatter was used to define the whole bead population. FL9 channel (ext/em: 635/750LP nm) was used to separate different bead sets each of which was bound with an individual enzyme. FL1 channel (ext/em: 488/530 nm) measures the FITC fluorescence associated with the beads. The data was analyzed by the HyperView® software developed by Dr. Bruce Edward at the University of New Mexico.</p></div><div id="ml282.s8"><h4>Secondary Assays</h4><div id="ml282.s9"><h5>Cytotoxicity of compounds</h5><p>U937 cells were grown to a density of 0.4 × 10<sup>6</sup> cells/mL. Compounds were added to a final concentration of 20 μM or otherwise indicated. As a control, cells were treated with DMSO of the same volume. After 24h incubation, the density and viability of the cells were measured with Countess Cell Counter according to the protocols from the manufacturer.</p></div><div id="ml282.s10"><h5>LDV binding assay</h5><p>The procedure followed the established protocols described previously [<a class="bk_pop" href="#ml282.r6">6</a>,<a class="bk_pop" href="#ml282.r8">8</a>–<a class="bk_pop" href="#ml282.r9">9</a>]. U937 ΔST cells (0.4~0.8 × 10<sup>6</sup> cells/mL) were constantly stirred with a magnetic stir bar at 500 rpm in a test tube. The fluorescence was recorded on a FACScan flow cytometer. The base line fluorescence of the cells was established for 30s. FITC-LDV at a concentration of 4nM was then added. After the fluorescence stabilized at around 120s, the chemotactic ligand <i>N</i>-formyl peptide was added for stimulation resulting activation of VLA-4 integrin and additional FITC-LDV binding. When a plateau was reached at around 280s, compounds at different concentrations were added to the cell suspension. Fluorescence was continually recorded until no further change was observed. The inhibition percentage was calculated according to <a href="#ml282.eq1">Equation 1</a>.</p><div class="pmc_disp_formula whole_rhythm clearfix" id="ml282.eq1"><div class="inline_block pmc_inline_block pmc_va_middle pmc_hide_overflow ten_col">
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||
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<math id="ml282.eq2" display="block"><semantics><mrow><mi>I</mi><mi>n</mi><mi>h</mi><mi>i</mi><mi>b</mi><mi>i</mi><mi>t</mi><mi>i</mi><mi>o</mi><mi>n</mi><mi> </mi><mi>p</mi><mi>e</mi><mi>r</mi><mi>c</mi><mi>e</mi><mi>n</mi><mi>t</mi><mi>a</mi><mi>g</mi><mi>e</mi><mo>=</mo><mrow><mo>(</mo><mrow><mn>1</mn><mo>-</mo><mfrac><mrow><mi>r</mi><mi>e</mi><mi>m</mi><mi>a</mi><mi>i</mi><mi>n</mi><mi>i</mi><mi>n</mi><mi>g</mi><mi> </mi><mi>f</mi><mi>l</mi><mi>u</mi><mi>o</mi><mi>r</mi><mi>e</mi><mi>s</mi><mi>c</mi><mi>e</mi><mi>n</mi><mi>c</mi><mi>e</mi><mi> </mi><mi>a</mi><mi>f</mi><mi>t</mi><mi>e</mi><mi>r</mi><mi> </mi><mi>c</mi><mi>o</mi><mi>m</mi><mi>p</mi><mi>o</mi><mi>u</mi><mi>n</mi><mi>d</mi><mi> </mi><mi>t</mi><mi>r</mi><mi>e</mi><mi>a</mi><mi>t</mi><mi>m</mi><mi>e</mi><mi>n</mi><mi>t</mi></mrow><mrow><mi>f</mi><mi>l</mi><mi>u</mi><mi>o</mi><mi>r</mi><mi>e</mi><mi>s</mi><mi>c</mi><mi>e</mi><mi>n</mi><mi>c</mi><mi>e</mi><mi> </mi><mi>a</mi><mi>f</mi><mi>t</mi><mi>e</mi><mi>r</mi><mi> </mi><mi>D</mi><mi>M</mi><mi>S</mi><mi>O</mi><mi> </mi><mi>t</mi><mi>r</mi><mi>e</mi><mi>a</mi><mi>t</mi><mi>m</mi><mi>e</mi><mi>n</mi><mi>t</mi></mrow></mfrac></mrow><mo>)</mo></mrow><mo>*</mo><mn>100</mn><mo>%</mo></mrow></semantics></math></div><div class="inline_block pmc_inline_block pmc_va_middle pmc_hide_overflow last bk_equ_label "><div><span class="nowrap">Equation 1</span></div></div></div></div><div id="ml282.s11"><h5>FITC-LDV dissociation assay</h5><p>The dissociation kinetics of FITC-LDV was measured by the addition of 100-fold of non-fluorescent
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LDV (The kinetic constants obtained are the same within experimental errors whether adding 100-fold or 200-fold of non-fluorescent LDV) [<a class="bk_pop" href="#ml282.r6">6</a>, <a class="bk_pop" href="#ml282.r9">9</a>]). The fluorescence decrease was recorded. For the resting state, when a fluorescence plateau was reached after the addition of FITC-LDV, LDV was added to the cell suspension. For the high affinity state, when the fluorescence reached equilibrium after the sequential addition of FITC-LDV and <i>N</i>-formyl peptide, LDV was added. To study the compounds effect, LDV was added at the time point when the fluorescence dropped to the minimum. The fluorescence decrease curve was fitted to either <a href="#ml282.eq3">Equation 2</a> to obtain the dissociation rate constant k<sub>off</sub>, or <a href="#ml282.eq4">Equation 3</a> to calculate the active receptor percentage according to <a href="#ml282.eq5">Equation 4</a>. In <a href="#ml282.eq4">Equation 3</a>, kh is the dissociation constant when the integrin is at the high affinity state while kl is the dissociation constant at the resting state. The values are 0.014 s<sup>−1</sup> and 0.036 s<sup>−1</sup>, respectively, as determined in separate experiments using <a href="#ml282.eq3">Equation 2</a>.</p><div class="pmc_disp_formula whole_rhythm clearfix" id="ml282.eq3"><div class="inline_block pmc_inline_block pmc_va_middle pmc_hide_overflow ten_col">
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<i>y</i> = <i>A</i> * <i>exp</i>(−<i>koff * x</i>) + <i>C</i></div><div class="inline_block pmc_inline_block pmc_va_middle pmc_hide_overflow last bk_equ_label "><div><span class="nowrap">Equation 2</span></div></div></div><div class="pmc_disp_formula whole_rhythm clearfix" id="ml282.eq4"><div class="inline_block pmc_inline_block pmc_va_middle pmc_hide_overflow ten_col">
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<i>y</i> = <i>Ah</i> * exp(−<i>kh* x</i>) + <i>Al</i> * exp (−<i>kl</i> * <i>x</i>) + <i>C</i></div><div class="inline_block pmc_inline_block pmc_va_middle pmc_hide_overflow last bk_equ_label "><div><span class="nowrap">Equation 3</span></div></div></div><div class="pmc_disp_formula whole_rhythm clearfix" id="ml282.eq5"><div class="inline_block pmc_inline_block pmc_va_middle pmc_hide_overflow ten_col">
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<math id="ml282.eq6" display="block"><semantics><mrow><mi>A</mi><mi>c</mi><mi>t</mi><mi>i</mi><mi>v</mi><mi>e</mi><mi> </mi><mi>r</mi><mi>e</mi><mi>c</mi><mi>e</mi><mi>p</mi><mi>t</mi><mi>o</mi><mi>r</mi><mi> </mi><mi>p</mi><mi>e</mi><mi>r</mi><mi>c</mi><mi>e</mi><mi>n</mi><mi>t</mi><mi>a</mi><mi>g</mi><mi>e</mi><mo>=</mo><mrow><mmultiscripts><mo stretchy="false">/</mo><mpadded lspace="-0.17em"><mrow><mo stretchy="false">(</mo><mi>A</mi><mi>h</mi><mo>+</mo><mi>A</mi><mi>l</mi><mo stretchy="false">)</mo></mrow></mpadded><none></none><mprescripts></mprescripts><none></none><mpadded width="-0.17em"><mrow><mi>A</mi><mi>h</mi></mrow></mpadded></mmultiscripts></mrow><mo>*</mo><mn>100</mn><mo>%</mo></mrow></semantics></math></div><div class="inline_block pmc_inline_block pmc_va_middle pmc_hide_overflow last bk_equ_label "><div><span class="nowrap">Equation 4</span></div></div></div></div><div id="ml282.s12"><h5>EGFR degradation in SCC-12F cells</h5><p>SCC-12F cells were seeded in 12-well plates at 0.12 × 10<sup>6</sup> cells/well and allowed to grow overnight. On the day of the experiment, the cells were starved in serum free medium containing 25 μg/mL cycloheximide for 2 h before compounds at different concentrations were added. The cells were treated for 30 min. Then, ligand EGF was added to 20 nM. At time 0, 15, 30, 60, and 120 min after the EGF addition, the suspension medium was removed and the cell was quickly washed with cold PBS and frozen at −80 °C. For electrophoresis and blotting, CelLytic™M Cell Lysis buffer containing protease inhibitor cocktails was added to the frozen cells to obtain the cell lysates according to the protocols from the manufacture. Protein concentration was quantified using BCA assay kit. For SDS-PAGE, 10 μg protein was loaded to each lane and proteins transferred to nitrocellulose. The nitrocellulose membranes were probed with antibodies directed against EGFR or actin and detected using peroxidase conjugated secondary antibodies and SuperSignal West Dura. Signal intensities were measured and quantified using a ChemiDoc™ XRS+ molecular imager coupled with Image Lab software.</p></div><div id="ml282.s13"><h5>EGFR degradation in Rab7 overexpressing HeLa cells</h5><p>EGFR degradation was also monitored in HeLa cells with some minor modifications. Briefly, HeLa cells overexpressing GFP-Rab7 wild-type protein were serum starved overnight, incubated with 100 μM <a href="/pcsubstance/?term=ML282[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML282</a> for 3 h, and then treated with cycloheximide and stimulated with 100 ng/ml EGF in serum free medium for 0–180 min. Cell lysates were prepared at various time points and immunoblotted for total EGFR while actin served as a loading control.</p></div></div></div><div id="ml282.s14"><h3>2.2. Probe Chemical Characterization</h3><div id="ml282.s15"><h4>A. Probe Chemical Structure, Physical Parameters and Probe Properties</h4><div id="ml282.f1" class="figure bk_fig"><div class="graphic"><img src="/books/NBK143553/bin/ml282f1.jpg" alt="Figure 1. Probe characteristics for ML282." /></div><h3><span class="label">Figure 1</span><span class="title">Probe characteristics for ML282</span></h3></div></div><div id="ml282.s16"><h4>B. Structure Verification and Purity: <sup>1</sup>H NMR, <sup>13</sup>C NMR, LCMS, and HRMS Data</h4><p><b>Proton and carbon NMR data for <a href="/pcsubstance/?term=ML282[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML282</a> (CID 1067700):</b> Detailed analytical methods and instrumentation are described in <a href="#ml282.s19">section 2.3</a>, entitled “Probe Preparation” under general experimental and analytical details. The numerical experimental proton and carbon data are represented below.</p><p><b>Proton NMR Data for <a href="/pcsubstance/?term=ML282[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML282</a> (CID 1067700):</b><sup>1</sup>H NMR (400 MHz, DMSO-d<sub>6</sub>) δ 14.84 (s, 1H), 13.39 (s, 1H), 11.81 (s, 1H), 7.98 (apparent dd, <i>J</i> = 1.2, 8.4, 2H), 7.74 – 7.62 (m, 1H), 7.55 (apparent t, <i>J</i> = 7.7, 2H), 4.67 (s, 2H), 2.75 (s, 2H), 1.24 (s, 6H).</p><p><b>Carbon NMR Data for <a href="/pcsubstance/?term=ML282[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML282</a> (CID 1067700):</b><sup>13</sup>C NMR (101 MHz, DMSO-d<sub>6</sub>) δ 174.43, 166.86, 165.35, 146.72, 133.08, 132.06, 129.10, 128.75, 128.41, 124.09, 116.50, 70.14, 58.82, 37.27, 26.19.</p><p><b>LCMS and HRMS Data for <a href="/pcsubstance/?term=ML282[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML282</a> (CID 1067700):</b> Detailed analytical methods and instrumentation are described in <a href="#ml282.s19">section 2.3</a>, entitled “Probe Preparation” under general experimental and analytical details. The numerical experimental LCMS and HRMS data are represented below. LCMS retention time: 1.871min. LCMS purity at 214 nm: 92.8%. HRMS: <i>m/z</i> calculated for C<sub>18</sub>H<sub>19</sub>N<sub>2</sub>O<sub>4</sub>S<sub>2</sub> [M<sup>+</sup>+1]: 391.0781, found 391.0777. </p></div><div id="ml282.s17"><h4>C. Solubility</h4><p>Solubility was measured in phosphate buffered saline (PBS) at room temperature (23 °C). PBS by definition is 137 mM NaCl, 2.7 mM KCl, 10 mM sodium phosphate dibasic, 2 mM potassium phosphate monobasic and a pH of 7.4. Detection was based on UV absorbance [<a class="bk_pop" href="#ml282.r10">10</a>]. Probe <a href="/pcsubstance/?term=ML282[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML282</a> (<a href="https://pubchem.ncbi.nlm.nih.gov/substance/85747738" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 85747738</a>) was found to have an excellent PBS solubility measurement of > 116 μg/mL, or > 297 μM, under these conditions. Solubility was also assessed in the each of the four media used in the individual assays. Probe <a href="/pcsubstance/?term=ML282[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML282</a> (<a href="https://pubchem.ncbi.nlm.nih.gov/substance/85747738" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 85747738</a>) was determined to have excellent assay media solubility, as depicted in <a class="figpopup" href="/books/NBK143553/table/ml282.t2/?report=objectonly" target="object" rid-figpopup="figml282t2" rid-ob="figobml282t2">Table 2</a>.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml282t2"><a href="/books/NBK143553/table/ml282.t2/?report=objectonly" target="object" title="Table 2" class="img_link icnblk_img figpopup" rid-figpopup="figml282t2" rid-ob="figobml282t2"><img class="small-thumb" src="/books/NBK143553/table/ml282.t2/?report=thumb" src-large="/books/NBK143553/table/ml282.t2/?report=previmg" alt="Table 2. Solubility for ML282 in Assay Media." /></a><div class="icnblk_cntnt"><h4 id="ml282.t2"><a href="/books/NBK143553/table/ml282.t2/?report=objectonly" target="object" rid-ob="figobml282t2">Table 2</a></h4><p class="float-caption no_bottom_margin">Solubility for ML282 in Assay Media. </p></div></div></div><div id="ml282.s18"><h4>D. Stability</h4><p>Stability was measured under two distinct conditions with <a href="/pcsubstance/?term=ML282[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML282</a> (<a href="https://pubchem.ncbi.nlm.nih.gov/substance/85747738" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 85747738</a>, <a class="figpopup" href="/books/NBK143553/figure/ml282.f2/?report=objectonly" target="object" rid-figpopup="figml282f2" rid-ob="figobml282f2">Fig. 2</a>). Stability, depicted as closed circles in the graph, was assessed at room temperature (23 °C) in PBS (no antioxidants or other protectants and DMSO concentration below 0.1%). Stability data is depicted as a graph showing the loss of compound with time over a 48 hr period with a minimum of 6 time points and providing the percent remaining compound at end of the 48 hr period [<a class="bk_pop" href="#ml282.r10">10</a>]. Under these conditions, 77% of <a href="/pcsubstance/?term=ML282[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML282</a> remains after 48 hours. It is unknown at this time if or what degradation might be occurring or what this result truly represents.