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<script type="text/javascript" src="/corehtml/pmc/jatsreader/ptpmc_3.22/js/jr.boots.min.js"> </script><title>Selective small molecule activator of the apoptotic arm of the UPR - Probe Reports from the NIH Molecular Libraries Program - NCBI Bookshelf</title>
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<meta name="citation_inbook_title" content="Probe Reports from the NIH Molecular Libraries Program [Internet]">
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<meta name="citation_title" content="Selective small molecule activator of the apoptotic arm of the UPR">
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<meta name="citation_publisher" content="National Center for Biotechnology Information (US)">
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<meta name="citation_date" content="2013/02/28">
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<meta name="citation_author" content="Daniel P. Flaherty">
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<meta name="citation_author" content="Jennifer E. Golden">
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<meta name="citation_author" content="Chunjing Liu">
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<meta name="citation_author" content="Michael Hedrick">
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<meta name="citation_author" content="Palak Gosalia">
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<meta name="citation_author" content="Yujie Li">
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<meta name="citation_author" content="Monika Milewski">
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<meta name="citation_author" content="Eliot Sugarman">
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<meta name="citation_author" content="Eigo Suyama">
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<meta name="citation_author" content="Kevin Nguyen">
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<meta name="citation_author" content="Stefan Vasile">
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<meta name="citation_author" content="Sumeet Salaniwal">
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<meta name="citation_author" content="Derek Stonich">
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<meta name="citation_author" content="Ying Su">
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<meta name="citation_author" content="Arianna Mangravita-Novo">
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<meta name="citation_author" content="Michael Vicchiarelli">
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<meta name="citation_author" content="Layton H. Smith">
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<meta name="citation_author" content="Jena Diwan">
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<meta name="citation_author" content="Thomas D.Y. Chung">
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<meta name="citation_author" content="Anthony B. Pinkerton">
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<meta name="citation_author" content="Jeffrey Aubé">
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<meta name="citation_author" content="Justin R. Miller">
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<meta name="citation_author" content="Danielle M. Garshott">
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<meta name="citation_author" content="Michael U. Callaghan">
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<meta name="citation_author" content="Andrew M. Fribley">
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<meta name="citation_author" content="Randal J. Kaufman">
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<meta name="citation_pmid" content="23658962">
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<meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK133431/">
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<meta name="DC.Title" content="Selective small molecule activator of the apoptotic arm of the UPR">
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<meta name="DC.Type" content="Text">
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<meta name="DC.Publisher" content="National Center for Biotechnology Information (US)">
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<meta name="DC.Contributor" content="Daniel P. Flaherty">
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<meta name="DC.Contributor" content="Jennifer E. Golden">
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<meta name="DC.Contributor" content="Chunjing Liu">
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<meta name="DC.Contributor" content="Michael Hedrick">
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<meta name="DC.Contributor" content="Palak Gosalia">
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<meta name="DC.Contributor" content="Yujie Li">
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<meta name="DC.Contributor" content="Monika Milewski">
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<meta name="DC.Contributor" content="Eliot Sugarman">
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<meta name="DC.Contributor" content="Eigo Suyama">
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<meta name="DC.Contributor" content="Kevin Nguyen">
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<meta name="DC.Contributor" content="Stefan Vasile">
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<meta name="DC.Contributor" content="Sumeet Salaniwal">
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<meta name="DC.Contributor" content="Derek Stonich">
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<meta name="DC.Contributor" content="Ying Su">
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<meta name="DC.Contributor" content="Arianna Mangravita-Novo">
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<meta name="DC.Contributor" content="Michael Vicchiarelli">
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<meta name="DC.Contributor" content="Layton H. Smith">
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<meta name="DC.Contributor" content="Jena Diwan">
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<meta name="DC.Contributor" content="Thomas D.Y. Chung">
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<meta name="DC.Contributor" content="Anthony B. Pinkerton">
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<meta name="DC.Contributor" content="Jeffrey Aubé">
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<meta name="DC.Contributor" content="Justin R. Miller">
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<meta name="DC.Contributor" content="Danielle M. Garshott">
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<meta name="DC.Contributor" content="Michael U. Callaghan">
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<meta name="DC.Contributor" content="Andrew M. Fribley">
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<meta name="DC.Contributor" content="Randal J. Kaufman">
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<meta name="DC.Date" content="2013/02/28">
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<meta name="DC.Identifier" content="https://www.ncbi.nlm.nih.gov/books/NBK133431/">
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<meta name="description" content="Many diseases, such as diabetes, Alzheimer’s, Parkinson’s, hemophilia, and lysosomal storage diseases and cancer involve folding defects or impaired transport of proteins from the endoplasmic reticulum (ER). Cells activate the Unfolded Protein Response (UPR) to restore homeostatic protein processing by clearing out the stress of accumulated misfolded proteins (adaptive arm). However, with prolonged stress an apoptotic arm of the UPR leads to selective cell death. We herein report the successful development of a first-in-class, potent (762 nM EC50), not generally cytotoxic, chemical probe, ML291, that selectively activates the apoptotic but not the adaptive arm of the UPR, that demonstrates efficacy in inducing cell death through activation of the apoptotic arm in relevant cells, and moreover activate genes associated with the apoptotic arm of the UPR (by qRT-PCR). The progenitor of this probe was identified through a high-throughput screen of the NIH Molecular Libraries Small Molecule Repository (MLSMR) of >350,000 compounds through complementary cell-based reporter assays using stably transfected CHO-K1 cells that specifically identify activators of the PERK/eIF2a/CHOP (apoptotic), but not the IRE1/XBP1 (adaptive) UPR subpathways. The identification, validation, structure activity relationship (SAR) elucidation and development of this probe are described. The probe may serve as the basis for eventual proof-of-concept tool compound for activation of the apoptotic arm of UPR as a therapeutic modality in certain diseases.">
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<meta name="og:title" content="Selective small molecule activator of the apoptotic arm of the UPR">
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<meta name="og:description" content="Many diseases, such as diabetes, Alzheimer’s, Parkinson’s, hemophilia, and lysosomal storage diseases and cancer involve folding defects or impaired transport of proteins from the endoplasmic reticulum (ER). Cells activate the Unfolded Protein Response (UPR) to restore homeostatic protein processing by clearing out the stress of accumulated misfolded proteins (adaptive arm). However, with prolonged stress an apoptotic arm of the UPR leads to selective cell death. We herein report the successful development of a first-in-class, potent (762 nM EC50), not generally cytotoxic, chemical probe, ML291, that selectively activates the apoptotic but not the adaptive arm of the UPR, that demonstrates efficacy in inducing cell death through activation of the apoptotic arm in relevant cells, and moreover activate genes associated with the apoptotic arm of the UPR (by qRT-PCR). The progenitor of this probe was identified through a high-throughput screen of the NIH Molecular Libraries Small Molecule Repository (MLSMR) of >350,000 compounds through complementary cell-based reporter assays using stably transfected CHO-K1 cells that specifically identify activators of the PERK/eIF2a/CHOP (apoptotic), but not the IRE1/XBP1 (adaptive) UPR subpathways. The identification, validation, structure activity relationship (SAR) elucidation and development of this probe are described. The probe may serve as the basis for eventual proof-of-concept tool compound for activation of the apoptotic arm of UPR as a therapeutic modality in certain diseases.">
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match">◀</a><button id="jr-fip-matches">no matches yet</button><a id="jr-fip-next" class="wsprkl btn" title="Jump to next match">▶</a></nav></nav></div><div id="jr-epub-interstitial" class="hidden"></div><div id="jr-content"><article data-type="main"><div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><div class="fm-sec"><h1 id="_NBK133431_"><span class="title" itemprop="name">Selective small molecule activator of the apoptotic arm of the UPR</span></h1><p class="contribs">Flaherty DP, Golden JE, Liu C, et al.</p><p class="fm-aai"><a href="#_NBK133431_pubdet_">Publication Details</a></p></div></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="_abs_rndgid_" itemprop="description"><p>Many diseases, such as diabetes, Alzheimer’s, Parkinson’s, hemophilia, and
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lysosomal storage diseases and cancer involve folding defects or impaired transport of proteins from
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the endoplasmic reticulum (ER). Cells activate the Unfolded Protein Response (UPR) to restore homeostatic protein processing by clearing out the stress of accumulated misfolded proteins (adaptive arm). However, with prolonged stress an apoptotic arm of the UPR leads to selective cell death. We herein report the successful development of a first-in-class, potent (762 nM EC<sub>50</sub>), not generally cytotoxic, chemical probe, <a href="/pcsubstance/?term=ML291[synonym]" ref="pagearea=abstract&targetsite=entrez&targetcat=term&targettype=pubchem">ML291</a>, that selectively activates the apoptotic but not the adaptive arm of the UPR, that demonstrates efficacy in inducing cell death through activation of the apoptotic arm in relevant cells, and moreover activate genes associated with the apoptotic arm of the UPR (by qRT-PCR). The progenitor of this probe was identified through a high-throughput screen of the NIH Molecular Libraries Small Molecule Repository (MLSMR) of >350,000 compounds through complementary cell-based reporter assays using stably transfected CHO-K1 cells that specifically identify activators of the PERK/eIF2a/CHOP (apoptotic), but not the IRE1/XBP1 (adaptive) UPR subpathways. The identification, validation, structure activity relationship (SAR) elucidation and development of this probe are described. The probe may serve as the basis for eventual proof-of-concept tool compound for activation of the apoptotic arm of UPR as a therapeutic modality in certain diseases.</p></div><div class="h2"></div><p><b>Assigned Assay Grant #:</b> 1 R03 MH089782-01</p><p><b>Screening Center Name & PI:</b> Sanford-Burnham Center for Chemical Genomics, John C. Reed, PI</p><p><b>Chemistry Center Name & PI:</b> University of Kansas Specialized Chemistry Center, Jeffrey Aubé, PI</p><p><b>Assay Submitter & Institution:</b> Randal J Kaufman, Sanford-Burnham Medical Research Institute (<i>formerly at U. Michigan</i>) & Collaborating PI: Andrew M. Fribley, Wayne State University</p><p><b>PubChem Summary Bioassay Identifier (AID):</b>