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml282f2" co-legend-rid="figlgndml282f2"><a href="/books/NBK143553/figure/ml282.f2/?report=objectonly" target="object" title="Figure 2" class="img_link icnblk_img figpopup" rid-figpopup="figml282f2" rid-ob="figobml282f2"><img class="small-thumb" src="/books/NBK143553/bin/ml282f2.gif" src-large="/books/NBK143553/bin/ml282f2.jpg" alt="Figure 2. Graph depicting stability of ML282 after 48 h in PBS (no additives)." /></a><div class="icnblk_cntnt" id="figlgndml282f2"><h4 id="ml282.f2"><a href="/books/NBK143553/figure/ml282.f2/?report=objectonly" target="object" rid-ob="figobml282f2">Figure 2</a></h4><p class="float-caption no_bottom_margin">Graph depicting stability of ML282 after 48 h in PBS (no additives). </p></div></div><p>To assess the chemical stability of <a href="/pcsubstance/?term=ML282[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML282</a> and its propensity towards nucleophilic attack, the compound was treated with a range of equivalents of L-glutathione in DMSO for 72 h at 37 °C (11). The three experiments were monitored by LCMS at each of the following time points: 1 h, 2 h, 4 h, 24 h, 48 h, and 72 h. <i>Procedure: To a solution of <a href="/pcsubstance/?term=ML282[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML282</a> (2-(3-benzoylthioureido)-5,5-dimethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxylic acid, <a href="https://pubchem.ncbi.nlm.nih.gov/substance/85747738" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 85747738</a>), 1.0 mg, 2.56 μmol, 1 eq) in DMSO (1.0 mL) was added:</i></p><ol class="lower-alpha"><li class="half_rhythm"><div>L-glutathione (1.0 mg, 3.25 μmol, 1.2 eq) and the mixture stirred at 37 °C for 72 h</div></li><li class="half_rhythm"><div>L-glutathione (1.6 mg, 5.12 μmol, 2.0 eq) and the mixture stirred at 37 °C for 72 h</div></li><li class="half_rhythm"><div>L-glutathione (2.4 mg, 7.68 μmol, 3.0 eq) and the mixture stirred at 37 °C for 72 h</div></li></ol><p>LCMS analysis of each reaction vial, taken after time (t) = 1 h, 2 h, 4 h, 24 h, 48 h, and 72 h, showed only the presence of 2-(3-benzoylthioureido)-5,5-dimethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxylic acid (<a href="https://pubchem.ncbi.nlm.nih.gov/substance/85747738" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 85747738</a>). No glutathione conjugate or other peaks were observed. These results suggest that the compound is not generally electrophilic or susceptible to protein-derived nucleophiles</p></div></div><div id="ml282.s19"><h3>2.3. Probe Preparation</h3><p><b>General experimental and analytical details:</b><sup>1</sup>H and <sup>13</sup>C NMR spectra were recorded on a Bruker AM 400 spectrometer (operating at 400 and 101 MHz respectively) or a Bruker AVIII spectrometer (operating at 500 and 126 MHz respectively) in CDCl<sub>3</sub> with 0.03% ™S as an internal standard or DMSO-d<sub>6</sub>. The chemical shifts (δ) reported are given in parts per million (ppm) and the coupling constants (<i>J</i>) are in Hertz (Hz). The spin multiplicities are reported as s = singlet, bs = broad singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublet and m = multiplet. The LCMS analysis was performed on an Agilent 1200 RRL chromatograph with photodiode array UV detection and an Agilent 6224 TOF mass spectrometer. The chromatographic method utilized the following parameters: a Waters Acquity BEH C-18 2.1 × 50mm, 1.7 um column; UV detection wavelength = 214 nm; flow rate = 0.4ml/min; gradient = 5 – 100% acetonitrile over 3 minutes with a hold of 0.8 minutes at 100% acetonitrile; the aqueous mobile phase contained 0.15% ammonium hydroxide (v/v). The mass spectrometer utilized the following parameters: an Agilent multimode source which simultaneously acquires ESI+/APCI+; a reference mass solution consisting of purine and hexakis(1H, 1H, 3H-tetrafluoropropoxy) phosphazine; and a make-up solvent of 90:10:0.1 MeOH:Water:Formic Acid which was introduced to the LC flow prior to the source to assist ionization. Melting points were determined on a Stanford Research Systems OptiMelt apparatus.</p><p><b>2-(3-Benzoylthioureido)-5,5-dimethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxylic acid (<a href="https://pubchem.ncbi.nlm.nih.gov/substance/85747738" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 85747738</a>, CID 1067700)</b> was purchased from ChemDiv, Inc. (CAS 314042-01-8) and purified by mass-directed reverse-phase chromatography to yield a white solid.</p><p><b><a href="/pcsubstance/?term=ML282[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML282</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/substance/85747738" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 85747738</a>, CID 1067700:</b> 2-(3-Benzoylthioureido)-5,5-dimethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-3-carboxylic acid was purchased from ChemDiv, Inc. (CAS 314042-01-8) and purified by mass-directed reverse-phase chromatography to yield a white solid. However, the probe can theoretically be prepared by the route depicted in <a class="figpopup" href="/books/NBK143553/figure/ml282.f3/?report=objectonly" target="object" rid-figpopup="figml282f3" rid-ob="figobml282f3">Figure 3</a> [<a class="bk_pop" href="#ml282.r12">12</a>].</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml282f3" co-legend-rid="figlgndml282f3"><a href="/books/NBK143553/figure/ml282.f3/?report=objectonly" target="object" title="Figure 3" class="img_link icnblk_img figpopup" rid-figpopup="figml282f3" rid-ob="figobml282f3"><img class="small-thumb" src="/books/NBK143553/bin/ml282f3.gif" src-large="/books/NBK143553/bin/ml282f3.jpg" alt="Figure 3. Synthetic route for probe and analog generation." /></a><div class="icnblk_cntnt" id="figlgndml282f3"><h4 id="ml282.f3"><a href="/books/NBK143553/figure/ml282.f3/?report=objectonly" target="object" rid-ob="figobml282f3">Figure 3</a></h4><p class="float-caption no_bottom_margin">Synthetic route for probe and analog generation. </p></div></div></div></div><div id="ml282.s20"><h2 id="_ml282_s20_">3. Results</h2><div id="ml282.s21"><h3>3.1. Dose Response Curves for Probe</h3><p>The effect of <a href="/pcsubstance/?term=ML282[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML282</a> (CID 1067700) on the binding of BODIPY FL-GTP to eight different GTPases was measured in dose response assays. The GTPases were grouped into two sets and tested in buffers containing either 1 mM EDTA or 1 mM Mg<sup>2+</sup>. The concentration of the fluorescent guanine nucleotide was held constant near the K<sub>d</sub> in each of the buffers. The inclusion of 1 mM EDTA was to chelate any residual Mg<sup>2+</sup> which functions to stabilize the guanine nucleotide binding to the GTPases. The buffer containing EDTA could, therefore, facilitate the reversible exchange of the guanine nucleotide and aid in the identification of compounds that inhibit the fluorescent nucleotide binding. However, our previous results showed that Rac1 and Rho enzymes are not stable in the EDTA buffer. Therefore, Rac1 and Rho GTPases were tested in the buffer containing 1 mM Mg<sup>2+</sup>. For comparison, Cdc42 and its mutant were tested in both buffers and yielded similar EC<sub>50</sub> values demonstrating that both buffers can be feasibly used. Based on the dose response curves, <a href="/pcsubstance/?term=ML282[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML282</a> inhibited BODIPY FL-GTP binding by all GTPases tested in both sets of reactions whether the buffer contained EDTA or Mg<sup>2+</sup>, and the EC<sub>50</sub> values were in the nanomolar range (<a class="figpopup" href="/books/NBK143553/figure/ml282.f4/?report=objectonly" target="object" rid-figpopup="figml282f4" rid-ob="figobml282f4">Fig. 4</a>).</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml282f4" co-legend-rid="figlgndml282f4"><a href="/books/NBK143553/figure/ml282.f4/?report=objectonly" target="object" title="Figure 4" class="img_link icnblk_img figpopup" rid-figpopup="figml282f4" rid-ob="figobml282f4"><img class="small-thumb" src="/books/NBK143553/bin/ml282f4.gif" src-large="/books/NBK143553/bin/ml282f4.jpg" alt="Figure 4. Dose-response curves of ML282 (CID 1067700) with different GTPases." /></a><div class="icnblk_cntnt" id="figlgndml282f4"><h4 id="ml282.f4"><a href="/books/NBK143553/figure/ml282.f4/?report=objectonly" target="object" rid-ob="figobml282f4">Figure 4</a></h4><p class="float-caption no_bottom_margin">Dose-response curves of ML282 (CID 1067700) with different GTPases. A. The assay buffer contained 1 mM EDTA. B. The assay buffer contained 1 mM Mg<sup>2+</sup>. </p></div></div><p>In a control experiment, we coated the beads with GST- tagged GFP. Incubation with compound <a href="/pcsubstance/?term=ML282[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML282</a> did not cause any changes to the beads’ fluorescence. Therefore, the fluorescence decrease we observed in the assay was not due to fluorescence quenching of GFP or to interference of the GST-tagged protein binding to the beads, but due to the bona fide inhibition of the fluorescent nucleotide binding.</p><p>According to the Cheng-Prusoff equation [<a class="bk_pop" href="#ml282.r13">13</a>], the compound IC<sub>50</sub> obtained under our assay condition is a close estimate of its K<sub>d</sub>. Probe <a href="/pcsubstance/?term=ML282[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML282</a> is the first compound shown to have nanomolar inhibition potency towards multiple GTPases, including Rab7. On the other hand, careful examination of the dose response curves indicates that although the compound inhibited all GTPases tested with similar potency, it appears that the inhibition modalities may be different. The dose response curve for Rab7 fits well with a classical one-site binding model with a hill slope close to one and nearly total inhibition achieved at high compound concentrations (<a class="figpopup" href="/books/NBK143553/figure/ml282.f4/?report=objectonly" target="object" rid-figpopup="figml282f4" rid-ob="figobml282f4">Fig. 4</a>). However, the compound only resulted in partial inhibition of Cdc42 and Ras even at high concentrations. Partial inhibition may suggest the presence of multiple forms of the protein and hint at the involvement of a complex inhibition mechanism. The different behavior of the compound towards various GTPases warrants further investigation and may serve as the basis for identifying a specific inhibitor for Rab7.</p></div><div id="ml282.s22"><h3>3.2. Cellular Activity</h3><p><i>ML282 (CID 106770) has no obvious cellular toxicity.</i></p><p>The most useful molecular probes have a generous “therapeutic” window in which they do not demonstrate cellular toxicity. As a model cell line used in biomedical research, U937 cells mature and differentiate in response to a number of soluble stimuli [<a class="bk_pop" href="#ml282.r14">14</a>]. Also, a mutant form of U937 cells was used in the cellular VLA4 binding assay. Therefore, the cytotoxicity of <a href="/pcsubstance/?term=ML282[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML282</a> and its analogues were evaluated in the U937 cells. The compound was included in the growth medium of U937 cells for 24h. The cell density and viability were subsequently measured. The cells had a growth rate comparable to that treated with the DMSO control and maintained their viability. Thus, <a href="/pcsubstance/?term=ML282[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML282</a> and its analogues demonstrate no obvious cytotoxicity and supports their use in cellular assays.</p></div><div id="ml282.s24"><h3>3.3. Profiling Assays</h3><p><b>Broad spectrum target profiling:</b>
|
||