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<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/449771" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">449771</a></p><div id="ml291.s1"><h2 id="_ml291_s1_">Probe Structure & Characteristics</h2><div id="ml291.fu1" class="figure"><div class="graphic"><img src="/books/NBK133431/bin/ml291fu1.jpg" alt="Image ml291fu1" /></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml291tu1"><a href="/books/NBK133431/table/ml291.tu1/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figml291tu1" rid-ob="figobml291tu1"><img class="small-thumb" src="/books/NBK133431/table/ml291.tu1/?report=thumb" src-large="/books/NBK133431/table/ml291.tu1/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ml291.tu1"><a href="/books/NBK133431/table/ml291.tu1/?report=objectonly" target="object" rid-ob="figobml291tu1">Table</a></h4></div></div></div><div id="ml291.s2"><h2 id="_ml291_s2_">1. Recommendations for Scientific Use of the Probe</h2><p><b>What limitations in current state of the art is the probe addressing?</b> Prior to this report, there were no published reports of any pharmacologically and chemically attractive, <i><u>selective</u></i> small molecule activator probes to dissect the molecular mechanisms the apoptotic arm of the UPR activation, even at the phenotypic cell death level.</p><p><b>What would the probe be used for</b>? A probe of the type described would be used to characterize the molecular mechanism of UPR activation through PERK and ATF6. We would use such probes to test the hypothesis that small molecules that induce ER stress and overwhelm the hyperactive secretory pathway of head and neck squamous cell carcinoma cells will be an effective therapeutic approach to kill tumor cells.</p><p><b>Who in the research community will use the probe</b>? The ability to chemically activate the apoptotic arm of the UPR (in the absence of the adaptive arm) would broadly appeal to the interests of the UPR-focused scientific community. Currently we are without selective non-contrived methods or models to activate the PERK-eIF2α-CHOP (apoptotic) or ATF6-CHOP pathways that do not involve genetic manipulation or viral infection. Studies by our group and others have reported that CHOP-null cells are resistant to death induced by a variety of chemical and pathophysiological stresses, however, the mechanism by which CHOP actives cell death remains incompletely elucidated. Interestingly, it has been proposed that non-UPR related insults, such as DNA damage, might involve or rely on CHOP activation for the efficient induction of cell death. CHOP-specific probes identified from this screen will provide a unique panel of tools to identify novel pathways by which CHOP is activated and glean a clearer picture of the mechanism by which CHOP orchestrates UPR-mediated cell death, a subject of tremendous interest in the UPR field.</p><p><b>What is the relevant biology to which the probe can be applied</b>? CHOP-specific probes will permit the more careful dissection of the apoptotic UPR pathway in a fashion that will shed new insight into its potential as a therapeutic target. Current therapies for patients suffering from UPR related diseases are limited to minimally effective gene therapy or extensive costly enzyme replacement therapies. We would also assess the potential of the apoptosis-inducing compounds to kill head and neck cancer cells using a variety of <i>in vitro</i> and xenograft animal models. Many different human cancer cells (cell lines and surgical specimens) have been shown to have increased levels of UPR activation. We hypothesize that <i>CHOP-specific probes will overwhelm the adaptive UPR capacity of malignant cells</i>, while healthy cells, with low or no basal UPR activation, would be able to mount an effective UPR and overcome the chemotherapeutic challenge and directly induce apoptosis. The advantage of such as strategy is apparent in that the treatment could be delivered systemically, inducing UPR-mediated cell death specifically in malignant cells. Our laboratory’s multi-disciplinary approach will help us to maximize the potential of the most promising probe leads to improve diverse disease states ranging from diabetes and Alzheimer’s disease to a wide range of cancers including breast, lung, and head and neck squamous cell carcinoma.</p></div><div id="ml291.s3"><h2 id="_ml291_s3_">2. Materials and Methods</h2><p>The details of the primary HTS and additional assays can be found in the “Assay Description” section in the PubChem BioAssay view under the AIDs as listed in <a class="figpopup" href="/books/NBK133431/table/ml291.t1/?report=objectonly" target="object" rid-figpopup="figml291t1" rid-ob="figobml291t1">Table 1</a>. Additionally, the details for the primary HTS are provided in the <a href="#ml291.app1">Appendix A</a> at the end of this probe report.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml291t1"><a href="/books/NBK133431/table/ml291.t1/?report=objectonly" target="object" title="Table 1" class="img_link icnblk_img figpopup" rid-figpopup="figml291t1" rid-ob="figobml291t1"><img class="small-thumb" src="/books/NBK133431/table/ml291.t1/?report=thumb" src-large="/books/NBK133431/table/ml291.t1/?report=previmg" alt="Table 1. Summary of Assays and AIDs." /></a><div class="icnblk_cntnt"><h4 id="ml291.t1"><a href="/books/NBK133431/table/ml291.t1/?report=objectonly" target="object" rid-ob="figobml291t1">Table 1</a></h4><p class="float-caption no_bottom_margin">Summary of Assays and AIDs. </p></div></div><div id="ml291.s4"><h3>2.1. Assays</h3><p>The parental cell line for both reporter cell lines is CHO-K1. The construction of the XBP1 reporter was described by Back <i>et al</i>.<sup><a class="bibr" href="#ml291.r48" rid="ml291.r48">48</a></sup> and the stable clone used for screening was identified by Andrew Fribley (unpublished). The CHOP luciferase construct originally contained a GFP reporter and was described by Novoa <i>et al.</i><sup><a class="bibr" href="#ml291.r49" rid="ml291.r49">49</a></sup> The re-construction of the luciferase reporter and a subsequent screen for activators of CHOP were described by Harding <i>et al.</i><sup><a class="bibr" href="#ml291.r50" rid="ml291.r50">50</a></sup></p></div><div id="ml291.s5"><h3>2.2. Probe Chemical Characterization</h3><div id="ml291.s6"><h4>Chemical name of probe compound & structure including stereochemistry</h4><p>The IUPAC name of the probe <a href="/pcsubstance/?term=ML291[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML291</a> is <i>N</i>-(4-((4-chloropiperidin-1-yl)sulfonyl)phenyl)-5-nitrofuran-2-carboxamide. The actual batch prepared, tested and submitted to the MLSMR is archived as <a href="https://pubchem.ncbi.nlm.nih.gov/substance/134228465" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 134228465</a> corresponding to CID 52940465.</p><div id="ml291.fu2" class="figure"><div class="graphic"><img src="/books/NBK133431/bin/ml291fu2.jpg" alt="Image ml291fu2" /></div></div><p>For detailed characterization see <a href="#ml291.s10">Section 2.3</a>. Images
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of spectral data (<sup>1</sup>HNMR, <sup>13</sup>CNMR, and LC/MS) used to support the structural
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assignment of <a href="/pcsubstance/?term=ML291[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML291</a> can be found in Supplementary Information at end.</p></div><div id="ml291.s7"><h4>Availability from a vendor</h4><p>This probe is not commercially available. A 25 mg sample of <a href="/pcsubstance/?term=ML291[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML291</a> synthesized at the KUSCC has been deposited in the MLSMR (see Probe Submission <a class="figpopup" href="/books/NBK133431/table/ml291.t2/?report=objectonly" target="object" rid-figpopup="figml291t2" rid-ob="figobml291t2">Table 2</a>).</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml291t2"><a href="/books/NBK133431/table/ml291.t2/?report=objectonly" target="object" title="Table 2" class="img_link icnblk_img figpopup" rid-figpopup="figml291t2" rid-ob="figobml291t2"><img class="small-thumb" src="/books/NBK133431/table/ml291.t2/?report=thumb" src-large="/books/NBK133431/table/ml291.t2/?report=previmg" alt="Table 2. Probe and Analog Submissions to the MLSMR for the UPR CHOP Activator Probe." /></a><div class="icnblk_cntnt"><h4 id="ml291.t2"><a href="/books/NBK133431/table/ml291.t2/?report=objectonly" target="object" rid-ob="figobml291t2">Table 2</a></h4><p class="float-caption no_bottom_margin">Probe and Analog Submissions to the MLSMR for the UPR CHOP Activator Probe. </p></div></div></div><div id="ml291.s8"><h4>Solubility and stability of probe</h4><p>The solubility of <a href="/pcsubstance/?term=ML291[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML291</a> 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 (See <a class="figpopup" href="/books/NBK133431/table/ml291.t3/?report=objectonly" target="object" rid-figpopup="figml291t3" rid-ob="figobml291t3">Table 3</a> “Summary of <i>in vitro</i> ADME Properties …”) Probe <a href="/pcsubstance/?term=ML291[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML291</a> (CID 52940465<b>,</b>
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<a href="https://pubchem.ncbi.nlm.nih.gov/substance/134228465" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 134228465</a>) was found to have a solubility measurement of 3.9 μg/mL, or 9.4 μM, under these conditions.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml291t3"><a href="/books/NBK133431/table/ml291.t3/?report=objectonly" target="object" title="Table 3" class="img_link icnblk_img figpopup" rid-figpopup="figml291t3" rid-ob="figobml291t3"><img class="small-thumb" src="/books/NBK133431/table/ml291.t3/?report=thumb" src-large="/books/NBK133431/table/ml291.t3/?report=previmg" alt="Table 3. Summary of in vitro ADME Properties of UPR CHOP Activator probe ML291." /></a><div class="icnblk_cntnt"><h4 id="ml291.t3"><a href="/books/NBK133431/table/ml291.t3/?report=objectonly" target="object" rid-ob="figobml291t3">Table 3</a></h4><p class="float-caption no_bottom_margin">Summary of <i>in vitro</i> ADME Properties of UPR CHOP Activator probe ML291. </p></div></div><p>Stability was measured under two distinct conditions with <a href="/pcsubstance/?term=ML291[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML291</a> (CID 52940465, <a href="https://pubchem.ncbi.nlm.nih.gov/substance/134228465" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 134228465</a>, <a class="figpopup" href="/books/NBK133431/figure/ml291.f1/?report=objectonly" target="object" rid-figpopup="figml291f1" rid-ob="figobml291f1">Figure 1</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, illustrated with closed squares in the graph, was also assessed with 50% acetonitrile added to account for challenges with solubility of the compound in PBS alone. Stability data in each case 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 the end of the 48 hr. With no additives (closed circles), 11.44% of <a href="/pcsubstance/?term=ML291[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML291</a> remains after 48 hours; however, this data is dependent on and misleading due to the solubility limitations in PBS buffer. With the addition of 50% acetonitrile to account for solubility (closed squares), 100% of <a href="/pcsubstance/?term=ML291[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML291</a> remained after 48 hours.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml291f1" co-legend-rid="figlgndml291f1"><a href="/books/NBK133431/figure/ml291.f1/?report=objectonly" target="object" title="Figure 1" class="img_link icnblk_img figpopup" rid-figpopup="figml291f1" rid-ob="figobml291f1"><img class="small-thumb" src="/books/NBK133431/bin/ml291f1.gif" src-large="/books/NBK133431/bin/ml291f1.jpg" alt="Figure 1. Stability of ML291 over 48 h in PBS and 1:1 PBS:acetonitrile." /></a><div class="icnblk_cntnt" id="figlgndml291f1"><h4 id="ml291.f1"><a href="/books/NBK133431/figure/ml291.f1/?report=objectonly" target="object" rid-ob="figobml291f1">Figure 1</a></h4><p class="float-caption no_bottom_margin">Stability of ML291 over 48 h in PBS and 1:1 PBS:acetonitrile. Apparent instability in PBS is actually due to poor solubility of ML291. </p></div></div><p>To assess the chemical stability of <a href="/pcsubstance/?term=ML291[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML291</a> and its susceptibility to nucleophilic addition, the probe was exposed to a five-fold excess of 50 μM glutathione (GSH), or 50 μM dithiothreitol (DTT) over 8 h. <a href="/pcsubstance/?term=ML291[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML291</a> was dissolved at 10 μM in 50% acetonitrile/50% PBS at pH 7.4 (1% DMSO) and incubated at room temperature with either no nucleophile (control), 50 μM GSH, or 50 μM DTT. The mixtures were sampled every hour for eight hours and analyzed by LCMS. The analytical LCMS system utilized for the analysis was a Waters Acquity system with UV-detection and mass-detection (Waters LCT Premier). The analytical method conditions included a Waters Acquity HSS T3 C18 column (2.1 × 50mm, 1.8um) and elution with a linear gradient of 1% water to 100% CH3CN at 0.6 mL/min flow rate. Peaks on the 214nm chromatographs were integrated using the Waters OpenLynx software. Absolute areas under the curve were compared at each time point to determine relative percent remaining. The masses of potential adducts were searched for in the final samples to determine if any detectable adduct formed. All samples were prepared in duplicate. Ethacrynic acid, a known Michael acceptor, was used as a positive control and showed ~ 55% and ~ 25% ethacrynic acid remaining at 8 h with GSH and DTT, respectively (control plots not shown for clarity).</p><p>For each of the conditions described in <a class="figpopup" href="/books/NBK133431/figure/ml291.f2/?report=objectonly" target="object" rid-figpopup="figml291f2" rid-ob="figobml291f2">Figure 2</a>, the percent remaining of <a href="/pcsubstance/?term=ML291[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML291</a> after 8 h was determined to be between 99–100% (<a class="figpopup" href="/books/NBK133431/figure/ml291.f2/?report=objectonly" target="object" rid-figpopup="figml291f2" rid-ob="figobml291f2">Figure 2</a>). LCMS analysis of aliquots of each sample from each condition did not reveal detectable DTT or GSH adduct masses. This experiment demonstrated that <a href="/pcsubstance/?term=ML291[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML291</a> was not prone to alteration by thiol nucleophiles over an 8 h period.