<a href="/pcsubstance/?term=ML282[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML282</a> was submitted for assessing off-target pharmacology using a Ricerca LeadProfiling® screen made up of 68 assays. The probe was assayed in duplicate at a concentration of 10 μM for all targets.</p><p><a href="/pcsubstance/?term=ML282[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML282</a> did not register any percent inhibition over 50% in this panel. The most significant findings were noted as 40% inhibition of the human serotonin receptor (5-HT<sub>2B</sub>) at 10 μM. All other findings registered below 22% inhibition at this concentration. Details of the panel results are provided in the <a href="#ml282.app1">Appendix</a>.</p></div></div><div id="ml282.s25"><h2 id="_ml282_s25_">4. Discussion</h2><div id="ml282.s26"><h3>4.1. Comparison to Existing Art and How the New Probe is an Improvement</h3><p>GTPases are important for cellular signal transduction, cytoskeleton reorganization, and membrane protein traffic and have been shown to be the causal agents for multiple human diseases by either mutation or expression level changes [<a class="bk_pop" href="#ml282.r15">15</a>]. For example, the mutation of Ras has been found in one third of all cancers, and Rab and Rho GTPases are also increasingly implicated in cancer as well as other human diseases [<a class="bk_pop" href="#ml282.r16">16</a>]. In many cases, GTPases are hyper- activated in the disease state. Therefore, the pursuit of GTPase inhibitors has been a universal subject that is carried on by both academic research laboratories and pharmaceutical companies parallel to the search for kinase inhibitors. The latter quest has successfully generated several commercialized drugs. Among others, erlotinib has been used as an EGFR inhibitor to treat non-small cell lung cancer [<a class="bk_pop" href="#ml282.r17">17</a>–<a class="bk_pop" href="#ml282.r18">18</a>] and pancreas cancer [<a class="bk_pop" href="#ml282.r19">19</a>–<a class="bk_pop" href="#ml282.r20">20</a>], while imatinib has been used as an ABL inhibitor to treat chronic myelogenous leukemia [<a class="bk_pop" href="#ml282.r21">21</a>] and gastrointestinal stromal tumors [<a class="bk_pop" href="#ml282.r22">22</a>]. Compared with the success achieved with kinase inhibitors, the identification of a GTPase inhibitor that can be a useful drug has remained enigmatic. One reason is that GTPases have versatile and overlapping functions so that toxicity has been a challenging issue. In addition, the guanine nucleotide binding affinity is quite high [<a class="bk_pop" href="#ml282.r23">23</a>–<a class="bk_pop" href="#ml282.r24">24</a>]. There have also been practical hurdles. One of them is the lack of a positive control. The pan-kinase inhibitor staurosporine has been the control compound for both biochemical inhibitor screening and cellular assay assessment [<a class="bk_pop" href="#ml282.r25">25</a>–<a class="bk_pop" href="#ml282.r27">27</a>]. However, there has not been a versatile GTPase inhibitor that could play an analogous role. Besides the limitation in drug discovery, the lack of a versatile GTPase inhibitor also discourages the function assignment for unknown factors where the intervening GTPase activity needs to be blocked. The current GTPase inhibitors include lipid transferase inhibitors, regulatory protein inhibitors, downstream effector inhibitors, or GTPase inhibitors with specificity for individual GTPases [<a class="bk_pop" href="#ml282.r16">16</a>. <a class="bk_pop" href="#ml282.r28">28</a>]. The first three categories act upon the proteins interacting with the GTPase instead of the GTPase itself, while the specific inhibitors are usually not potent or have limited utility in drug discovery and basic research. The compound <a href="/pcsubstance/?term=ML282[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML282</a> (CID 1067700) that we report here shows potent inhibition towards multiple GTPases in both biochemical and cellular assays and can be an ideal molecular probe for the purpose of drug discovery and fundamental research.</p></div></div><div id="ml282.s27"><h2 id="_ml282_s27_">5. References</h2><dl class="temp-labeled-list"><dt>1.</dt><dd><div class="bk_ref" id="ml282.r1">Berndt N, Hamilton AD, Sebti SM. Targeting protein prenylation for cancer therapy. <span><span class="ref-journal">Nat Rev Cancer. </span>2011;<span class="ref-vol">11</span>(11):775–91.</span> [<a href="/pmc/articles/PMC4037130/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4037130</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/22020205" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 22020205</span></a>]</div></dd><dt>2.</dt><dd><div class="bk_ref" id="ml282.r2">Surviladze Z, et al. A Potent and Selective Inhibitor of Cdc42 GTPase. 2010. [<a href="https://pubmed.ncbi.nlm.nih.gov/21433396" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21433396</span></a>]</div></dd><dt>3.</dt><dd><div class="bk_ref" id="ml282.r3">Cherfils J, Melancon P. On the action of Brefeldin A on Sec7-stimulated membrane-recruitment and GDP/GTP exchange of Arf proteins. <span><span class="ref-journal">Biochem Soc Trans. </span>2005;<span class="ref-vol">33</span>(Pt 4):635–8.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16042561" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16042561</span></a>]</div></dd><dt>4.</dt><dd><div class="bk_ref" id="ml282.r4">Peyroche A, et al. Brefeldin A acts to stabilize an abortive ARF-GDP-Sec7 domain protein complex: involvement of specific residues of the Sec7 domain. <span><span class="ref-journal">Mol Cell. </span>1999;<span class="ref-vol">3</span>(3):275–85.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/10198630" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10198630</span></a>]</div></dd><dt>5.</dt><dd><div class="bk_ref" id="ml282.r5">Nassar N, et al. Structure-function based design of small molecule inhibitors targeting Rho family GTPases. <span><span class="ref-journal">Curr Top Med Chem. </span>2006;<span class="ref-vol">6</span>(11):1109–16.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16842149" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16842149</span></a>]</div></dd><dt>6.</dt><dd><div class="bk_ref" id="ml282.r6">Chigaev A, et al. Real time analysis of the affinity regulation of alpha 4-integrin. The physiologically activated receptor is intermediate in affinity between resting and Mn(2+) or antibody activation. <span><span class="ref-journal">J Biol Chem. </span>2001;<span class="ref-vol">276</span>(52):48670–8.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/11641394" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11641394</span></a>]</div></dd><dt>7.</dt><dd><div class="bk_ref" id="ml282.r7">Surviladze Z, et al. Identification of a small GTPase inhibitor using a high-throughput flow cytometry bead-based multiplex assay. <span><span class="ref-journal">J Biomol Screen. </span>2010;<span class="ref-vol">15</span>(1):10–20.</span> [<a href="/pmc/articles/PMC3433230/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3433230</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/20008126" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20008126</span></a>]</div></dd><dt>8.</dt><dd><div class="bk_ref" id="ml282.r8">Chigaev A, Sklar LA. Overview: assays for studying integrin-dependent cell adhesion. <span><span class="ref-journal">Methods Mol Biol. </span>2012;<span class="ref-vol">757</span>:3–14.</span> [<a href="/pmc/articles/PMC3805125/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3805125</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21909902" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21909902</span></a>]</div></dd><dt>9.</dt><dd><div class="bk_ref" id="ml282.r9">Chigaev A, Smagley Y, Sklar LA. Nitric oxide/cGMP pathway signaling actively down-regulates alpha4beta1-integrin affinity: an unexpected mechanism for inducing cell de-adhesion. <span><span class="ref-journal">BMC Immunol. </span>2011;<span class="ref-vol">12</span>:28.</span> [<a href="/pmc/articles/PMC3125286/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3125286</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21586157" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21586157</span></a>]</div></dd><dt>10.</dt><dd><div class="bk_ref" id="ml282.r10">Data obtained from Layton Smith’s pharmacology lab at the Sanford Burnham Institute.</div></dd><dt>11.</dt><dd><div class="bk_ref" id="ml282.r11">Experiments performed by Dr. Denise Simpson, KU SCC.</div></dd><dt>12.</dt><dd><div class="bk_ref" id="ml282.r12">Andersen HS, Olsen OH, Iversen LF, Sorensen ALP, Mortensen SB, Christensen MS, Branner S, Hansen TK, Lau JF, Jeppesen L, Moran EJ, Su J, Bakir F, Judge L, Shahbaz M, Collins T, Vo T, Newman MJ, Ripka WC, Moller NPH. Discovery and SAR of a novel selective and and orally bioavailable nonpeptide classical competitive inhibitor class of protein-tyrosine phosphatase 1B. <span><span class="ref-journal">J. Med. Chem. </span>2002;<span class="ref-vol">45</span>:4444–4459.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12238924" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12238924</span></a>]</div></dd><dt>13.</dt><dd><div class="bk_ref" id="ml282.r13">Copeland RA. <span class="ref-journal">Evaluation of enzyme inhibitors in drug discovery : a guide for medicinal chemists and pharmacologists.</span> xvii. Hoboken, NJ: Wiley-Interscience; 2005. 271 p. [<a href="https://pubmed.ncbi.nlm.nih.gov/16350889" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16350889</span></a>]</div></dd><dt>14.</dt><dd><div class="bk_ref" id="ml282.r14">Zella D, et al. Interferon-gamma increases expression of chemokine receptors CCR1, CCR3, and CCR5, but not CXCR4 in monocytoid U937 cells. <span><span class="ref-journal">Blood. </span>1998;<span class="ref-vol">91</span>(12):4444–50.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/9616137" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9616137</span></a>]</div></dd><dt>15.</dt><dd><div class="bk_ref" id="ml282.r15">Colicelli J. Human RAS superfamily proteins and related GTPases. <span><span class="ref-journal">Sci STKE. </span>2004;<span class="ref-vol">2004</span>(250):RE13.</span> [<a href="/pmc/articles/PMC2828947/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2828947</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/15367757" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15367757</span></a>]</div></dd><dt>16.</dt><dd><div class="bk_ref" id="ml282.r16">Vigil D, et al. Ras superfamily GEFs and GAPs: validated and tractable targets for cancer therapy? <span><span class="ref-journal">Nat Rev Cancer. </span>2010;<span class="ref-vol">10</span>(12):842–57.</span> [<a href="/pmc/articles/PMC3124093/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3124093</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21102635" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21102635</span></a>]</div></dd><dt>17.</dt><dd><div class="bk_ref" id="ml282.r17">Reck M, et al. Erlotinib in advanced non-small cell lung cancer: efficacy and safety findings of the global phase IV Tarceva Lung Cancer Survival Treatment study. <span><span class="ref-journal">J Thorac Oncol. </span>2010;<span class="ref-vol">5</span>(10):1616–22.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/20736854" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20736854</span></a>]</div></dd><dt>18.</dt><dd><div class="bk_ref" id="ml282.r18">Gridelli C, et al. Erlotinib in the treatment of non-small cell lung cancer: current status and future developments. <span><span class="ref-journal">Anticancer Res. </span>2010;<span class="ref-vol">30</span>(4):1301–10.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/20530444" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20530444</span></a>]</div></dd><dt>19.</dt><dd><div class="bk_ref" id="ml282.r19">Bayraktar S, Rocha-Lima CM. Advanced or metastatic pancreatic cancer: molecular targeted therapies. <span><span class="ref-journal">Mt Sinai J Med. </span>2010;<span class="ref-vol">77</span>(6):606–19.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/21105124" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21105124</span></a>]</div></dd><dt>20.</dt><dd><div class="bk_ref" id="ml282.r20">Mountzios G, Syrigos KN. A benefit-risk assessment of erlotinib in non-small-cell lung cancer and pancreatic cancer. <span><span class="ref-journal">Drug Saf. </span>2011;<span class="ref-vol">34</span>(3):175–86.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/21332242" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21332242</span></a>]</div></dd><dt>21.</dt><dd><div class="bk_ref" id="ml282.r21">Catellani S, et al. Imatinib treatment induces CD5+ B lymphocytes and IgM natural antibodies with anti-leukemic reactivity in patients with chronic myelogenous leukemia. <span><span class="ref-journal">PLoS One. </span>2011;<span class="ref-vol">6</span>(4):e18925.</span> [<a href="/pmc/articles/PMC3078937/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3078937</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/21533122" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21533122</span></a>]</div></dd><dt>22.</dt><dd><div class="bk_ref" id="ml282.r22">Mazzeo F, et al. Nonadherence to imatinib treatment in patients with gastrointestinal stromal tumors: the ADAGIO study. <span><span class="ref-journal">Anticancer Res. </span>2011;<span class="ref-vol">31</span>(4):1407–9.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/21508393" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21508393</span></a>]</div></dd><dt>23.</dt><dd><div class="bk_ref" id="ml282.r23">Etienne-Manneville S, Hall A. Rho GTPases in cell biology. <span><span class="ref-journal">Nature. </span>2002;<span class="ref-vol">420</span>(6916):629–35.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12478284" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12478284</span></a>]</div></dd><dt>24.</dt><dd><div class="bk_ref" id="ml282.r24">Jaffe AB, Hall A. Rho GTPases: biochemistry and biology. <span><span class="ref-journal">Annu Rev Cell Dev Biol. </span>2005;<span class="ref-vol">21</span>:247–69.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16212495" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16212495</span></a>]</div></dd><dt>25.</dt><dd><div class="bk_ref" id="ml282.r25">Lapenna S, Giordano A. Cell cycle kinases as therapeutic targets for cancer. <span><span class="ref-journal">Nat Rev Drug Discov. </span>2009;<span class="ref-vol">8</span>(7):547–66.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/19568282" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19568282</span></a>]</div></dd><dt>26.</dt><dd><div class="bk_ref" id="ml282.r26">Hill MM, Hemmings BA. Inhibition of protein kinase B/Akt. implications for cancer therapy. <span><span class="ref-journal">Pharmacol Ther. </span>2002;<span class="ref-vol">93</span>(2–3):243–51.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12191616" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12191616</span></a>]</div></dd><dt>27.</dt><dd><div class="bk_ref" id="ml282.r27">Ustun C, DeRemer DL, Akin C. Tyrosine kinase inhibitors in the treatment of systemic mastocytosis. <span><span class="ref-journal">Leuk Res. </span>2011;<span class="ref-vol">35</span>(9):1143–52.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/21641642" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 21641642</span></a>]</div></dd><dt>28.</dt><dd><div class="bk_ref" id="ml282.r28">Schafer WR, et al. Genetic and pharmacological suppression of oncogenic mutations in ras genes of yeast and humans. <span><span class="ref-journal">Science. </span>1989;<span class="ref-vol">245</span>(4916):379–85.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/2569235" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 2569235</span></a>]</div></dd></dl></div><div id="ml282.app1"><h2 id="_ml282_app1_">APPENDIX. Ricerca Profiling Results for ML282</h2><p><a href="/pcsubstance/?term=ML282[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML282</a> did not register any percent inhibition over 50% in this panel. The most significant findings were noted as 40% inhibition of the human serotonin receptor (5-HT<sub>2B</sub>) at 10 μM. All other findings registered below 22% inhibition at this concentration. Details of the panel results are provided below.</p><div id="ml282.s29"><h3>Summary</h3><div id="ml282.s30"><h4>STUDY OBJECTIVE</h4><p>To evaluate, in Radioligand Binding assays, the activity of compound 125264860 (UK-6, PT# 1156808).</p></div><div id="ml282.s31"><h4>METHODS</h4><p>Methods employed in this study have been adapted from the scientific literature to maximize reliability and reproducibility. Reference standards were run as an integral part of each assay to ensure the validity of the results obtained. Assays were performed under conditions described in the accompanying “Methods” section of this report.</p><p>Where presented, IC<sub>50</sub> values were determined by a non-linear, least squares regression analysis using MathIQ™ (ID Business Solutions Ltd., UK). Where inhibition constants (K<sub>i</sub>) are presented, the K<sub>i</sub> values were calculated using the equation of Cheng and Pursoff (Cheng, Y., Prusoff, W.H., Biochem, Pharmacol. <u>22</u>:3099–3108, 1973 using the observed IC<sub>50</sub> of the tested compound, the concentration of radioligand employed in the assay, and the historical values for the K<sub>D</sub> of the ligand (obtained experimentally at <b>Ricerca Biosciences, LLC</b>). Where presented the Hill coefficient, (n<sub>H</sub>), defining the slope of the competitive binding curve, was calculated using MathIQ™. Hill coefficients significantly different than 1.0, may suggest that the binding displacement does not follow the laws of mass action with a single binding site. Where IC<sub>50</sub>, K­<sub>i</sub>, and/or n<sub>H</sub> data are presented without Standard Error of the Mean (SEM), data are insufficient to be quantitative, and the values presented (K<sub>i</sub>, IC<sub>50</sub>, n<sub>H</sub>) should be interpreted with caution.</p></div><div id="ml282.s32"><h4>RESULTS</h4><p>A summary of results meeting the significance criteria is presented in the following sections, Complete results are presented under the section labeled “Experimental Results”. Individual responses, if requested are presented under the section labeled “Individual Responses”.</p></div><div id="ml282.s33"><h4>SUMMARY/CONCLUSION</h4><p>Significant results are displayed in the following table(s) in rank of potency for estimated IC­<sub>50</sub> and/or K<sub>i</sub> values.</p></div></div><div id="ml282.s34"><h3>Experimental Results</h3><div id="ml282.tu1" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK143553/table/ml282.tu1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml282.tu1_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Cat#</th><th id="hd_h_ml282.tu1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Assay Name</th><th id="hd_h_ml282.tu1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Batch<sup><a class="bk_pop" href="#ml282.tfn7">*</a></sup></th><th id="hd_h_ml282.tu1_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Spec.</th><th id="hd_h_ml282.tu1_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Rep.</th><th id="hd_h_ml282.tu1_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Conc.</th><th id="hd_h_ml282.tu1_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">%Inh.</th><th id="hd_h_ml282.tu1_1_1_1_8" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">IC<sub>50</sub><sup><a class="bk_pop" href="#ml282.tfn7">*</a></sup></th><th id="hd_h_ml282.tu1_1_1_1_9" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">K<sub>i</sub></th><th id="hd_h_ml282.tu1_1_1_1_10" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">n<sub>H</sub></th><th id="hd_h_ml282.tu1_1_1_1_11" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">R</th></tr></thead><tbody><tr><th headers="hd_h_ml282.tu1_1_1_1_1 hd_h_ml282.tu1_1_1_1_2 hd_h_ml282.tu1_1_1_1_3 hd_h_ml282.tu1_1_1_1_4 hd_h_ml282.tu1_1_1_1_5 hd_h_ml282.tu1_1_1_1_6 hd_h_ml282.tu1_1_1_1_7 hd_h_ml282.tu1_1_1_1_8 hd_h_ml282.tu1_1_1_1_9 hd_h_ml282.tu1_1_1_1_10 hd_h_ml282.tu1_1_1_1_11" id="hd_b_ml282.tu1_1_1_1_1" colspan="11" rowspan="1" style="text-align:left;vertical-align:top;">Compound: 125264860, PT #: 1156808</th></tr><tr><td headers="hd_h_ml282.tu1_1_1_1_1 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">200510</td><td headers="hd_h_ml282.tu1_1_1_1_2 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Adenosine A<sub>1</sub></td><td headers="hd_h_ml282.tu1_1_1_1_3 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">307264</td><td headers="hd_h_ml282.tu1_1_1_1_4 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml282.tu1_1_1_1_5 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml282.tu1_1_1_1_6 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml282.tu1_1_1_1_7 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">7</td><td headers="hd_h_ml282.tu1_1_1_1_8 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_9 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_10 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_11 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml282.tu1_1_1_1_1 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">200610</td><td headers="hd_h_ml282.tu1_1_1_1_2 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Adenosine A<sub>2A</sub></td><td headers="hd_h_ml282.tu1_1_1_1_3 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">307124</td><td headers="hd_h_ml282.tu1_1_1_1_4 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml282.tu1_1_1_1_5 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml282.tu1_1_1_1_6 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml282.tu1_1_1_1_7 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">12</td><td headers="hd_h_ml282.tu1_1_1_1_8 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_9 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_10 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_11 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml282.tu1_1_1_1_1 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">200720</td><td headers="hd_h_ml282.tu1_1_1_1_2 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Adenosine A<sub>3</sub></td><td headers="hd_h_ml282.tu1_1_1_1_3 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">307115</td><td headers="hd_h_ml282.tu1_1_1_1_4 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml282.tu1_1_1_1_5 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml282.tu1_1_1_1_6 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml282.tu1_1_1_1_7 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">8</td><td headers="hd_h_ml282.tu1_1_1_1_8 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_9 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_10 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_11 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml282.tu1_1_1_1_1 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">203100</td><td headers="hd_h_ml282.tu1_1_1_1_2 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Adrenergic α<sub>1A</sub></td><td headers="hd_h_ml282.tu1_1_1_1_3 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">307444</td><td headers="hd_h_ml282.tu1_1_1_1_4 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">rat</td><td headers="hd_h_ml282.tu1_1_1_1_5 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml282.tu1_1_1_1_6 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml282.tu1_1_1_1_7 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">0</td><td headers="hd_h_ml282.tu1_1_1_1_8 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_9 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_10 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_11 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml282.tu1_1_1_1_1 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">203200</td><td headers="hd_h_ml282.tu1_1_1_1_2 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Adrenergic α<sub>1B</sub></td><td headers="hd_h_ml282.tu1_1_1_1_3 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">307445</td><td headers="hd_h_ml282.tu1_1_1_1_4 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">rat</td><td headers="hd_h_ml282.tu1_1_1_1_5 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml282.tu1_1_1_1_6 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml282.tu1_1_1_1_7 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">−1</td><td headers="hd_h_ml282.tu1_1_1_1_8 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_9 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_10 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_11 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml282.tu1_1_1_1_1 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">203400</td><td headers="hd_h_ml282.tu1_1_1_1_2 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Adrenergic α<sub>1D</sub></td><td headers="hd_h_ml282.tu1_1_1_1_3 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">307125</td><td headers="hd_h_ml282.tu1_1_1_1_4 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml282.tu1_1_1_1_5 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml282.tu1_1_1_1_6 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml282.tu1_1_1_1_7 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">18</td><td headers="hd_h_ml282.tu1_1_1_1_8 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_9 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_10 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_11 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml282.tu1_1_1_1_1 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">203620</td><td headers="hd_h_ml282.tu1_1_1_1_2 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Adrenergic α<sub>2A</sub></td><td headers="hd_h_ml282.tu1_1_1_1_3 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">307447</td><td headers="hd_h_ml282.tu1_1_1_1_4 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml282.tu1_1_1_1_5 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml282.tu1_1_1_1_6 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml282.tu1_1_1_1_7 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">9</td><td headers="hd_h_ml282.tu1_1_1_1_8 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_9 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_10 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_11 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml282.tu1_1_1_1_1 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">204010</td><td headers="hd_h_ml282.tu1_1_1_1_2 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Adrenergic β<sub>1</sub></td><td headers="hd_h_ml282.tu1_1_1_1_3 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">307126</td><td headers="hd_h_ml282.tu1_1_1_1_4 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml282.tu1_1_1_1_5 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml282.tu1_1_1_1_6 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml282.tu1_1_1_1_7 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">4</td><td headers="hd_h_ml282.tu1_1_1_1_8 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_9 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_10 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_11 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml282.tu1_1_1_1_1 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">204110</td><td headers="hd_h_ml282.tu1_1_1_1_2 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Adrenergic β<sub>2</sub></td><td headers="hd_h_ml282.tu1_1_1_1_3 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">307127</td><td headers="hd_h_ml282.tu1_1_1_1_4 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml282.tu1_1_1_1_5 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml282.tu1_1_1_1_6 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml282.tu1_1_1_1_7 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">6</td><td headers="hd_h_ml282.tu1_1_1_1_8 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_9 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_10 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_11 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml282.tu1_1_1_1_1 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">285010</td><td headers="hd_h_ml282.tu1_1_1_1_2 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Androgen (Testosterone)AR</td><td headers="hd_h_ml282.tu1_1_1_1_3 