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml291f2" co-legend-rid="figlgndml291f2"><a href="/books/NBK133431/figure/ml291.f2/?report=objectonly" target="object" title="Figure 2" class="img_link icnblk_img figpopup" rid-figpopup="figml291f2" rid-ob="figobml291f2"><img class="small-thumb" src="/books/NBK133431/bin/ml291f2.gif" src-large="/books/NBK133431/bin/ml291f2.jpg" alt="Figure 2. Chemical stability of ML291, represented by percent of parent remaining over time, in the presence of five-fold molar equivalent of GSH or DTT, incubated at room temperature in 1:1 ACN:PBS, pH 7.4, 1% (v/v) DMSO." /></a><div class="icnblk_cntnt" id="figlgndml291f2"><h4 id="ml291.f2"><a href="/books/NBK133431/figure/ml291.f2/?report=objectonly" target="object" rid-ob="figobml291f2">Figure 2</a></h4><p class="float-caption no_bottom_margin">Chemical stability of ML291, represented by percent of parent remaining over time, in the presence of five-fold molar equivalent of GSH or DTT, incubated at room temperature in 1:1 ACN:PBS, pH 7.4, 1% (v/v) DMSO. </p></div></div></div><div id="ml291.s9"><h4>MLS# of probe molecule and five related samples that were submitted to the SMR collection</h4><p>Five analogues were selected for the support of probe <a href="/pcsubstance/?term=ML291[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML291</a>. All five compounds, including the probe, were synthesized by the KU SCC and are summarized in <a class="figpopup" href="/books/NBK133431/table/ml291.t2/?report=objectonly" target="object" rid-figpopup="figml291t2" rid-ob="figobml291t2">Table 2</a>.</p></div></div><div id="ml291.s10"><h3>2.3. Probe Preparation</h3><p>Synthesis and Structural Verification Information of probe <a href="/pcsubstance/?term=ML291[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML291</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/substance/123083137" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 123083137</a> corresponding to CID 52940465 (See <a class="figpopup" href="/books/NBK133431/figure/ml291.f5/?report=objectonly" target="object" rid-figpopup="figml291f5" rid-ob="figobml291f5">Scheme 1</a>).</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml291f5" co-legend-rid="figlgndml291f5"><a href="/books/NBK133431/figure/ml291.f5/?report=objectonly" target="object" title="Scheme 1" class="img_link icnblk_img figpopup" rid-figpopup="figml291f5" rid-ob="figobml291f5"><img class="small-thumb" src="/books/NBK133431/bin/ml291f5.gif" src-large="/books/NBK133431/bin/ml291f5.jpg" alt="Scheme 1" /></a><div class="icnblk_cntnt" id="figlgndml291f5"><h4 id="ml291.f5"><a href="/books/NBK133431/figure/ml291.f5/?report=objectonly" target="object" rid-ob="figobml291f5">Scheme 1</a></h4></div></div><p>The probe was prepared using the following protocols:</p><div id="ml291.fu3" class="figure"><div class="graphic"><img src="/books/NBK133431/bin/ml291fu3.jpg" alt="Image ml291fu3" /></div></div><p><b>4-chloro-1-((4-nitrophenyl)sulfonyl)piperidine:</b> To a vial was added 4-nitrobenzenesulfonyl chloride (0.32 g, 1.4 mmol), pyridine (0.11 g, 1.4 mmol) and THF (1.5 mL). The reaction was stirred at room temperature while 4-chloropiperidine (0.13 g, 1.0 mmol) was added dropwise over 10 minutes. The reaction was subsequently heated to 60 °C for 20 minutes and monitored by TLC. Upon completion the reaction was cooled to room temperature, diluted with EtOAc (10 mL) and washed with saturated aq. NaHCO<sub>3</sub> (10 mL). The EtOAc layer was separated, dried with MgSO<sub>4</sub>, filtered, adsorbed to silica and purified by silica gel flash column chromatography (15 min, 0 – 30% v/v EtOAc/hexanes) to produce pure 4-chloro-1-((4-nitrophenyl)sulfonyl)piperidine (0.29 g, 0.96 mmol, 96% yield). <sup>1</sup>H NMR (400 MHz, CDCl<sub>3</sub>): <i>δ</i> 8.40 (d, <i>J</i> = 9.0 Hz, 2H), 7.96 (d, <i>J</i> = 9.0 Hz, 2H), 4.22 (m, 1H), 3.29 (m, 2H), 3.18 (m, 2H), 2.16 (m, 2H), 1.97 (m, 2H).</p><div id="ml291.fu4" class="figure"><div class="graphic"><img src="/books/NBK133431/bin/ml291fu4.jpg" alt="Image ml291fu4" /></div></div><p><b>4-((4-chloropiperidin-1-yl)sulfonyl)aniline:</b> To a vial containing 4-chloro-1-((4-nitrophenyl)sulfonyl)piperidine (0.29 g, 0.96 mmol) was added 1:1 MeOH:CH<sub>2</sub>Cl<sub>2</sub> (3 mL:3 mL), and the reaction was cooled to 0°C. Raney nickel (0.006 g, 0.096 mmol) was added followed by portionwise addition of sodium borohydride (0.073 g, 1.9 mmol). Once addition was complete, the reaction mixture was stirred at 0°C for 30 minutes and was then diluted with CH<sub>2</sub>Cl<sub>2</sub> (10 mL) and filtered slowly. The CH<sub>2</sub>Cl<sub>2</sub> layer was washed with water (10 mL), separated, dried with MgSO<sub>4</sub>, filtered, adsorbed to silica and purified by silica gel flash column chromatography (15 min, 0 – 5 % v/v MeOH/DCM) to produce pure 4-((4-chloropiperidin-1-yl)sulfonyl)aniline (0.23 g, 0.82 mmol, 86% yield). <sup>1</sup>H NMR (400 MHz, CDCl<sub>3</sub>): δ 7.66 (d, <i>J</i> = 8.7 Hz, 2H), 7.06 (d, <i>J</i> = 8.6 Hz, 2H), 7.03 (s, 1H), 5.32 (s,1H), 4.12 (m, 1H), 3.16 (m, 2H), 3.10 (m, 2H), 2.13 (m, 2H), 1.95 (m, 2H).</p><div id="ml291.fu5" class="figure"><div class="graphic"><img src="/books/NBK133431/bin/ml291fu5.jpg" alt="Image ml291fu5" /></div></div><p><b><i>N</i></b><b>-(4-((4-chloropiperidin-1-yl)sulfonyl)phenyl)-5-nitrofuran-2-carboxamide: <a href="/pcsubstance/?term=ML291[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML291</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/substance/134228465" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 134228465</a>; CID 52940465.</b> To a microwave vial was added 4-((4-chloropiperidin-1-yl)sulfonyl)aniline (0.23 g, 0.82 mmol), 5-nitro-2-furoyl chloride (0.16 g, 0.90 mmol) and acetonitrile (3 mL). The vial was sealed and heated to 150 °C in the microwave for 20 minutes. The reaction then cooled to room temperature and was diluted with CH<sub>2</sub>Cl<sub>2</sub> (10 mL) and washed with saturated NaHCO<sub>3</sub> (10 mL). The CH<sub>2</sub>Cl<sub>2</sub> layer was separated, dried with MgSO<sub>4</sub>, filtered and adsorbed to silica gel. The crude product was purified by silica gel flash column chromatography (20 min, 0 – 5% v/v MeOH/CH<sub>2</sub>Cl<sub>2</sub>) to produce pure <i>N</i>-(4-((4-chloropiperidin-1-yl)sulfonyl)phenyl)-5-nitrofuran-2-carboxamide, <a href="/pcsubstance/?term=ML291[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML291</a> (0.11 g, 0.26 mmol, 31% yield). <sup>1</sup>H NMR (400 MHz, DMSO-<i>d</i><sub>6</sub>): <i>δ</i> 11.01 (s, 1H), 8.03 (d, <i>J</i> = 8.8 Hz, 2H), 7.83 (d, <i>J</i> = 3.9 Hz, 1H), 7.79 (d, <i>J</i> = 8.8 Hz, 2H), 7.70 (d, <i>J</i> = 3.9 Hz, 1H), 4.27 (m, 1H), 3.17 (m, 2H), 2.87 (m, 2H), 2.10 (m, 2H), 1.79 (m, 2H). <sup>13</sup>C NMR (100 MHz, DMSO-<i>d</i><sub>6</sub>): δ 154.9, 151.9, 147.3, 142.2, 130.4, 128.6, 120.4, 117.2, 113.4, 56.1, 43.4, 33.9. LCMS retention time: 3.147 min. LCMS Purity at 214 nm: 97.5%. HRMS: <i>m/z</i> calcd for C<sub>16</sub>H<sub>17</sub>ClN<sub>3</sub>O<sub>6</sub>S (M + H<sup>+</sup>) 414.0521, found 414.0522. Melting point: 228 – 232 °C.</p><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% TMS as an internal standard or DMSO-<i>d<sub>6</sub></i>. 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, br. s = 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>Proton NMR Data for <a href="/pcsubstance/?term=ML291[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML291</a>/<a href="https://pubchem.ncbi.nlm.nih.gov/substance/123083137" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 123083137</a>/CID 52940465:</b>
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<sup>1</sup>H NMR (400 MHz; DMSO-<i>d</i><sub>6</sub>): δ (ppm) 11.01 (s, 1H), 8.03 (d, <i>J</i> = 8.8 Hz, 2H), 7.83 (d, <i>J</i> = 3.9 Hz, 1H), 7.79 (d, <i>J</i> = 8.8 Hz, 2H), 7.70 (d, <i>J</i> = 3.9 Hz, 1H), 4.27 (m, 1H), 3.17 (m, 2H), 2.87 (m, 2H), 2.10 (m, 2H), 1.79 (m, 2H).</p><p><b>Carbon NMR Data for <a href="/pcsubstance/?term=ML291[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML291</a>/<a href="https://pubchem.ncbi.nlm.nih.gov/substance/123083137" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 123083137</a>/CID 52940465:</b>
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<sup>13</sup>C NMR (100 MHz; DMSO-<i>d</i><sub>6</sub>): δ (ppm) 154.9, 151.9, 147.3, 142.2, 130.4, 128.6, 120.4, 117.2, 113.4, 56.1, 43.4, 33.9.</p><p><b>LCMS and HRMS Data for <a href="/pcsubstance/?term=ML291[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML291</a>, CID 52940465:</b> Detailed analytical methods and instrumentation are described in <a href="#ml291.s10">section 2.3</a>, entitled “Probe Preparation” under general experimental and analytical details. The numerical experimental LCMS and HRMS data are represented as follows:</p><p>For <a href="https://pubchem.ncbi.nlm.nih.gov/substance/123083137" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 123083137</a>: LCMS retention time: 3.074 min. LCMS purity at 214 nm: 95.4%. HRMS: <i>m/z</i> calcd for C<sub>16</sub>H<sub>17</sub>ClN<sub>3</sub>O<sub>6</sub>S (M + H<sup>+</sup>) 414.0521, found 414.0527. The experimental LCMS and HRMS spectra are included for reference (<a href="#ml291.app1">Appendix A</a>, <a class="figpopup" href="/books/NBK133431/figure/ml291.f8/?report=objectonly" target="object" rid-figpopup="figml291f8" rid-ob="figobml291f8">Figure A6C</a> and <a class="figpopup" href="/books/NBK133431/figure/ml291.f9/?report=objectonly" target="object" rid-figpopup="figml291f9" rid-ob="figobml291f9">A6D</a>, respectively).</p><p>For <a href="https://pubchem.ncbi.nlm.nih.gov/substance/134228465" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 134228465</a>: LCMS retention time: 3.125 min. LCMS purity at 214 nm: 97.5%. HRMS: <i>m/z</i> calcd for C<sub>16</sub>H<sub>17</sub>ClN<sub>3</sub>O<sub>6</sub>S (M + H<sup>+</sup>) 414.0521, found 414.0522. The experimental LCMS and HRMS spectra are included for reference (<a href="#ml291.app1">Appendix A</a>, <a class="figpopup" href="/books/NBK133431/figure/ml291.f10/?report=objectonly" target="object" rid-figpopup="figml291f10" rid-ob="figobml291f10">Figure A6E</a> and <a class="figpopup" href="/books/NBK133431/figure/ml291.f11/?report=objectonly" target="object" rid-figpopup="figml291f11" rid-ob="figobml291f11">A6F</a>, respectively).</p></div></div><div id="ml291.s11"><h2 id="_ml291_s11_">3. Results</h2><div id="ml291.s12"><h3>3.1. Dose Response Curves for Probe</h3><p><a class="figpopup" href="/books/NBK133431/figure/ml291.f3/?report=objectonly" target="object" rid-figpopup="figml291f3" rid-ob="figobml291f3">Figure 3</a> illustrates the reproducibility of the efficacy response of <a href="/pcsubstance/?term=ML291[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML291</a> over 4 replicates and it’s selectivity for activating the apoptotic (CHOP) but not the adaptive (XBP1) UPR subpathways in this CHO-K1 cell luciferase reporter system.</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml291f3" co-legend-rid="figlgndml291f3"><a href="/books/NBK133431/figure/ml291.f3/?report=objectonly" target="object" title="Figure 3" class="img_link icnblk_img figpopup" rid-figpopup="figml291f3" rid-ob="figobml291f3"><img class="small-thumb" src="/books/NBK133431/bin/ml291f3.gif" src-large="/books/NBK133431/bin/ml291f3.jpg" alt="Figure 3. Activation of luciferase reporters driven by UPR sub-pathway promoters for the apoptotic (CHOP) and adaptive (XBP1) arms." /></a><div class="icnblk_cntnt" id="figlgndml291f3"><h4 id="ml291.f3"><a href="/books/NBK133431/figure/ml291.f3/?report=objectonly" target="object" rid-ob="figobml291f3">Figure 3</a></h4><p class="float-caption no_bottom_margin">Activation of luciferase reporters driven by UPR sub-pathway promoters for the apoptotic (CHOP) and adaptive (XBP1) arms. Engineered CHO-K1 cell were incubated with ML291 for overnight (~16 hr) and luciferase induction measured with SteadyGlo™ <a href="/books/NBK133431/figure/ml291.f3/?report=objectonly" target="object" rid-ob="figobml291f3">(more...)</a></p></div></div></div><div id="ml291.s13"><h3>3.2. Cellular Activity</h3><p>If our putative activator of the apoptotic arm of the unfolded protein response (UPR) selectively activates these apoptotic pathways in cell, we would expect the <a href="/pcsubstance/?term=ML291[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML291</a> would induce cell death (cytotoxicity as measured by ATPLite® - production of ATP from living cells) in cells where these pathways are operant, but no activate them in the absence of the pathways. This is exactly the result obtained (<a class="figpopup" href="/books/NBK133431/figure/ml291.f4/?report=objectonly" target="object" rid-figpopup="figml291f4" rid-ob="figobml291f4">Figure 4</a>) from mouse embryonic fibroblast (MEF) cell lines engineered to have the wild-type apoptotic pathways intact (MEF w/<i>wt</i>-CHOP) compared to MEF cells where this pathway has been knocked-out (MEF w/CHOP KO). <a href="/pcsubstance/?term=ML291[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML291</a> does not non-specifically kill MEFs; however, <a href="/pcsubstance/?term=ML291[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML291</a> does potently kill MEFs in the presence of an intact CHOP pathway (implying activation of apoptotic pathways). Dr. Fribley’s laboratory replicated (n=4) this result and estimates the activator potency in MEF wt-CHOP as ~ 4.8 μM EC<sub>50</sub>, which compares favorably (~ 6-fold shift) with its potency in the CHO-K1 cell reporter assays (762 nM EC<sub>50</sub>)</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml291f4" co-legend-rid="figlgndml291f4"><a href="/books/NBK133431/figure/ml291.f4/?report=objectonly" target="object" title="Figure 4" class="img_link icnblk_img figpopup" rid-figpopup="figml291f4" rid-ob="figobml291f4"><img class="small-thumb" src="/books/NBK133431/bin/ml291f4.gif" src-large="/books/NBK133431/bin/ml291f4.jpg" alt="Figure 4. Cellular Efficacy of ML291 for Activating the CHOP Pathway Induced cytotoxicity in MEF with wt-CHOP vs. CHOP-KO." /></a><div class="icnblk_cntnt" id="figlgndml291f4"><h4 id="ml291.f4"><a href="/books/NBK133431/figure/ml291.f4/?report=objectonly" target="object" rid-ob="figobml291f4">Figure 4</a></h4><p class="float-caption no_bottom_margin">Cellular Efficacy of ML291 for Activating the CHOP Pathway Induced cytotoxicity in MEF with wt-CHOP <i>vs.</i> CHOP-KO. (After 16 hr exposure to probe) </p></div></div></div><div id="ml291.s14"><h3>3.3. Profiling Assays</h3><p>The nominated probe <a href="/pcsubstance/?term=ML291[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML291</a> was evaluated in a detailed <i>in vitro</i> pharmacology screen as shown in <a class="figpopup" href="/books/NBK133431/table/ml291.t3/?report=objectonly" target="object" rid-figpopup="figml291t3" rid-ob="figobml291t3">Table 3</a>.</p><p><a href="/pcsubstance/?term=ML291[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML291</a> has poor to modest solubility ranging from 8.7 – 9.7 μM (3.6 – 4.0 μg/mL) in aqueous buffers between a pH range of 5.2–7.4. Solubility is highest at the physiological of pH 7.4. This solubility is about 11 – 13 fold over its EC<sub>50</sub> (762 nM), so its apparent potency is not severely limited by its solubility.</p><p>The PAMPA (<b>P</b>arallel <b>A</b>rtificial <b>M</b>embrane <b>P</b>ermeability <b>A</b>ssay) assay is used as an <i>in vitro</i> model of passive, transcellular permeability. An artificial membrane immobilized on a filter is placed between a donor and acceptor compartment. At the start of the test, drug is introduced in the donor compartment. Following the permeation period, the concentration of drug in the donor and acceptor compartments is measured using UV spectroscopy. <a href="/pcsubstance/?term=ML291[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML291</a> exhibits good permeability at pHs of 5.0, 6.2 and 7.4 in the donor compartment, with highest permeability at pH 6.2.</p><p>Plasma protein binding is a measure of a drug’s efficiency to bind to the proteins within blood plasma. The less bound a drug is, the more efficiently it can traverse cell membranes or diffuse. Highly plasma protein bound drugs are confined to the vascular space, thereby having a relatively low volume of distribution. In contrast, drugs that remain largely unbound in plasma are generally available for distribution to other organs and tissues. <a href="/pcsubstance/?term=ML291[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML291</a> was highly plasma protein bound to human plasma proteins (>99%), though it is somewhat less tightly bound to mouse plasma proteins (~84%), which will be a consideration in translating any future mouse model data to humans.</p><p>Plasma stability is a measure of the stability of small molecules and peptides in plasma and is an important parameter, which strongly can influence the <i>in vivo</i> efficacy of a test compound. Drug candidates are exposed in plasma to enzymatic processes (proteinases, esterases), and they can undergo intramolecular rearrangement or bind irreversibly (covalently) to proteins. <a href="/pcsubstance/?term=ML291[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML291</a> appears to be moderately stable in human plasma (~84% remaining), but less so in mouse plasma (~52% remaining).</p><p>The microsomal stability assay is commonly used to rank compounds according to their metabolic stability. This assay addresses the pharmacologic question of how long the parent compound will remain circulating in plasma within the body. <a href="/pcsubstance/?term=ML291[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML291</a> is almost completely metabolized in both human and mouse liver homogenates within 1 hour.</p><p><a href="/pcsubstance/?term=ML291[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML291</a> shows some toxicity (~11 μM LC<sub>50</sub>) toward human hepatocytes.</p><div id="ml291.s15"><h4>Profiling against other GPCRs</h4><p><a href="/pcsubstance/?term=ML291[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML291</a> was submitted to Ricerca Biosciences LLC (<u><a href="http://www.ricerca.com/discovery-pharmacology.asp" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">http://www.ricerca.com/discovery-pharmacology.asp</a></u> Bothell, WA, USA) to evaluate it in radioligand binding assays against activity against a panel of 67 GPCRs, ion channels and transporters at 10 μM. <a href="/pcsubstance/?term=ML291[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML291</a> only scored as having significant activity (68% inhibition) against the dopamine transporter (DAT), so it does not appear to be generally promiscuous compound with respect to these receptors. <i>See <a href="#ml291.app2">Appendix B</a>: Ricerca LeadProfiling® Report for <a href="/pcsubstance/?term=ML291[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML291</a>.</i></p></div><div id="ml291.s16"><h4>Profiling against the NCI-60 Panel</h4><p><a href="/pcsubstance/?term=ML291[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML291</a> was submitted to the NCI DPT for screening against the NCI-60 panel of tumor cell lines (<u><a href="http://dtp.cancer.gov/branches/btb/ivclsp.html" ref="pagearea=body&targetsite=external&targetcat=link&targettype=uri">http://dtp.cancer.gov/branches/btb/ivclsp.html</a></u>) and in summary <a href="/pcsubstance/?term=ML291[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML291</a> has broad growth inhibitory activity and has greater than average anti-tumor cell cytotoxicity against the colon, melanoma, and renal cancer cell lines that comprise the NCI-60 panel. <i>See <a href="#ml291.app3">Appendix C</a>: NCI-60 panel profiling Report for <a href="/pcsubstance/?term=ML291[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML291</a>.</i></p></div></div></div><div id="ml291.s17"><h2 id="_ml291_s17_">4. Discussion</h2><div id="ml291.s18"><h3>4.1. Comparison to Existing Art and How the New Probe is an Improvement</h3><p>In November of 2010, at time of our initial scaffold selection to advance into probe development we found no chemical matter for UPR apoptotic arm activation described in the published literature and patents using SciFinder and Prous Integrity as search engines. Additional recent SciFinder searches uncovered no significant prior art, using the search terms: Unfolded Protein Response, CHOP activator, CHOP agonist, CHOP, PERK-eIF2α-CHOP, Apoptotic UPR.</p><p>Aside from unpublished results from the assay providers’ laboratories (Dr. Fribley and Dr. Kaufman), there are no patents or publications describing advanced small molecule activators of the apoptotic arm of the UPR. Dr. Fribley has some preliminary data describing two hydrazide containing thiuram compounds, disulfram and NSC-1771. These two compounds while active in both reporter assays and cell based apoptosis assays, represented very simple, unattractive and non-pharmacophoric scaffolds. <a href="/pcsubstance/?term=ML291[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML291</a> provides an improvement in potency and selectivity and provides a more valuable pharmacologic scaffold.</p></div></div><div id="ml291.s19"><h2 id="_ml291_s19_">5. References</h2><dl class="temp-labeled-list"><dl class="bkr_refwrap"><dt>1.</dt><dd><div class="bk_ref" id="ml291.r1">Larsson O, Li S, Issaenko OA, Avdulov S, Peterson M, Smith K, et al. Eukaryotic translation initiation factor 4E induced progression of primary human mammary epithelial cells along the cancer pathway is associated with targeted translational deregulation of oncogenic drivers and inhibitors. <span><span class="ref-journal">Cancer Res. </span>2007;<span class="ref-vol">67</span>(14):6814–24.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17638893" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17638893</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>2.</dt><dd><div class="bk_ref" id="ml291.r2">Sorrells DL, Meschonat C, Black D, Li BD. Pattern of amplification and overexpression of the eukaryotic initiation factor 4E gene in solid tumor. <span><span class="ref-journal">J Surg Res. </span>1999;<span class="ref-vol">85</span>(1):37–42.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/10383835" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10383835</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>3.</dt><dd><div class="bk_ref" id="ml291.r3">Sonenberg N, Hinnebusch AG. Regulation of translation initiation in eukaryotes: mechanisms and biological targets. <span><span class="ref-journal">Cell. </span>2009;<span class="ref-vol">136</span>(4):731–45.</span> [<a href="/pmc/articles/PMC3610329/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC3610329</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19239892" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19239892</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>4.</dt><dd><div class="bk_ref" id="ml291.r4">Nathan CO, Liu L, Li BD, Abreo FW, Nandy I, De Benedetti A. Detection of the proto-oncogene eIF4E in surgical margins may predict recurrence in head and neck cancer. <span><span class="ref-journal">Oncogene. </span>1997;<span class="ref-vol">15</span>(5):579–84.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/9247311" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9247311</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>5.</dt><dd><div class="bk_ref" id="ml291.r5">Pervin S, Tran AH, Zekavati S, Fukuto JM, Singh R, Chaudhuri G. Increased susceptibility of breast cancer cells to stress mediated inhibition of protein synthesis. <span><span class="ref-journal">Cancer Res. </span>2009;<span class="ref-vol">68</span>(12):4862–74.</span> [<a href="/pmc/articles/PMC4416651/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC4416651</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/18559534" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18559534</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>6.</dt><dd><div class="bk_ref" id="ml291.r6">Kaufman RJ. Stress signaling from the lumen of the endoplasmic reticulum: coordination of gene transcriptional and translational controls. <span><span class="ref-journal">Genes Dev. </span>1999;<span class="ref-vol">13</span>(10):1211–33.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/10346810" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10346810</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>7.</dt><dd><div class="bk_ref" id="ml291.r7">Kaufman RJ. Orchestrating the unfolded protein response in health and disease. <span><span class="ref-journal">J Clin Invest. </span>2002;<span class="ref-vol">110</span>(10):1389–98.</span> [<a href="/pmc/articles/PMC151822/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC151822</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/12438434" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12438434</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>8.</dt><dd><div class="bk_ref" id="ml291.r8">Ron D. Translational control in the endoplasmic reticulum stress response. <span><span class="ref-journal">J Clin Invest. </span>2002;<span class="ref-vol">110</span>(10):1383–8.</span> [<a href="/pmc/articles/PMC151821/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC151821</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/12438433" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12438433</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>9.</dt><dd><div class="bk_ref" id="ml291.r9">Schroder M, Kaufman RJ. ER stress and the unfolded protein response. <span><span class="ref-journal">Mutat Res. </span>2005;<span class="ref-vol">569</span>(1–2):29–63.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15603751" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15603751</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>10.</dt><dd><div class="bk_ref" id="ml291.r10">McCracken AA, Brodsky JL. Recognition and delivery of ERAD substrates to the proteasome and alternative paths for cell survival. <span><span class="ref-journal">Curr Top Microbiol Immunol. </span>2005;<span class="ref-vol">300</span>:17–40.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16573235" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16573235</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>11.</dt><dd><div class="bk_ref" id="ml291.r11">Bernales S, Papa FR, Walter P. Intracellular signaling by the unfolded protein response. <span><span class="ref-journal">Annu Rev Cell Dev Biol. </span>2006;<span class="ref-vol">22</span>:487–508.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16822172" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16822172</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>12.</dt><dd><div class="bk_ref" id="ml291.r12">Schroder M, Kaufman RJ. The mammalian unfolded protein response. <span><span class="ref-journal">Annu Rev Biochem. </span>2005;<span class="ref-vol">74</span>:739–89.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15952902" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15952902</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>13.</dt><dd><div class="bk_ref" id="ml291.r13">Rutkowski DT, Arnold SM, Miller CN, Wu J, Li J, Gunnison KM, et al. Adaptation to ER stress is mediated by differential stabilities of pro-survival and pro-apoptotic mRNAs and proteins. <span><span class="ref-journal">PLoS Biol. </span>2006;<span class="ref-vol">4</span>(11):e374.</span> [<a href="/pmc/articles/PMC1634883/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1634883</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/17090218" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17090218</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>14.</dt><dd><div class="bk_ref" id="ml291.r14">Rutkowski DT, Kaufman RJ. A trip to the ER: coping with stress. <span><span class="ref-journal">Trends Cell Biol. </span>2004;<span class="ref-vol">14</span>(1):20–8.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/14729177" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 14729177</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>15.</dt><dd><div class="bk_ref" id="ml291.r15">Scheuner D, Kaufman RJ. The unfolded protein response: a pathway that links insulin demand with –cell failure and diabetes. <span><span class="ref-journal">Endocr Rev. </span>2008;<span class="ref-vol">29</span>(3):317–333.</span> [<a href="/pmc/articles/PMC2528859/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2528859</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/18436705" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18436705</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>16.