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">307551</td><td headers="hd_h_ml282.tu1_1_1_1_4 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">rat</td><td headers="hd_h_ml282.tu1_1_1_1_5 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml282.tu1_1_1_1_6 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml282.tu1_1_1_1_7 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">−2</td><td headers="hd_h_ml282.tu1_1_1_1_8 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_9 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_10 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_11 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml282.tu1_1_1_1_1 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">212510</td><td headers="hd_h_ml282.tu1_1_1_1_2 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Bradykinin B<sub>1</sub></td><td headers="hd_h_ml282.tu1_1_1_1_3 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">307276</td><td headers="hd_h_ml282.tu1_1_1_1_4 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml282.tu1_1_1_1_5 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml282.tu1_1_1_1_6 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml282.tu1_1_1_1_7 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">−13</td><td headers="hd_h_ml282.tu1_1_1_1_8 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_9 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_10 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_11 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml282.tu1_1_1_1_1 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">212620</td><td headers="hd_h_ml282.tu1_1_1_1_2 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Bradykinin B<sub>2</sub></td><td headers="hd_h_ml282.tu1_1_1_1_3 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">307235</td><td headers="hd_h_ml282.tu1_1_1_1_4 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml282.tu1_1_1_1_5 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml282.tu1_1_1_1_6 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml282.tu1_1_1_1_7 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">6</td><td headers="hd_h_ml282.tu1_1_1_1_8 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_9 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_10 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_11 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml282.tu1_1_1_1_1 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">214510</td><td headers="hd_h_ml282.tu1_1_1_1_2 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Calcium Channel L-Type, Benezothiazepine</td><td headers="hd_h_ml282.tu1_1_1_1_3 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">307270</td><td headers="hd_h_ml282.tu1_1_1_1_4 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">rat</td><td headers="hd_h_ml282.tu1_1_1_1_5 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml282.tu1_1_1_1_6 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml282.tu1_1_1_1_7 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">−9</td><td headers="hd_h_ml282.tu1_1_1_1_8 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_9 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_10 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_11 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml282.tu1_1_1_1_1 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">214600</td><td headers="hd_h_ml282.tu1_1_1_1_2 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Calcium Channel L-Type, Dihydropyridine</td><td headers="hd_h_ml282.tu1_1_1_1_3 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">307263</td><td headers="hd_h_ml282.tu1_1_1_1_4 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">rat</td><td headers="hd_h_ml282.tu1_1_1_1_5 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml282.tu1_1_1_1_6 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml282.tu1_1_1_1_7 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">10</td><td headers="hd_h_ml282.tu1_1_1_1_8 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_9 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_10 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_11 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml282.tu1_1_1_1_1 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">216000</td><td headers="hd_h_ml282.tu1_1_1_1_2 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Calcium Channel N-Type</td><td headers="hd_h_ml282.tu1_1_1_1_3 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">307169</td><td headers="hd_h_ml282.tu1_1_1_1_4 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">rat</td><td headers="hd_h_ml282.tu1_1_1_1_5 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml282.tu1_1_1_1_6 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml282.tu1_1_1_1_7 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">9</td><td headers="hd_h_ml282.tu1_1_1_1_8 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_9 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_10 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_11 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml282.tu1_1_1_1_1 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">217030</td><td headers="hd_h_ml282.tu1_1_1_1_2 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Cannabinoid CB<sub>1</sub></td><td headers="hd_h_ml282.tu1_1_1_1_3 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">307262</td><td headers="hd_h_ml282.tu1_1_1_1_4 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml282.tu1_1_1_1_5 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml282.tu1_1_1_1_6 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml282.tu1_1_1_1_7 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">−14</td><td headers="hd_h_ml282.tu1_1_1_1_8 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_9 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_10 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_11 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml282.tu1_1_1_1_1 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">219500</td><td headers="hd_h_ml282.tu1_1_1_1_2 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Dopamine D<sub>1</sub></td><td headers="hd_h_ml282.tu1_1_1_1_3 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">307130</td><td headers="hd_h_ml282.tu1_1_1_1_4 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml282.tu1_1_1_1_5 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml282.tu1_1_1_1_6 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml282.tu1_1_1_1_7 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">6</td><td headers="hd_h_ml282.tu1_1_1_1_8 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_9 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_10 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_11 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml282.tu1_1_1_1_1 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">219700</td><td headers="hd_h_ml282.tu1_1_1_1_2 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Dopamine D<sub>2S</sub></td><td headers="hd_h_ml282.tu1_1_1_1_3 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">307454</td><td headers="hd_h_ml282.tu1_1_1_1_4 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml282.tu1_1_1_1_5 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml282.tu1_1_1_1_6 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml282.tu1_1_1_1_7 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">3</td><td headers="hd_h_ml282.tu1_1_1_1_8 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_9 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_10 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_11 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml282.tu1_1_1_1_1 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">219800</td><td headers="hd_h_ml282.tu1_1_1_1_2 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Dopamine D<sub>3</sub></td><td headers="hd_h_ml282.tu1_1_1_1_3 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">307455</td><td headers="hd_h_ml282.tu1_1_1_1_4 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml282.tu1_1_1_1_5 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml282.tu1_1_1_1_6 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml282.tu1_1_1_1_7 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">0</td><td headers="hd_h_ml282.tu1_1_1_1_8 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_9 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_10 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_11 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml282.tu1_1_1_1_1 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">219900</td><td headers="hd_h_ml282.tu1_1_1_1_2 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Dopamine D<sub>4,2</sub></td><td headers="hd_h_ml282.tu1_1_1_1_3 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">307132</td><td headers="hd_h_ml282.tu1_1_1_1_4 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml282.tu1_1_1_1_5 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml282.tu1_1_1_1_6 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml282.tu1_1_1_1_7 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">2</td><td headers="hd_h_ml282.tu1_1_1_1_8 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_9 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_10 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_11 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml282.tu1_1_1_1_1 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2240410</td><td headers="hd_h_ml282.tu1_1_1_1_2 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Endothelin ET<sub>A</sub></td><td headers="hd_h_ml282.tu1_1_1_1_3 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">307133</td><td headers="hd_h_ml282.tu1_1_1_1_4 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml282.tu1_1_1_1_5 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml282.tu1_1_1_1_6 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml282.tu1_1_1_1_7 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">11</td><td headers="hd_h_ml282.tu1_1_1_1_8 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_9 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_10 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_11 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml282.tu1_1_1_1_1 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">224110</td><td headers="hd_h_ml282.tu1_1_1_1_2 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Endothelin ET<sub>B</sub></td><td headers="hd_h_ml282.tu1_1_1_1_3 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">307415</td><td headers="hd_h_ml282.tu1_1_1_1_4 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml282.tu1_1_1_1_5 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml282.tu1_1_1_1_6 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml282.tu1_1_1_1_7 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">−10</td><td headers="hd_h_ml282.tu1_1_1_1_8 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_9 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_10 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_11 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml282.tu1_1_1_1_1 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">225510</td><td headers="hd_h_ml282.tu1_1_1_1_2 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Epidermal Growth Factor (EGF)</td><td headers="hd_h_ml282.tu1_1_1_1_3 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">307233</td><td headers="hd_h_ml282.tu1_1_1_1_4 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml282.tu1_1_1_1_5 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml282.tu1_1_1_1_6 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml282.tu1_1_1_1_7 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">−4</td><td headers="hd_h_ml282.tu1_1_1_1_8 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_9 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_10 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_11 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml282.tu1_1_1_1_1 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">226010</td><td headers="hd_h_ml282.tu1_1_1_1_2 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Estrogen ERα</td><td headers="hd_h_ml282.tu1_1_1_1_3 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">307134</td><td headers="hd_h_ml282.tu1_1_1_1_4 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml282.tu1_1_1_1_5 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml282.tu1_1_1_1_6 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml282.tu1_1_1_1_7 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">0</td><td headers="hd_h_ml282.tu1_1_1_1_8 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_9 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_10 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_11 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml282.tu1_1_1_1_1 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">226600</td><td headers="hd_h_ml282.tu1_1_1_1_2 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">GABA<sub>A,</sub> Flunitrazepam, Central</td><td headers="hd_h_ml282.tu1_1_1_1_3 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">307261</td><td headers="hd_h_ml282.tu1_1_1_1_4 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">rat</td><td headers="hd_h_ml282.tu1_1_1_1_5 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml282.tu1_1_1_1_6 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml282.tu1_1_1_1_7 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">17</td><td headers="hd_h_ml282.tu1_1_1_1_8 