</dt><dd><div class="bk_ref" id="ml291.r16">Prostko CR, Brostrom MA, Malara EM, Brostrom CO. Phosphorylation of eukaryotic initiation factor (eIF) 2 alpha and inhibition of eIF-2B in GH3 pituitary cells by perturbants of early protein processing that induce GRP78. <span><span class="ref-journal">J Biol Chem. </span>1992;<span class="ref-vol">267</span>(24):16751–4.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/1512215" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 1512215</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>17.</dt><dd><div class="bk_ref" id="ml291.r17">Harding HP, Zhang Y, Ron D. Protein translation and folding are coupled by an endoplasmic-reticulumresident kinase. <span><span class="ref-journal">Nature. </span>1999;<span class="ref-vol">397</span>(6716):271–4.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/9930704" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 9930704</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>18.</dt><dd><div class="bk_ref" id="ml291.r18">Bertolotti A, Zhang Y, Hendershot LM, Harding HP, Ron D. Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response. <span><span class="ref-journal">Nat Cell Biol. </span>2000;<span class="ref-vol">2</span>(6):326–32.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/10854322" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10854322</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>19.</dt><dd><div class="bk_ref" id="ml291.r19">Shen J, Chen X, Hendershot L, Prywes R. ER stress regulation of ATF6 localization by dissociation of BiP/GRP78 binding and unmasking of Golgi localization signals. <span><span class="ref-journal">Dev Cell. </span>2002;<span class="ref-vol">3</span>(1):99–111.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12110171" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12110171</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>20.</dt><dd><div class="bk_ref" id="ml291.r20">Iwakoshi NN, Lee AH, Glimcher LH. The X-box binding protein-1 transcription factor is required for plasma cell differentiation and the unfolded protein response. <span><span class="ref-journal">Immunol Rev. </span>2003;<span class="ref-vol">194</span>:29–38.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12846805" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12846805</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>21.</dt><dd><div class="bk_ref" id="ml291.r21">Iwakoshi NN, Pypaert M, Glimcher LH. The transcription factor XBP-1 is essential for the development and survival of dendritic cells. <span><span class="ref-journal">J Exp Med. </span>2007;<span class="ref-vol">204</span>(10):2267–75.</span> [<a href="/pmc/articles/PMC2118458/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2118458</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/17875675" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17875675</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>22.</dt><dd><div class="bk_ref" id="ml291.r22">Lee AH, Chu GC, Iwakoshi NN, Glimcher LH. XBP-1 is required for biogenesis of cellular secretory machinery of exocrine glands. <span><span class="ref-journal">EMBO J. </span>2005;<span class="ref-vol">24</span>(24):4368–80.</span> [<a href="/pmc/articles/PMC1356340/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1356340</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/16362047" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16362047</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>23.</dt><dd><div class="bk_ref" id="ml291.r23">Lee AH, Iwakoshi NN, Glimcher LH. XBP-1 regulates a subset of endoplasmic reticulum resident chaperone genes in the unfolded protein response. <span><span class="ref-journal">Mol Cell Biol. </span>2003;<span class="ref-vol">23</span>(21):7448–59.</span> [<a href="/pmc/articles/PMC207643/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC207643</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/14559994" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 14559994</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>24.</dt><dd><div class="bk_ref" id="ml291.r24">Oda Y, Okada T, Yoshida H, Kaufman RJ, Nagata K, Mori K. Derlin-2 and Derlin-3 are regulated by the mammalian unfolded protein response and are required for ER-associated degradation. <span><span class="ref-journal">J Cell Biol. </span>2006;<span class="ref-vol">172</span>(3):383–93.</span> [<a href="/pmc/articles/PMC2063648/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2063648</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/16449189" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16449189</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>25.</dt><dd><div class="bk_ref" id="ml291.r25">Yoshida H, Matsui T, Hosokawa N, Kaufman RJ, Nagata K, Mori K. A time-dependent phase shift in the mammalian unfolded protein response. <span><span class="ref-journal">Dev Cell. </span>2003;<span class="ref-vol">4</span>(2):265–71.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12586069" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12586069</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>26.</dt><dd><div class="bk_ref" id="ml291.r26">Sonenberg N, Dever TE. Eukaryotic translation initiation factors and regulators. <span><span class="ref-journal">Curr Opin Struct Biol. </span>2003;<span class="ref-vol">13</span>(1):56–63.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12581660" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12581660</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>27.</dt><dd><div class="bk_ref" id="ml291.r27">Scheuner D, Song B, McEwen E, Liu C, Laybutt R, Gillespie P, et al. Translational control is required for the unfolded protein response and in vivo glucose homeostasis. <span><span class="ref-journal">Mol Cell. </span>2001;<span class="ref-vol">7</span>(6):1165–76.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/11430820" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11430820</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>28.</dt><dd><div class="bk_ref" id="ml291.r28">Harding HP, Novoa I, Zhang Y, Zeng H, Wek R, Schapira M, et al. Regulated translation initiation controls stress-induced gene expression in mammalian cells. <span><span class="ref-journal">Mol Cell. </span>2000;<span class="ref-vol">6</span>(5):1099–108.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/11106749" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11106749</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>29.</dt><dd><div class="bk_ref" id="ml291.r29">Harding HP, Zhang Y, Zeng H, Novoa I, Lu PD, Calfon M, et al. An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. <span><span class="ref-journal">Mol Cell. </span>2003;<span class="ref-vol">11</span>(3):619–33.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12667446" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12667446</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>30.</dt><dd><div class="bk_ref" id="ml291.r30">Lu PD, Jousse C, Marciniak SJ, Zhang Y, Novoa I, Scheuner D, et al. Cytoprotection by pre-emptive conditional phosphorylation of translation initiation factor 2. <span><span class="ref-journal">EMBO J. </span>2004;<span class="ref-vol">23</span>(1):169–79.</span> [<a href="/pmc/articles/PMC1271668/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1271668</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/14713949" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 14713949</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>31.</dt><dd><div class="bk_ref" id="ml291.r31">Jiang HY, Wek SA, McGrath BC, Lu D, Hai T, Harding HP, et al. Activating transcription factor 3 is integral to the eukaryotic initiation factor 2 kinase stress response. <span><span class="ref-journal">Mol Cell Biol. </span>2004;<span class="ref-vol">24</span>(3):1365–77.</span> [<a href="/pmc/articles/PMC321431/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC321431</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/14729979" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 14729979</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>32.</dt><dd><div class="bk_ref" id="ml291.r32">Marciniak SJ, Yun CY, Oyadomari S, Novoa I, Zhang Y, Jungreis R, et al. CHOP induces death by promoting protein synthesis and oxidation in the stressed endoplasmic reticulum. <span><span class="ref-journal">Genes Dev. </span>2004;<span class="ref-vol">18</span>(24):3066–77.</span> [<a href="/pmc/articles/PMC535917/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC535917</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/15601821" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15601821</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>33.</dt><dd><div class="bk_ref" id="ml291.r33">Matsumoto M, Minami M, Takeda K, Sakao Y, Akira S. Ectopic expression of CHOP (GADD153) induces apoptosis in M1 myeloblastic leukemia cells. <span><span class="ref-journal">FEBS Lett. </span>1996;<span class="ref-vol">395</span>(2–3):143–7.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/8898082" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 8898082</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>34.</dt><dd><div class="bk_ref" id="ml291.r34">Oyadomari S, Koizumi A, Takeda K, Gotoh T, Akira S, Araki E, et al. Targeted disruption of the Chop gene delays endoplasmic reticulum stress-mediated diabetes. <span><span class="ref-journal">J Clin Invest. </span>2002;<span class="ref-vol">109</span>(4):525–32.</span> [<a href="/pmc/articles/PMC150879/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC150879</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/11854325" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11854325</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>35.</dt><dd><div class="bk_ref" id="ml291.r35">Oyadomari S, Mori M. Roles of CHOP/GADD153 in endoplasmic reticulum stress. <span><span class="ref-journal">Cell Death Differ. </span>2004;<span class="ref-vol">11</span>(4):381–9.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/14685163" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 14685163</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>36.</dt><dd><div class="bk_ref" id="ml291.r36">Scheuner D, Vander Mierde D, Song B, Flamez D, Creemers JW, Tsukamoto K, et al. Control of mRNA translation preserves endoplasmic reticulum function in beta cells and maintains glucose homeostasis. <span><span class="ref-journal">Nat Med. </span>2005;<span class="ref-vol">11</span>(7):757–64.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15980866" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15980866</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>37.</dt><dd><div class="bk_ref" id="ml291.r37">Yamaguchi H, Wang HG. CHOP is involved in endoplasmic reticulum stress-induced apoptosis by enhancing DR5 expression in human carcinoma cells. <span><span class="ref-journal">J Biol Chem. </span>2004;<span class="ref-vol">279</span>(44):45495–502.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15322075" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15322075</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>38.</dt><dd><div class="bk_ref" id="ml291.r38">McCullough KD, Martindale JL, Klotz LO, Aw TY, Holbrook NJ. Gadd153 sensitizes cells to endoplasmic reticulum stress by down-regulating Bcl2 and perturbing the cellular redox state. <span><span class="ref-journal">Mol Cell Biol. </span>2001;<span class="ref-vol">21</span>(4):1249–59.</span> [<a href="/pmc/articles/PMC99578/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC99578</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/11158311" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11158311</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>39.</dt><dd><div class="bk_ref" id="ml291.r39">Ohoka N, Yoshii S, Hattori T, Onozaki K, Hayashi H. TRB3, a novel ER stress-inducible gene, is induced via ATF4-CHOP pathway and is involved in cell death. <span><span class="ref-journal">EMBO J. </span>2005;<span class="ref-vol">24</span>(6):1243–55.</span> [<a href="/pmc/articles/PMC556400/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC556400</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/15775988" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15775988</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>40.</dt><dd><div class="bk_ref" id="ml291.r40">Back SH, Scheuner D, Han J, Song B, Ribick M, Wang J, Gildersleeve R, Pennathur S, Kaufman RJ. Translation attenuation through eIF 2α phosphorylation preserves ER integrity, prevents oxidative stress, and maintains insulin production in beta cells. <span><span class="ref-journal">Cell Metabolism. </span>2009;<span class="ref-vol">10</span>(1):13–26.</span> [<a href="/pmc/articles/PMC2742645/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2742645</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19583950" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19583950</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>41.</dt><dd><div class="bk_ref" id="ml291.r41">Marciniak SJ, Ron D. Endoplasmic reticulum stress signaling in disease. <span><span class="ref-journal">Physiol Rev. </span>2006;<span class="ref-vol">86</span>(4):1133–49.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/17015486" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 17015486</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>42.</dt><dd><div class="bk_ref" id="ml291.r42">Zhang K, Kaufman RJ. The unfolded protein response: a stress signaling pathway critical for health and disease. <span><span class="ref-journal">Neurology. </span>2006;<span class="ref-vol">66</span>(2 Suppl 1):S102–9.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16432136" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16432136</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>43.</dt><dd><div class="bk_ref" id="ml291.r43">Argiris A, Karamouzis MV, Raben D, Ferris RL. Head and neck cancer. <span><span class="ref-journal">Lancet. </span>2008;<span class="ref-vol">371</span>(9625):1695–709.</span> [<a href="/pmc/articles/PMC7720415/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC7720415</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/18486742" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18486742</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>44.</dt><dd><div class="bk_ref" id="ml291.r44">Rosenwald IB. The role of translation in neoplastic transformation from a pathologist’s point of view. <span><span class="ref-journal">Oncogene. </span>2004;<span class="ref-vol">23</span>(18):3230–47.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15094773" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 15094773</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>45.</dt><dd><div class="bk_ref" id="ml291.r45">Franklin S, Pho T, Abreo FW, Nassar R, De Benedetti A, Stucker FJ, et al. Detection of the proto-oncogene eIF4E in larynx and hypopharynx cancers. <span><span class="ref-journal">Arch Otolaryngol Head Neck Surg. </span>1999;<span class="ref-vol">125</span>(2):177–82.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/10037284" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 10037284</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>46.</dt><dd><div class="bk_ref" id="ml291.r46">Wang S, Lloyd RV, Hutzler MJ, Rosenwald IB, Safran MS, Patwardhan NA, et al. Expression of eukaryotic translation initiation factors 4E and 2alpha correlates with the progression of thyroid carcinoma. <span><span class="ref-journal">Thyroid. </span>2001;<span class="ref-vol">11</span>(12):1101–7.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12186496" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12186496</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>47.</dt><dd><div class="bk_ref" id="ml291.r47">Oda T, Kosuge Y, Arakawa M, Ishige K, Ito Y. Distinct mechanism of cell death is responsible for tunicamycin-induced ER stress in SK-N-SH and SH-SY5Y cells. <span><span class="ref-journal">Neurosci Res. </span>2008;<span class="ref-vol">60</span>(1):29–39.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/18029041" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 18029041</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>48.</dt><dd><div class="bk_ref" id="ml291.r48">Back SH, Lee K, Vink E, Kaufman RJ. Cytoplasmic IRE1alpha-mediated XBP1 mRNA splicing in the absence of nuclear processing and endoplasmic reticulum stress. <span><span class="ref-journal">J Biol Chem. </span>2006;<span class="ref-vol">281</span>(27):18691–706.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/16644724" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16644724</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>49.</dt><dd><div class="bk_ref" id="ml291.r49">Novoa I, Zeng H, Harding JP, Ron D. Feedback inhibition of the unfolded protein response by GADD34-mediated dephosphorylation of eIF2alpha. <span><span class="ref-journal">J Cell Biol. </span>2001;<span class="ref-vol">153</span>(5):1011–22.</span> [<a href="/pmc/articles/PMC2174339/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2174339</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/11381086" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11381086</span></a>]</div></dd></dl><dl class="bkr_refwrap"><dt>50.</dt><dd><div class="bk_ref" id="ml291.r50">Harding H, Zhang Y, Khershonsky S, Marciniak SM, Scheuner D, Kaufman RJ, Javitt N, Chang Y-T, Ron D. Bioactive small molecules reveal antagonism between the integrated stress response and sterol regulated gene expression. <span><span class="ref-journal">Cell Metabolism. </span>2005;<span class="ref-vol">2</span>:361–71.</span> [<a href="/pmc/articles/PMC1361344/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC1361344</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/16330322" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 16330322</span></a>]</div></dd></dl></dl></div><div id="ml291.app1"><h2 id="_ml291_app1_">APPENDIX A. Quality Control Data for Probe <a href="/pcsubstance/?term=ML291[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML291</a> (<a href="https://pubchem.ncbi.nlm.nih.gov/substance/123083137" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 123083137</a>, CID 52940465)</h2><div id="ml291.s20"><h3>1H-NMR and <sup>13</sup>C-NMR spectra</h3><div id="ml291.f6" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%20A6A.%20Proton%201H%20NMR%20spectra%20for%20ML291%20(SID%20123083137%2C%20CID%2052940465).&p=BOOKS&id=133431_ml291f6.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK133431/bin/ml291f6.jpg" alt="Figure A6A. Proton 1H NMR spectra for ML291 (SID 123083137, CID 52940465)." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure A6A</span><span class="title">Proton <sup>1</sup>H NMR spectra for <a href="/pcsubstance/?term=ML291[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML291</a> (<a href="https://pubchem.ncbi.nlm.nih.gov/substance/123083137" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 123083137</a>, CID 52940465)</span></h3></div><div id="ml291.f7" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%20A6B.%20Carbon%2013C-NMR%20data%20for%20ML291%20(SID%20123083137%2C%20CID%2052940465).&p=BOOKS&id=133431_ml291f7.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK133431/bin/ml291f7.jpg" alt="Figure A6B. Carbon 13C-NMR data for ML291 (SID 123083137, CID 52940465)." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure A6B</span><span class="title">Carbon <sup>13</sup>C-NMR data for <a href="/pcsubstance/?term=ML291[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML291</a> (<a href="https://pubchem.ncbi.nlm.nih.gov/substance/123083137" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 123083137</a>, CID 52940465)</span></h3></div></div><div id="ml291.s21"><h3>LCMS Purity data: HRMS and HPLC</h3><div id="ml291.f8" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%20A6C.%20LCMS%20purity%20data%20at%20214%20nm%20for%20ML291%201st%20batch%20(SID%20123083137%2C%20CID%2052940465)%3B%20LCMS%20retention%20time%3A%203.074%20min%3B%20purity%20at%20214%20nm%20%3D%2095.4%25.&p=BOOKS&id=133431_ml291f8.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK133431/bin/ml291f8.jpg" alt="Figure A6C. LCMS purity data at 214 nm for ML291 1st batch (SID 123083137, CID 52940465); LCMS retention time: 3.074 min; purity at 214 nm = 95.4%." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure A6C</span><span class="title">LCMS purity data at 214 nm for <a href="/pcsubstance/?term=ML291[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML291</a> 1<sup>st</sup> batch (<a href="https://pubchem.ncbi.nlm.nih.gov/substance/123083137" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 123083137</a>, CID 52940465); LCMS retention time: 3.074 min; purity at 214 nm = 95.4%</span></h3></div><div id="ml291.f9" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%20A6D.%20HRMS%20data%20for%20ML291%201st%20batch%20(SID%20123083137%2C%20CID%2052940465)%3B%20HRMS%20m%2Fz%20calculated%20for%20C16H17ClN3O6S%20%5BM%20%2B%20H%2B%5D%3A%20414.0521%2C%20found%20414.0527.&p=BOOKS&id=133431_ml291f9.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK133431/bin/ml291f9.jpg" alt="Figure A6D. HRMS data for ML291 1st batch (SID 123083137, CID 52940465); HRMS m/z calculated for C16H17ClN3O6S [M + H+]: 414.0521, found 414.0527." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure A6D</span><span class="title">HRMS data for <a href="/pcsubstance/?term=ML291[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML291</a> 1<sup>st</sup> batch (<a href="https://pubchem.ncbi.nlm.nih.gov/substance/123083137" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 123083137</a>, CID 52940465); HRMS <i>m</i>/<i>z</i> calculated for C<sub>16</sub>H<sub>17</sub>ClN<sub>3</sub>O<sub>6</sub>S [M + H<sup>+</sup>]: 414.0521, found 414.0527</span></h3></div><div id="ml291.f10" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%20A6E.%20LCMS%20purity%20data%20at%20214%20nm%20for%20ML291%202nd%20batch%20%02013submitted%20to%20the%20MLSMR%20(SID%20134228465%2C%20CID%2052940465)%3B%20LCMS%20retention%20time%3A%203.125%20min%3B%20purity%20at%20214%20nm%20%3D%2097.5%25.&p=BOOKS&id=133431_ml291f10.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK133431/bin/ml291f10.jpg" alt="Figure A6E. LCMS purity data at 214 nm for ML291 2nd batch –submitted to the MLSMR (SID 134228465, CID 52940465); LCMS retention time: 3.125 min; purity at 214 nm = 97.5%." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure A6E</span><span class="title">LCMS purity data at 214 nm for <a href="/pcsubstance/?term=ML291[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML291</a> 2<sup>nd</sup> batch –submitted to the MLSMR (<a href="https://pubchem.ncbi.nlm.nih.gov/substance/134228465" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 134228465</a>, CID 52940465); LCMS retention time: 3.125 min; purity at 214 nm = 97.5%</span></h3></div><div id="ml291.f11" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%20A6F.%20HRMS%20data%20for%20ML291%202nd%20batch%20%02013submitted%20to%20the%20MLSMR%20(SID%20134228465%2C%20CID%2052940465)%3B%20HRMS%20m%2Fz%20calculated%20for%20C16H17ClN3O6S%20%5BM%20%2B%20H%2B%5D%3A%20414.0521%2C%20found%20414.0522.&p=BOOKS&id=133431_ml291f11.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK133431/bin/ml291f11.jpg" alt="Figure A6F. HRMS data for ML291 2nd batch –submitted to the MLSMR (SID 134228465, CID 52940465); HRMS m/z calculated for C16H17ClN3O6S [M + H+]: 414.0521, found 414.0522." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure A6F</span><span class="title">HRMS data for <a href="/pcsubstance/?term=ML291[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML291</a> 2<sup>nd</sup> batch –submitted to the MLSMR (<a href="https://pubchem.ncbi.nlm.nih.gov/substance/134228465" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 134228465</a>, CID 52940465); HRMS <i>m</i>/<i>z</i> calculated for C<sub>16</sub>H<sub>17</sub>ClN<sub>3</sub>O<sub>6</sub>S [M + H<sup>+</sup>]: 414.0521, found 414.0522</span></h3></div></div></div><div id="ml291.app2"><h2 id="_ml291_app2_">APPENDIX B. Ricerca LeadProfiling® Report for <a href="/pcsubstance/?term=ML291[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML291</a></h2><div id="ml291.s22"><h3>STUDY OBJECTIVE</h3><p>To evaluate, in Radioligand Binding assays, the activity of compound <a href="https://pubchem.ncbi.nlm.nih.gov/substance/123083137" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID123083137</a>.</p></div><div id="ml291.s23"><h3>METHODS</h3><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. Where presented, IC50 values were determined by a non-linear, least squares regression analysis using MathIQTM (ID Business Solutions Ltd., UK). Where inhibition constants (Ki) are presented, the Ki values were calculated using the equation of Cheng and Prusoff (Cheng, Y., Prusoff, W.H., Biochem. Pharmacol. 22:3099–3108, 1973) using the observed IC50 of the tested compound, the concentration of radioligand employed in the assay, and the historical values for the KD of the ligand (obtained experimentally at Ricerca Biosciences, LLC). Where presented, the Hill coefficient (nH), defining the slope of the competitive binding curve, was calculated using MathIQTM. 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 IC50, Ki, and/or nH data are presented without Standard Error of the Mean (SEM), data are insufficient to be quantitative, and the values presented (Ki, IC50, nH) should be interpreted with caution.</p></div><div id="ml291.s24"><h3>RESULTS</h3><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="ml291.s25"><h3>SUMMARY/CONCLUSION</h3><p>Significant results are displayed in the following table(s) in rank order of potency for estimated IC50 and/or Ki values.</p><div id="ml291.s26"><h4>Summary of Significant Results</h4><p>Biochemical assay results are presented as the percent inhibition of specific binding or activity throughout the report. All other results are expressed in terms of that assay’s quantitation method (see <a href="#ml291.s23">Methods</a> section).</p><ul><li class="half_rhythm"><div>For primary assays, only the lowest concentration with a significant response judged by the assays’ criteria, is shown in this summary.</div></li><li class="half_rhythm"><div>Where applicable, either the secondary assay results with the lowest dose/concentration meeting the significance criteria or, if inactive, the highest dose/concentration that did not meet the significance criteria is shown.</div></li><li class="half_rhythm"><div>Unless otherwise requested, primary screening in duplicate with quantitative data (e.g., IC50 ± SEM, Ki ± SEM and nH) are shown where applicable for individual requested assays. In screening packages, primary screening in duplicate with semi-quantitative data (e.g., estimated IC50, Ki and nH) are shown where applicable (concentration range of 4 log units); available secondary functional assays are carried out (30 mM) and MEC or MIC determined only if active in primary assays >50% at 1 log unit below initial test concentration.</div></li><li class="half_rhythm"><div>Please see Experimental Results section for details of all responses. Significant responses (≥ 50% inhibition or stimulation for Biochemical assays) were noted in the primary assays listed below:</div></li></ul><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml291tu2"><a href="/books/NBK133431/table/ml291.tu2/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figml291tu2" rid-ob="figobml291tu2"><img class="small-thumb" src="/books/NBK133431/table/ml291.tu2/?report=thumb" src-large="/books/NBK133431/table/ml291.tu2/?report=previmg" alt="Image " /></a><div class="icnblk_cntnt"><h4 id="ml291.tu2"><a href="/books/NBK133431/table/ml291.tu2/?report=objectonly" target="object" rid-ob="figobml291tu2">Table</a></h4></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml291tu3"><a href="/books/NBK133431/table/ml291.tu3/?report=objectonly" target="object" title="Table" class="img_link icnblk_img figpopup" rid-figpopup="figml291tu3" rid-ob="figobml291tu3"><img class="small-thumb" src="/books/NBK133431/table/ml291.tu3/?report=thumb" src-large="/books/NBK133431/table/ml291.tu3/?report=previmg" alt="EXPERIMENTAL RESULTS FOR SID 123083137 ON OTHER TARGETS." /></a><div class="icnblk_cntnt"><h4 id="ml291.tu3"><a href="/books/NBK133431/table/ml291.tu3/?report=objectonly" target="object" rid-ob="figobml291tu3">Table</a></h4><p class="float-caption no_bottom_margin">EXPERIMENTAL RESULTS FOR SID 123083137 ON OTHER TARGETS. </p></div></div></div></div></div><div id="ml291.app3"><h2 id="_ml291_app3_">Appendix C. NCI-60 panel profiling Report for <a href="/pcsubstance/?term=ML291[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML291</a></h2><div id="ml291.fu6" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ml291fu6a&p=BOOKS&id=133431_ml291fu6a.