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_9 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_10 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_11 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml282.tu1_1_1_1_1 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">226500</td><td headers="hd_h_ml282.tu1_1_1_1_2 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">GABA<sub>A</sub>, Muscimol, Central</td><td headers="hd_h_ml282.tu1_1_1_1_3 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">307271</td><td headers="hd_h_ml282.tu1_1_1_1_4 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">rat</td><td headers="hd_h_ml282.tu1_1_1_1_5 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml282.tu1_1_1_1_6 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml282.tu1_1_1_1_7 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">−1</td><td headers="hd_h_ml282.tu1_1_1_1_8 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_9 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_10 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_11 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml282.tu1_1_1_1_1 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">228610</td><td headers="hd_h_ml282.tu1_1_1_1_2 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">GABA<sub>B1A</sub></td><td headers="hd_h_ml282.tu1_1_1_1_3 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">307172</td><td headers="hd_h_ml282.tu1_1_1_1_4 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml282.tu1_1_1_1_5 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml282.tu1_1_1_1_6 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml282.tu1_1_1_1_7 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">−21</td><td headers="hd_h_ml282.tu1_1_1_1_8 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_9 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_10 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_11 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml282.tu1_1_1_1_1 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">232030</td><td headers="hd_h_ml282.tu1_1_1_1_2 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Glucocorticoid</td><td headers="hd_h_ml282.tu1_1_1_1_3 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">307168</td><td headers="hd_h_ml282.tu1_1_1_1_4 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml282.tu1_1_1_1_5 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml282.tu1_1_1_1_6 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml282.tu1_1_1_1_7 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">7</td><td headers="hd_h_ml282.tu1_1_1_1_8 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_9 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_10 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_11 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml282.tu1_1_1_1_1 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">232700</td><td headers="hd_h_ml282.tu1_1_1_1_2 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Glutamate, Kainate</td><td headers="hd_h_ml282.tu1_1_1_1_3 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">307279</td><td headers="hd_h_ml282.tu1_1_1_1_4 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">rat</td><td headers="hd_h_ml282.tu1_1_1_1_5 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml282.tu1_1_1_1_6 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml282.tu1_1_1_1_7 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">10</td><td headers="hd_h_ml282.tu1_1_1_1_8 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_9 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_10 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_11 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml282.tu1_1_1_1_1 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">232810</td><td headers="hd_h_ml282.tu1_1_1_1_2 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Glutamate, NMDA, Agonism</td><td headers="hd_h_ml282.tu1_1_1_1_3 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">307135</td><td headers="hd_h_ml282.tu1_1_1_1_4 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">rat</td><td headers="hd_h_ml282.tu1_1_1_1_5 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml282.tu1_1_1_1_6 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml282.tu1_1_1_1_7 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">18</td><td headers="hd_h_ml282.tu1_1_1_1_8 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_9 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_10 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_11 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml282.tu1_1_1_1_1 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">232910</td><td headers="hd_h_ml282.tu1_1_1_1_2 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Glutamate, NMDA, Glycine</td><td headers="hd_h_ml282.tu1_1_1_1_3 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">307136</td><td headers="hd_h_ml282.tu1_1_1_1_4 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">rat</td><td headers="hd_h_ml282.tu1_1_1_1_5 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml282.tu1_1_1_1_6 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml282.tu1_1_1_1_7 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">0</td><td headers="hd_h_ml282.tu1_1_1_1_8 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_9 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_10 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_11 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml282.tu1_1_1_1_1 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">233000</td><td headers="hd_h_ml282.tu1_1_1_1_2 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Glutamate, NMDA, Phencyclidine</td><td headers="hd_h_ml282.tu1_1_1_1_3 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">307272</td><td headers="hd_h_ml282.tu1_1_1_1_4 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">rat</td><td headers="hd_h_ml282.tu1_1_1_1_5 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml282.tu1_1_1_1_6 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml282.tu1_1_1_1_7 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">7</td><td headers="hd_h_ml282.tu1_1_1_1_8 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_9 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_10 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_11 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml282.tu1_1_1_1_1 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">239610</td><td headers="hd_h_ml282.tu1_1_1_1_2 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Histamine H<sub>1</sub></td><td headers="hd_h_ml282.tu1_1_1_1_3 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">307137</td><td headers="hd_h_ml282.tu1_1_1_1_4 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml282.tu1_1_1_1_5 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml282.tu1_1_1_1_6 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml282.tu1_1_1_1_7 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">7</td><td headers="hd_h_ml282.tu1_1_1_1_8 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_9 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_10 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_11 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml282.tu1_1_1_1_1 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">239710</td><td headers="hd_h_ml282.tu1_1_1_1_2 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Histamine H<sub>2</sub></td><td headers="hd_h_ml282.tu1_1_1_1_3 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">307138</td><td headers="hd_h_ml282.tu1_1_1_1_4 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml282.tu1_1_1_1_5 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml282.tu1_1_1_1_6 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml282.tu1_1_1_1_7 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">1</td><td headers="hd_h_ml282.tu1_1_1_1_8 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_9 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_10 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_11 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml282.tu1_1_1_1_1 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">239820</td><td headers="hd_h_ml282.tu1_1_1_1_2 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Histamine H<sub>3</sub></td><td headers="hd_h_ml282.tu1_1_1_1_3 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">307158</td><td headers="hd_h_ml282.tu1_1_1_1_4 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml282.tu1_1_1_1_5 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml282.tu1_1_1_1_6 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml282.tu1_1_1_1_7 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">−6</td><td headers="hd_h_ml282.tu1_1_1_1_8 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_9 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_10 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_11 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml282.tu1_1_1_1_1 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">241000</td><td headers="hd_h_ml282.tu1_1_1_1_2 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Imidazoline I<sub>2</sub>, Central</td><td headers="hd_h_ml282.tu1_1_1_1_3 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">307281</td><td headers="hd_h_ml282.tu1_1_1_1_4 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">rat</td><td headers="hd_h_ml282.tu1_1_1_1_5 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml282.tu1_1_1_1_6 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml282.tu1_1_1_1_7 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">−3</td><td headers="hd_h_ml282.tu1_1_1_1_8 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_9 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_10 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_11 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml282.tu1_1_1_1_1 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">243520</td><td headers="hd_h_ml282.tu1_1_1_1_2 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Interleukin IL-1</td><td headers="hd_h_ml282.tu1_1_1_1_3 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">307139</td><td headers="hd_h_ml282.tu1_1_1_1_4 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">mouse</td><td headers="hd_h_ml282.tu1_1_1_1_5 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml282.tu1_1_1_1_6 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml282.tu1_1_1_1_7 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">22</td><td headers="hd_h_ml282.tu1_1_1_1_8 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_9 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_10 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_11 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml282.tu1_1_1_1_1 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">250460</td><td headers="hd_h_ml282.tu1_1_1_1_2 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Leukotriene, Cysteinyl CysL T<sub>1</sub></td><td headers="hd_h_ml282.tu1_1_1_1_3 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">307554</td><td headers="hd_h_ml282.tu1_1_1_1_4 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml282.tu1_1_1_1_5 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml282.tu1_1_1_1_6 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml282.tu1_1_1_1_7 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">−5</td><td headers="hd_h_ml282.tu1_1_1_1_8 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_9 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_10 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_11 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml282.tu1_1_1_1_1 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">251600</td><td headers="hd_h_ml282.tu1_1_1_1_2 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Melatonin MT<sub>1</sub></td><td headers="hd_h_ml282.tu1_1_1_1_3 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">307162</td><td headers="hd_h_ml282.tu1_1_1_1_4 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml282.tu1_1_1_1_5 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml282.tu1_1_1_1_6 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml282.tu1_1_1_1_7 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">2</td><td headers="hd_h_ml282.tu1_1_1_1_8 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_9 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_10 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_11 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml282.tu1_1_1_1_1 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">252610</td><td headers="hd_h_ml282.tu1_1_1_1_2 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Muscarinic M<sub>1</sub></td><td headers="hd_h_ml282.tu1_1_1_1_3 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">307255</td><td headers="hd_h_ml282.tu1_1_1_1_4 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml282.tu1_1_1_1_5 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml282.tu1_1_1_1_6 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml282.tu1_1_1_1_7 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">−1</td><td headers="hd_h_ml282.tu1_1_1_1_8 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_9 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_10 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_11 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml282.tu1_1_1_1_1 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">252710</td><td headers="hd_h_ml282.tu1_1_1_1_2 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Muscarinic M<sub>2</sub></td><td headers="hd_h_ml282.tu1_1_1_1_3 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">307256</td><td headers="hd_h_ml282.tu1_1_1_1_4 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml282.tu1_1_1_1_5 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml282.tu1_1_1_1_6 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml282.tu1_1_1_1_7 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">2</td><td headers="hd_h_ml282.tu1_1_1_1_8 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_9 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_10 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_11 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml282.tu1_1_1_1_1 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">252810</td><td headers="hd_h_ml282.tu1_1_1_1_2 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Muscarinic M<sub>3</sub></td><td headers="hd_h_ml282.tu1_1_1_1_3 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">307257</td><td headers="hd_h_ml282.tu1_1_1_1_4 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml282.tu1_1_1_1_5 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml282.tu1_1_1_1_6 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml282.tu1_1_1_1_7 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">4</td><td headers="hd_h_ml282.tu1_1_1_1_8 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_9 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_10 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_11 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml282.tu1_1_1_1_1 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">257010</td><td headers="hd_h_ml282.tu1_1_1_1_2 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Neuropeptide Y Y<sub>1</sub></td><td headers="hd_h_ml282.tu1_1_1_1_3 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">307553</td><td headers="hd_h_ml282.tu1_1_1_1_4 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml282.tu1_1_1_1_5 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml282.tu1_1_1_1_6 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml282.tu1_1_1_1_7 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">5</td><td headers="hd_h_ml282.tu1_1_1_1_8 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_9 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_10 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_11 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml282.tu1_1_1_1_1 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">257110</td><td headers="hd_h_ml282.tu1_1_1_1_2 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Neuropeptide Y Y<sub>2</sub></td><td headers="hd_h_ml282.tu1_1_1_1_3 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">307428</td><td headers="hd_h_ml282.tu1_1_1_1_4 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml282.tu1_1_1_1_5 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml282.tu1_1_1_1_6 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml282.tu1_1_1_1_7 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">6</td><td headers="hd_h_ml282.tu1_1_1_1_8 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_9 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_10 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_11 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml282.tu1_1_1_1_1 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">258590</td><td headers="hd_h_ml282.tu1_1_1_1_2 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Nicotinic Acetylcholine</td><td headers="hd_h_ml282.tu1_1_1_1_3 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">307282</td><td headers="hd_h_ml282.tu1_1_1_1_4 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml282.tu1_1_1_1_5 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml282.tu1_1_1_1_6 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml282.tu1_1_1_1_7 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">−10</td><td headers="hd_h_ml282.tu1_1_1_1_8 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_9 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_10 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_11 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml282.tu1_1_1_1_1 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">258700</td><td headers="hd_h_ml282.tu1_1_1_1_2 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Nicotinic Acetylcholine α Bungarotoxin</td><td headers="hd_h_ml282.tu1_1_1_1_3 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">307283</td><td headers="hd_h_ml282.tu1_1_1_1_4 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml282.tu1_1_1_1_5 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml282.tu1_1_1_1_6 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml282.tu1_1_1_1_7 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">−3</td><td headers="hd_h_ml282.tu1_1_1_1_8 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_9 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_10 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_11 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml282.tu1_1_1_1_1 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">260130</td><td headers="hd_h_ml282.tu1_1_1_1_2 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Opiate δ<sub>1</sub> (OP1, DOP)</td><td headers="hd_h_ml282.tu1_1_1_1_3 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">307556</td><td headers="hd_h_ml282.tu1_1_1_1_4 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml282.tu1_1_1_1_5 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml282.tu1_1_1_1_6 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml282.tu1_1_1_1_7 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">0</td><td headers="hd_h_ml282.tu1_1_1_1_8 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_9 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_10 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_11 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml282.tu1_1_1_1_1 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">260210</td><td headers="hd_h_ml282.tu1_1_1_1_2 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Opiate κ(OP2, KOP)</td><td headers="hd_h_ml282.tu1_1_1_1_3 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">307557</td><td headers="hd_h_ml282.tu1_1_1_1_4 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml282.tu1_1_1_1_5 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml282.tu1_1_1_1_6 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml282.tu1_1_1_1_7 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">3</td><td headers="hd_h_ml282.tu1_1_1_1_8 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_9 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_10 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_11 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml282.tu1_1_1_1_1 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">260410</td><td headers="hd_h_ml282.tu1_1_1_1_2 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Opiate μ(OP3, MOP)</td><td headers="hd_h_ml282.tu1_1_1_1_3 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">307273</td><td headers="hd_h_ml282.tu1_1_1_1_4 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml282.tu1_1_1_1_5 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml282.tu1_1_1_1_6 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml282.tu1_1_1_1_7 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">−1</td><td headers="hd_h_ml282.tu1_1_1_1_8 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_9 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_10 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_11 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml282.tu1_1_1_1_1 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">264500</td><td headers="hd_h_ml282.tu1_1_1_1_2 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Phorbol Ester</td><td headers="hd_h_ml282.tu1_1_1_1_3 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">307284</td><td headers="hd_h_ml282.tu1_1_1_1_4 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">mouse</td><td headers="hd_h_ml282.tu1_1_1_1_5 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml282.tu1_1_1_1_6 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml282.tu1_1_1_1_7 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">6</td><td headers="hd_h_ml282.tu1_1_1_1_8 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_9 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_10 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_11 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml282.tu1_1_1_1_1 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">265010</td><td headers="hd_h_ml282.tu1_1_1_1_2 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Platelet Activating Factor (PAF)</td><td headers="hd_h_ml282.tu1_1_1_1_3 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">307232</td><td headers="hd_h_ml282.tu1_1_1_1_4 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml282.tu1_1_1_1_5 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml282.tu1_1_1_1_6 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml282.tu1_1_1_1_7 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">8</td><td headers="hd_h_ml282.tu1_1_1_1_8 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_9 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_10 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_11 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml282.tu1_1_1_1_1 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">265600</td><td headers="hd_h_ml282.tu1_1_1_1_2 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Potassium Channel[K<sub>ATP</sub>]</td><td headers="hd_h_ml282.tu1_1_1_1_3 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">307285</td><td headers="hd_h_ml282.tu1_1_1_1_4 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">ham</td><td headers="hd_h_ml282.tu1_1_1_1_5 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml282.tu1_1_1_1_6 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml282.tu1_1_1_1_7 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">1</td><td headers="hd_h_ml282.tu1_1_1_1_8 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_9 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_10 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_11 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml282.tu1_1_1_1_1 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">265900</td><td headers="hd_h_ml282.tu1_1_1_1_2 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Potassium Channel hERG</td><td headers="hd_h_ml282.tu1_1_1_1_3 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">307269</td><td headers="hd_h_ml282.tu1_1_1_1_4 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml282.tu1_1_1_1_5 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml282.tu1_1_1_1_6 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml282.tu1_1_1_1_7 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">−18</td><td headers="hd_h_ml282.tu1_1_1_1_8 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_9 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_10 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_11 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml282.tu1_1_1_1_1 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">268420</td><td headers="hd_h_ml282.tu1_1_1_1_2 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Prostanoid EP<sub>4</sub></td><td headers="hd_h_ml282.tu1_1_1_1_3 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">307152</td><td headers="hd_h_ml282.tu1_1_1_1_4 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml282.tu1_1_1_1_5 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml282.tu1_1_1_1_6 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml282.tu1_1_1_1_7 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">13</td><td headers="hd_h_ml282.tu1_1_1_1_8 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_9 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_10 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_11 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml282.tu1_1_1_1_1 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">268700</td><td headers="hd_h_ml282.tu1_1_1_1_2 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Purinergic P<sub>2X</sub></td><td headers="hd_h_ml282.tu1_1_1_1_3 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">307432</td><td headers="hd_h_ml282.tu1_1_1_1_4 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">rabbit</td><td headers="hd_h_ml282.tu1_1_1_1_5 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml282.tu1_1_1_1_6 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml282.tu1_1_1_1_7 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">8</td><td headers="hd_h_ml282.tu1_1_1_1_8 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_9 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_10 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_11 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml282.tu1_1_1_1_1 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">268810</td><td headers="hd_h_ml282.tu1_1_1_1_2 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Purinergic P<sub>2Y</sub></td><td headers="hd_h_ml282.tu1_1_1_1_3 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">307143</td><td headers="hd_h_ml282.tu1_1_1_1_4 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">rat</td><td headers="hd_h_ml282.tu1_1_1_1_5 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml282.tu1_1_1_1_6 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml282.tu1_1_1_1_7 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">9</td><td headers="hd_h_ml282.tu1_1_1_1_8 