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK133431/bin/ml291fu6a.jpg" alt="Image ml291fu6a" class="tileshop" title="Click on image to zoom" /></a></div><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ml291fu6b&p=BOOKS&id=133431_ml291fu6b.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK133431/bin/ml291fu6b.jpg" alt="Image ml291fu6b" class="tileshop" title="Click on image to zoom" /></a></div></div><div id="ml291.fu7" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ml291fu7a&p=BOOKS&id=133431_ml291fu7a.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK133431/bin/ml291fu7a.jpg" alt="Image ml291fu7a" class="tileshop" title="Click on image to zoom" /></a></div><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ml291fu7b&p=BOOKS&id=133431_ml291fu7b.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img src="/books/NBK133431/bin/ml291fu7b.jpg" alt="Image ml291fu7b" class="tileshop" title="Click on image to zoom" /></a></div></div></div><div style="display:none"><div style="display:none" id="figml291f8"><img alt="Image ml291f8" src-large="/books/NBK133431/bin/ml291f8.jpg" /></div><div style="display:none" id="figml291f9"><img alt="Image ml291f9" src-large="/books/NBK133431/bin/ml291f9.jpg" /></div><div style="display:none" id="figml291f10"><img alt="Image ml291f10" src-large="/books/NBK133431/bin/ml291f10.jpg" /></div><div style="display:none" id="figml291f11"><img alt="Image ml291f11" src-large="/books/NBK133431/bin/ml291f11.jpg" /></div></div><div id="bk_toc_contnr"></div></div></div><div class="fm-sec"><h2 id="_NBK133431_pubdet_">Publication Details</h2><h3>Author Information and Affiliations</h3><p class="contrib-group"><h4>Authors</h4><span itemprop="author">Daniel P. Flaherty</span>,<sup>1</sup> <span itemprop="author">Jennifer E. Golden</span>,<sup>1</sup> <span itemprop="author">Chunjing Liu</span>,<sup>2</sup> <span itemprop="author">Michael Hedrick</span>,<sup>4</sup> <span itemprop="author">Palak Gosalia</span>,<sup>4</sup> <span itemprop="author">Yujie Li</span>,<sup>4</sup> <span itemprop="author">Monika Milewski</span>,<sup>4</sup> <span itemprop="author">Eliot Sugarman</span>,<sup>5</sup> <span itemprop="author">Eigo Suyama</span>,<sup>5</sup> <span itemprop="author">Kevin Nguyen</span>,<sup>5</sup> <span itemprop="author">Stefan Vasile</span>,<sup>5</sup> <span itemprop="author">Sumeet Salaniwal</span>,<sup>4</sup> <span itemprop="author">Derek Stonich</span>,<sup>4</sup> <span itemprop="author">Ying Su</span>,<sup>4</sup> <span itemprop="author">Arianna Mangravita-Novo</span>,<sup>5</sup> <span itemprop="author">Michael Vicchiarelli</span>,<sup>5</sup> <span itemprop="author">Layton H. Smith</span>,<sup>5</sup> <span itemprop="author">Jena Diwan</span>,<sup>4</sup> <span itemprop="author">Thomas D.Y. Chung</span>,<sup>4</sup><sup>,*</sup> <span itemprop="author">Anthony B. Pinkerton</span>,<sup>4</sup> <span itemprop="author">Jeffrey Aubé</span>,<sup>3</sup> <span itemprop="author">Justin R. Miller</span>,<sup>6</sup> <span itemprop="author">Danielle M. Garshott</span>,<sup>6</sup> <span itemprop="author">Michael U. Callaghan</span>,<sup>6</sup> <span itemprop="author">Andrew M. Fribley</span>,<sup>6</sup> and <span itemprop="author">Randal J. Kaufman</span><sup>7</sup>.</p><h4>Affiliations</h4><div class="affiliation"><sup>1</sup>
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University of Kansas Specialized Chemistry Center, Delbert M. Shankel Structural Biology Center, 2034 Becker Drive, Lawrence, KS, USA</div><div class="affiliation"><sup>2</sup>
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University of Kansas COBRE Center for Cancer Experimental Therapeutics, Delbert M. Shankel Structural Biology Center, 2034 Becker Drive, Lawrence, KS, USA</div><div class="affiliation"><sup>3</sup>
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Department of Medicinal Chemistry, University of Kansas, Malott Hall, Lawrence, KS, USA</div><div class="affiliation"><sup>4</sup>
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Sanford-Burnham Center for Chemical Genomics at Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.</div><div class="affiliation"><sup>5</sup>
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Sanford-Burnham Center for Chemical Genomics at Sanford-Burnham Medical Research Institute at Lake Nona, Orlando, FL 32827, USA; John C. Reed, PI</div><div class="affiliation"><sup>6</sup>
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Wayne State University, Carmen and Ann Adams Department of Pediatrics Division of Hematology/Oncology, 2228 Elliman Building 421 E. Canfield Detroit, MI 48201, USA</div><div class="affiliation"><sup>7</sup>
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Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Rd, La Jolla, CA 92037, USA</div><div class="affiliation"><sup>*</sup> Corresponding author: Thomas D.Y. Chung, Ph.D.
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<span class="before-email-separator"></span><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="gro.mahnrubdrofnas@gnuhct" class="oemail">gro.mahnrubdrofnas@gnuhct</a></div><h3>Publication History</h3><p class="small">Received: <span itemprop="datePublished">April 1, 2012</span>; Last Update: <span itemprop="dateModified">February 28, 2013</span>.</p><h3>Copyright</h3><div><div class="half_rhythm"><a href="/books/about/copyright/">Copyright Notice</a></div></div><h3>Publisher</h3><p>National Center for Biotechnology Information (US), Bethesda (MD)</p><h3>NLM Citation</h3><p>Flaherty DP, Golden JE, Liu C, et al. Selective small molecule activator of the apoptotic arm of the UPR. 2012 Apr 1 [Updated 2013 Feb 28]. In: Probe Reports from the NIH Molecular Libraries Program [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2010-. <span class="bk_cite_avail"></span></p></div><div class="small-screen-prev"><a href="/books/n/mlprobe/ml292/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M75,30 c-80,60 -80,0 0,60 c-30,-60 -30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Prev</text></svg></a></div><div class="small-screen-next"><a href="/books/n/mlprobe/ml290/?report=reader"><svg xmlns="http://www.w3.org/2000/svg" viewBox="0 0 100 100" preserveAspectRatio="none"><path d="M25,30c80,60 80,0 0,60 c30,-60 30,0 0,-60"></path><text x="20" y="28" textLength="60" style="font-size:25px">Next</text></svg></a></div></article><article data-type="fig" id="figobml291fu1"><div id="ml291.fu1" class="figure"><div class="graphic"><img data-src="/books/NBK133431/bin/ml291fu1.jpg" alt="Image ml291fu1" /></div></div></article><article data-type="table-wrap" id="figobml291tu1"><div id="ml291.tu1" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK133431/table/ml291.tu1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml291.tu1_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_ml291.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID/ML#</th><th id="hd_h_ml291.tu1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Target Name</th><th id="hd_h_ml291.tu1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">EC<sub>50</sub> (nM) [SID, AID]<sup>*</sup></th><th id="hd_h_ml291.tu1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Anti-target Name</th><th id="hd_h_ml291.tu1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">EC<sub>50</sub> (nM) [SID, AID] <sup>**</sup></th><th id="hd_h_ml291.tu1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Fold Selectivity (XBP1/CHOP)</th></tr></thead><tbody><tr><td headers="hd_h_ml291.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID 52940465/<a href="/pcsubstance/?term=ML291[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML291</a></td><td headers="hd_h_ml291.tu1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">UPR-CHOP</td><td headers="hd_h_ml291.tu1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">762 nM<sup>*</sup>[<a href="https://pubchem.ncbi.nlm.nih.gov/substance/123083137" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID123083137</a> & <a href="https://pubchem.ncbi.nlm.nih.gov/substance/134228465" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID134228465</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/602434" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 602434</a>]<sup>*</sup></td><td headers="hd_h_ml291.tu1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">UPR-XBP1</td><td headers="hd_h_ml291.tu1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">> 80 μM<sup>**</sup>[<a href="https://pubchem.ncbi.nlm.nih.gov/substance/123083137" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID123083137</a> & <a href="https://pubchem.ncbi.nlm.nih.gov/substance/134228465" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID134228465</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/602416" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 602416</a>]</td><td headers="hd_h_ml291.tu1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">> 105</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>*</dt><dd><div id="ml291.tfn1"><p class="no_margin">Reported value is an average of values from two separate batches of probe compound, <a href="https://pubchem.ncbi.nlm.nih.gov/substance/123083137" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID123083137</a>, EC<sub>50</sub> = 740 nM and for <a href="https://pubchem.ncbi.nlm.nih.gov/substance/134228465" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 134228465</a>, EC<sub>50</sub> = 780 nM, respectively.</p></div></dd></dl><dl class="bkr_refwrap"><dt>**</dt><dd><div id="ml291.tfn2"><p class="no_margin">Reported value is an average of values from two separate batches of probe compound, <a href="https://pubchem.ncbi.nlm.nih.gov/substance/123083137" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID123083137</a>, EC<sub>50</sub> > 80 μM and for <a href="https://pubchem.ncbi.nlm.nih.gov/substance/134228465" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 134228465</a>, EC<sub>50</sub> > 80 μM, respectively.</p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobml291t1"><div id="ml291.t1" class="table"><h3><span class="label">Table 1</span><span class="title">Summary of Assays and AIDs</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK133431/table/ml291.t1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml291.t1_lrgtbl__"><table class="no_top_margin"><thead><tr><th id="hd_h_ml291.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">PubChemBioAssay Name</th><th id="hd_h_ml291.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">AIDs</th><th id="hd_h_ml291.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Probe Type</th><th id="hd_h_ml291.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Assay Type</th><th id="hd_h_ml291.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Assay Format</th><th id="hd_h_ml291.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Assay Detection & well format</th></tr></thead><tbody><tr><td headers="hd_h_ml291.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Summary assay for the identification of small molecule activators of the apoptotic arm of the Unfolded Protein response</td><td headers="hd_h_ml291.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/449771" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 449771</a></td><td headers="hd_h_ml291.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Activator</td><td headers="hd_h_ml291.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Summary</td><td headers="hd_h_ml291.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">N/A</td><td headers="hd_h_ml291.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">N/A</td></tr><tr><td headers="hd_h_ml291.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">uHTS identification of small molecule activators of the apoptotic arm of the Unfolded Protein response via a luminescent-based reporter assay</td><td headers="hd_h_ml291.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/449763" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 449763</a></td><td headers="hd_h_ml291.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Activator</td><td headers="hd_h_ml291.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Primary</td><td headers="hd_h_ml291.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Cell-based</td><td headers="hd_h_ml291.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Luminescence & 1536 well</td></tr><tr><td headers="hd_h_ml291.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Single concentration confirmation of small molecule activators of the apoptotic arm of the Unfolded Protein response via a luminescent-based reporter assay</td><td headers="hd_h_ml291.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/463112" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 463112</a></td><td headers="hd_h_ml291.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Activator</td><td headers="hd_h_ml291.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Confirmatory (Cherry Pick)</td><td headers="hd_h_ml291.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Cell-based</td><td headers="hd_h_ml291.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Luminescence & 1536 well</td></tr><tr><td headers="hd_h_ml291.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Dose response confirmation of small molecule activators of the apoptotic arm of the Unfolded Protein response via a luminescent-based reporter assay</td><td headers="hd_h_ml291.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/489024" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 489024</a></td><td headers="hd_h_ml291.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Activator</td><td headers="hd_h_ml291.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Confirmatory (Dose Response)</td><td headers="hd_h_ml291.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Cell-based</td><td headers="hd_h_ml291.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Luminescence & 1536 well</td></tr><tr><td headers="hd_h_ml291.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SAR analysis of small molecule activators of the apoptotic arm of the Unfolded Protein response via a luminescent-based reporter assay</td><td headers="hd_h_ml291.