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_9 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_10 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_11 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml282.tu1_1_1_1_1 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">270000</td><td headers="hd_h_ml282.tu1_1_1_1_2 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Rolipram</td><td headers="hd_h_ml282.tu1_1_1_1_3 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">307286</td><td headers="hd_h_ml282.tu1_1_1_1_4 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">rat</td><td headers="hd_h_ml282.tu1_1_1_1_5 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml282.tu1_1_1_1_6 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml282.tu1_1_1_1_7 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">5</td><td headers="hd_h_ml282.tu1_1_1_1_8 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_9 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_10 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_11 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml282.tu1_1_1_1_1 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">271110</td><td headers="hd_h_ml282.tu1_1_1_1_2 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serotonin (5-Hydroxytryptamine) 5-HT<sub>1A</sub></td><td headers="hd_h_ml282.tu1_1_1_1_3 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">307163</td><td headers="hd_h_ml282.tu1_1_1_1_4 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml282.tu1_1_1_1_5 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml282.tu1_1_1_1_6 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml282.tu1_1_1_1_7 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">4</td><td headers="hd_h_ml282.tu1_1_1_1_8 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_9 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_10 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_11 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml282.tu1_1_1_1_1 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">271700</td><td headers="hd_h_ml282.tu1_1_1_1_2 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serotonin (5-Hydroxytryptamine) 5-HT<sub>2B</sub></td><td headers="hd_h_ml282.tu1_1_1_1_3 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">307254</td><td headers="hd_h_ml282.tu1_1_1_1_4 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml282.tu1_1_1_1_5 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml282.tu1_1_1_1_6 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml282.tu1_1_1_1_7 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">40</td><td headers="hd_h_ml282.tu1_1_1_1_8 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_9 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_10 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_11 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml282.tu1_1_1_1_1 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">271910</td><td headers="hd_h_ml282.tu1_1_1_1_2 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serotonin (5-Hydroxytryptamine) 5-HT<sub>3</sub></td><td headers="hd_h_ml282.tu1_1_1_1_3 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">307154</td><td headers="hd_h_ml282.tu1_1_1_1_4 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml282.tu1_1_1_1_5 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml282.tu1_1_1_1_6 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml282.tu1_1_1_1_7 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">11</td><td headers="hd_h_ml282.tu1_1_1_1_8 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_9 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_10 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_11 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml282.tu1_1_1_1_1 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">278110</td><td headers="hd_h_ml282.tu1_1_1_1_2 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Sigma σ<sub>1</sub></td><td headers="hd_h_ml282.tu1_1_1_1_3 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">307154</td><td headers="hd_h_ml282.tu1_1_1_1_4 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml282.tu1_1_1_1_5 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml282.tu1_1_1_1_6 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml282.tu1_1_1_1_7 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">−1</td><td headers="hd_h_ml282.tu1_1_1_1_8 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_9 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_10 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_11 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml282.tu1_1_1_1_1 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">255520</td><td headers="hd_h_ml282.tu1_1_1_1_2 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Tachykinin NK<sub>1</sub></td><td headers="hd_h_ml282.tu1_1_1_1_3 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">307426</td><td headers="hd_h_ml282.tu1_1_1_1_4 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml282.tu1_1_1_1_5 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml282.tu1_1_1_1_6 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml282.tu1_1_1_1_7 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">5</td><td headers="hd_h_ml282.tu1_1_1_1_8 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_9 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_10 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_11 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml282.tu1_1_1_1_1 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">285900</td><td headers="hd_h_ml282.tu1_1_1_1_2 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Thyroid Hormone</td><td headers="hd_h_ml282.tu1_1_1_1_3 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">307120</td><td headers="hd_h_ml282.tu1_1_1_1_4 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">rat</td><td headers="hd_h_ml282.tu1_1_1_1_5 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml282.tu1_1_1_1_6 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml282.tu1_1_1_1_7 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">9</td><td headers="hd_h_ml282.tu1_1_1_1_8 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_9 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_10 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_11 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml282.tu1_1_1_1_1 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">220320</td><td headers="hd_h_ml282.tu1_1_1_1_2 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Transporter, Dopamine (DAT)</td><td headers="hd_h_ml282.tu1_1_1_1_3 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">307266</td><td headers="hd_h_ml282.tu1_1_1_1_4 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml282.tu1_1_1_1_5 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml282.tu1_1_1_1_6 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml282.tu1_1_1_1_7 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">−7</td><td headers="hd_h_ml282.tu1_1_1_1_8 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_9 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_10 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_11 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml282.tu1_1_1_1_1 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">226400</td><td headers="hd_h_ml282.tu1_1_1_1_2 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Transporter, GABA</td><td headers="hd_h_ml282.tu1_1_1_1_3 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">307274</td><td headers="hd_h_ml282.tu1_1_1_1_4 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">rat</td><td headers="hd_h_ml282.tu1_1_1_1_5 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml282.tu1_1_1_1_6 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml282.tu1_1_1_1_7 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">2</td><td headers="hd_h_ml282.tu1_1_1_1_8 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_9 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_10 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_11 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml282.tu1_1_1_1_1 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">204410</td><td headers="hd_h_ml282.tu1_1_1_1_2 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Transporter, Norepinephrine (NET)</td><td headers="hd_h_ml282.tu1_1_1_1_3 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">307265</td><td headers="hd_h_ml282.tu1_1_1_1_4 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml282.tu1_1_1_1_5 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml282.tu1_1_1_1_6 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml282.tu1_1_1_1_7 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">11</td><td headers="hd_h_ml282.tu1_1_1_1_8 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_9 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_10 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_11 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr><tr><td headers="hd_h_ml282.tu1_1_1_1_1 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">274030</td><td headers="hd_h_ml282.tu1_1_1_1_2 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Transporter, Serotonin (5-Hydroxytryptamine)</td><td headers="hd_h_ml282.tu1_1_1_1_3 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">307280</td><td headers="hd_h_ml282.tu1_1_1_1_4 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml282.tu1_1_1_1_5 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml282.tu1_1_1_1_6 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml282.tu1_1_1_1_7 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">3</td><td headers="hd_h_ml282.tu1_1_1_1_8 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_9 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_10 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td><td headers="hd_h_ml282.tu1_1_1_1_11 hd_b_ml282.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;"></td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div id="ml282.tfn10"><p class="no_margin">Note: Items meeting criteria for significance (≥50% stimulation or inhibition) are highlighted.</p></div></dd><dt>*</dt><dd><div id="ml282.tfn7"><p class="no_margin">Batch: Represents compounds tested concurrently in the same assay(s).</p></div></dd><dt></dt><dd><div id="ml282.tfn8"><p class="no_margin">R=See Remarks (if any) at end of this section.</p></div></dd><dt></dt><dd><div id="ml282.tfn9"><p class="no_margin">ham=Hamster; hum= Human</p></div></dd></dl></div></div></div></div></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/NBK143553/?report=reader">PubReader</a></li><li><a href="/books/NBK143553/?report=printable">Print View</a></li><li><a data-jig="ncbidialog" href="#_ncbi_dlg_citbx_NBK143553" data-jigconfig="width:400,modal:true">Cite this Page</a><div id="_ncbi_dlg_citbx_NBK143553" style="display:none" title="Cite this Page"><div class="bk_tt">Hong L, Simons P, Waller A, et al. A small molecule pan-inhibitor of Ras-superfamily GTPases with high efficacy towards Rab7. 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="#ml282.s1" ref="log$=inpage&link_id=inpage">Probe Structure & Characteristics</a></li><li><a href="#ml282.s2" ref="log$=inpage&link_id=inpage">Recommendations for Scientific Use of the Probe</a></li><li><a href="#ml282.s3" ref="log$=inpage&link_id=inpage">Materials and Methods</a></li><li><a href="#ml282.s20" ref="log$=inpage&link_id=inpage">Results</a></li><li><a href="#ml282.s25" ref="log$=inpage&link_id=inpage">Discussion</a></li><li><a href="#ml282.s27" ref="log$=inpage&link_id=inpage">References</a></li><li><a href="#ml282.app1" ref="log$=inpage&link_id=inpage">Ricerca Profiling Results for ML282</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Related information</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="discovery_db_links" id="Shutter"></a></div><div class="portlet_content"><ul><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=pmc&DbFrom=books&Cmd=Link&LinkName=books_pmc_refs&IdsFromResult=3036330" ref="log$=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=3036330" ref="log$=recordlinks">PubChem BioAssay for Chemical Probe</a><div class="brieflinkpop offscreen_noflow">PubChem BioAssay records reporting screening data for the development of the chemical probe(s) described in this book chapter</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=pcsubstance&DbFrom=books&Cmd=Link&LinkName=books_pcsubstance&IdsFromResult=3036330" ref="log$=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=3036330" ref="log$=recordlinks">PubMed</a><div class="brieflinkpop offscreen_noflow">Links to PubMed</div></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Similar articles in PubMed</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="PBooksDiscovery_RA" id="Shutter"></a></div><div class="portlet_content"><ul><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/22486388" ref="ordinalpos=1&linkpos=1&log$=relatedarticles&logdbfrom=pubmed">A competitive nucleotide binding inhibitor: in vitro characterization of Rab7 GTPase inhibition.</a><span class="source">[ACS Chem Biol. 2012]</span><div class="brieflinkpop offscreen_noflow">A competitive nucleotide binding inhibitor: in vitro characterization of Rab7 GTPase inhibition.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Agola JO, Hong L, Surviladze Z, Ursu O, Waller A, Strouse JJ, Simpson DS, Schroeder CE, Oprea TI, Golden JE, et al. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">ACS Chem Biol. 2012 Jun 15; 7(6):1095-108. 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