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/540312" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 540312</a>; <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588594" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 588594</a>; <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/602434" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 602434</a></td><td headers="hd_h_ml291.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Activator</td><td headers="hd_h_ml291.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Secondary (Dry Powder)</td><td headers="hd_h_ml291.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Cell-based</td><td headers="hd_h_ml291.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Luminescence & 1536 well</td></tr><tr><td headers="hd_h_ml291.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SAR analysis counterscreen of small molecule activators of the apoptotic arm of the Unfolded Protein Response via a luminescent-based reporter assay</td><td headers="hd_h_ml291.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/489040" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 489040</a>;<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/540305" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 540305</a>; <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588582" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 588582</a>; <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/602416" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 602416</a></td><td headers="hd_h_ml291.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Activator</td><td headers="hd_h_ml291.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Secondary (Dry Powder)</td><td headers="hd_h_ml291.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Cell-based</td><td headers="hd_h_ml291.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Luminescence & 1536 well</td></tr><tr><td headers="hd_h_ml291.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SAR analysis of cytotoxicity in CHO-CHOP cells after 24 hours of exposure to small molecule activators of the apoptotic arm of the Unfolded Protein Response</td><td headers="hd_h_ml291.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588556" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 588556</a></td><td headers="hd_h_ml291.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Activator</td><td headers="hd_h_ml291.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Secondary (Dry Powder)</td><td headers="hd_h_ml291.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Cell-based</td><td headers="hd_h_ml291.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Luminescence & 1536 well</td></tr><tr><td headers="hd_h_ml291.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SAR analysis of cytotoxicity in the CHO-CHOP cells after 6 hours of exposure to small molecule activators of the apoptotic arm of the Unfolded Protein response</td><td headers="hd_h_ml291.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588557" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 588557</a></td><td headers="hd_h_ml291.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Activator</td><td headers="hd_h_ml291.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Secondary (Dry Powder)</td><td headers="hd_h_ml291.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Cell-based</td><td headers="hd_h_ml291.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Luminescence & 1536 well</td></tr><tr><td headers="hd_h_ml291.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SAR analysis of cytotoxicity in CHO-XBP1 cells after 24 hours of exposure to small molecule activators of the apoptotic arm of the Unfolded Protein response</td><td headers="hd_h_ml291.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588558" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 588558</a></td><td headers="hd_h_ml291.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Activator</td><td headers="hd_h_ml291.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Secondary (Dry Powder)</td><td headers="hd_h_ml291.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Cell-based</td><td headers="hd_h_ml291.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Luminescence & 1536 well</td></tr><tr><td headers="hd_h_ml291.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SAR analysis of cytotoxicity in CHO-XBP1 cells following 6 hours of exposure to small molecule activators of the apoptotic arm of the Unfolded Protein response</td><td headers="hd_h_ml291.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588570" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 588570</a></td><td headers="hd_h_ml291.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Activator</td><td headers="hd_h_ml291.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Secondary (Dry Powder)</td><td headers="hd_h_ml291.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Cell-based</td><td headers="hd_h_ml291.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Luminescence & 1536 well</td></tr></tbody></table></div></div></article><article data-type="fig" id="figobml291fu2"><div id="ml291.fu2" class="figure"><div class="graphic"><img data-src="/books/NBK133431/bin/ml291fu2.jpg" alt="Image ml291fu2" /></div></div></article><article data-type="table-wrap" id="figobml291t2"><div id="ml291.t2" class="table"><h3><span class="label">Table 2</span><span class="title">Probe and Analog Submissions to the MLSMR for the UPR CHOP Activator Probe</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK133431/table/ml291.t2/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml291.t2_lrgtbl__"><table class="no_margin"><thead><tr><th id="hd_h_ml291.t2_1_1_1_1" colspan="8" rowspan="1" style="text-align:left;vertical-align:middle;">Probe <a href="/pcsubstance/?term=ML291[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML291</a> - CID52940465 and Supporting Data for Analogs</th></tr><tr><th headers="hd_h_ml291.t2_1_1_1_1 hd_h_ml291.t2_1_1_2_1" id="hd_h_ml291.t2_1_1_2_1" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">Probe/Analog</th><th headers="hd_h_ml291.t2_1_1_1_1 hd_h_ml291.t2_1_1_2_2" id="hd_h_ml291.t2_1_1_2_2" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">MLS_ID (MLSMR)</th><th headers="hd_h_ml291.t2_1_1_1_1 hd_h_ml291.t2_1_1_2_3" id="hd_h_ml291.t2_1_1_2_3" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">CID</th><th headers="hd_h_ml291.t2_1_1_1_1 hd_h_ml291.t2_1_1_2_4" id="hd_h_ml291.t2_1_1_2_4" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">SID</th><th headers="hd_h_ml291.t2_1_1_1_1" id="hd_h_ml291.t2_1_1_2_5" colspan="2" rowspan="1" style="text-align:center;vertical-align:middle;">IC<sub>50</sub> (μM)</th><th headers="hd_h_ml291.t2_1_1_1_1 hd_h_ml291.t2_1_1_2_6" id="hd_h_ml291.t2_1_1_2_6" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">Amt (mg)</th><th headers="hd_h_ml291.t2_1_1_1_1 hd_h_ml291.t2_1_1_2_7" id="hd_h_ml291.t2_1_1_2_7" rowspan="2" colspan="1" style="text-align:center;vertical-align:middle;">Date Submitted to the MLSMR</th></tr><tr><th headers="hd_h_ml291.t2_1_1_1_1 hd_h_ml291.t2_1_1_2_5" id="hd_h_ml291.t2_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">UPR CHOP Assay<sup>b</sup></th><th headers="hd_h_ml291.t2_1_1_1_1 hd_h_ml291.t2_1_1_2_5" id="hd_h_ml291.t2_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">UPR XBP1 Assay<sup>b</sup></th></tr></thead><tbody><tr><td headers="hd_h_ml291.t2_1_1_1_1 hd_h_ml291.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Probe<b><a href="/pcsubstance/?term=ML291[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML291</a></b></td><td headers="hd_h_ml291.t2_1_1_1_1 hd_h_ml291.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">MLS003940499</td><td headers="hd_h_ml291.t2_1_1_1_1 hd_h_ml291.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CID 52940465</td><td headers="hd_h_ml291.t2_1_1_1_1 hd_h_ml291.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134228465" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 134228465</a></td><td headers="hd_h_ml291.t2_1_1_1_1 hd_h_ml291.t2_1_1_2_5 hd_h_ml291.t2_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.78</td><td headers="hd_h_ml291.t2_1_1_1_1 hd_h_ml291.t2_1_1_2_5 hd_h_ml291.t2_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">> 80</td><td headers="hd_h_ml291.t2_1_1_1_1 hd_h_ml291.t2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">21.1</td><td headers="hd_h_ml291.t2_1_1_1_1 hd_h_ml291.t2_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">02/10/2012</td></tr><tr><td headers="hd_h_ml291.t2_1_1_1_1 hd_h_ml291.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Analog 1</td><td headers="hd_h_ml291.t2_1_1_1_1 hd_h_ml291.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">MLS003940500</td><td headers="hd_h_ml291.t2_1_1_1_1 hd_h_ml291.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CID 17146663</td><td headers="hd_h_ml291.t2_1_1_1_1 hd_h_ml291.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134228466" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 134228466</a></td><td headers="hd_h_ml291.t2_1_1_1_1 hd_h_ml291.t2_1_1_2_5 hd_h_ml291.t2_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.76</td><td headers="hd_h_ml291.t2_1_1_1_1 hd_h_ml291.t2_1_1_2_5 hd_h_ml291.t2_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">> 80</td><td headers="hd_h_ml291.t2_1_1_1_1 hd_h_ml291.t2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">22.2</td><td headers="hd_h_ml291.t2_1_1_1_1 hd_h_ml291.t2_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">02/10/2012</td></tr><tr><td headers="hd_h_ml291.t2_1_1_1_1 hd_h_ml291.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Analog 2</td><td headers="hd_h_ml291.t2_1_1_1_1 hd_h_ml291.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">MLS003940501</td><td headers="hd_h_ml291.t2_1_1_1_1 hd_h_ml291.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CID 9415121</td><td headers="hd_h_ml291.t2_1_1_1_1 hd_h_ml291.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134228467" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 134228467</a></td><td headers="hd_h_ml291.t2_1_1_1_1 hd_h_ml291.t2_1_1_2_5 hd_h_ml291.t2_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.74</td><td headers="hd_h_ml291.t2_1_1_1_1 hd_h_ml291.t2_1_1_2_5 hd_h_ml291.t2_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">> 80</td><td headers="hd_h_ml291.t2_1_1_1_1 hd_h_ml291.t2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">23.2</td><td headers="hd_h_ml291.t2_1_1_1_1 hd_h_ml291.t2_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">02/10/2012</td></tr><tr><td headers="hd_h_ml291.t2_1_1_1_1 hd_h_ml291.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Analog 3</td><td headers="hd_h_ml291.t2_1_1_1_1 hd_h_ml291.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">MLS003940502</td><td headers="hd_h_ml291.t2_1_1_1_1 hd_h_ml291.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CID 52940467</td><td headers="hd_h_ml291.t2_1_1_1_1 hd_h_ml291.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134228468" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 134228468</a></td><td headers="hd_h_ml291.t2_1_1_1_1 hd_h_ml291.t2_1_1_2_5 hd_h_ml291.t2_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.43</td><td headers="hd_h_ml291.t2_1_1_1_1 hd_h_ml291.t2_1_1_2_5 hd_h_ml291.t2_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">> 80</td><td headers="hd_h_ml291.t2_1_1_1_1 hd_h_ml291.t2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">21.9</td><td headers="hd_h_ml291.t2_1_1_1_1 hd_h_ml291.t2_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">02/10/2012</td></tr><tr><td headers="hd_h_ml291.t2_1_1_1_1 hd_h_ml291.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Analog 4</td><td headers="hd_h_ml291.t2_1_1_1_1 hd_h_ml291.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">MLS003940503</td><td headers="hd_h_ml291.t2_1_1_1_1 hd_h_ml291.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CID 52940455</td><td headers="hd_h_ml291.t2_1_1_1_1 hd_h_ml291.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134228469" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 134228469</a></td><td headers="hd_h_ml291.t2_1_1_1_1 hd_h_ml291.t2_1_1_2_5 hd_h_ml291.t2_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.65</td><td headers="hd_h_ml291.t2_1_1_1_1 hd_h_ml291.t2_1_1_2_5 hd_h_ml291.t2_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">> 80</td><td headers="hd_h_ml291.t2_1_1_1_1 hd_h_ml291.t2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">22.5</td><td headers="hd_h_ml291.t2_1_1_1_1 hd_h_ml291.t2_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">02/10/2012</td></tr><tr><td headers="hd_h_ml291.t2_1_1_1_1 hd_h_ml291.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Analog 5</td><td headers="hd_h_ml291.t2_1_1_1_1 hd_h_ml291.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">MLS003940504</td><td headers="hd_h_ml291.t2_1_1_1_1 hd_h_ml291.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CID 51035286</td><td headers="hd_h_ml291.t2_1_1_1_1 hd_h_ml291.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/134228470" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 134228470</a></td><td headers="hd_h_ml291.t2_1_1_1_1 hd_h_ml291.t2_1_1_2_5 hd_h_ml291.t2_1_1_3_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.77</td><td headers="hd_h_ml291.t2_1_1_1_1 hd_h_ml291.t2_1_1_2_5 hd_h_ml291.t2_1_1_3_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">> 80</td><td headers="hd_h_ml291.t2_1_1_1_1 hd_h_ml291.t2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">22.5</td><td headers="hd_h_ml291.t2_1_1_1_1 hd_h_ml291.t2_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">02/10/2012</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>a</dt><dd><div id="ml291.tfn3"><p class="no_margin">Data is representative of only one batch (SID) listed, which was sent to the MLSMR. Data is an average of four runs (n= 4) for the UPR CHOP and UPR XBP1 assays.</p></div></dd></dl><dl class="bkr_refwrap"><dt>b</dt><dd><div id="ml291.tfn4"><p class="no_margin">Conditions: F12 nutrient mix HAMs supplemented with 10% hi-FBS, 1X Penicillin/Streptomycin, 1X MEM-NEAA.</p></div></dd></dl><dl class="bkr_refwrap"><dt></dt><dd><div id="ml291.tfn5"><p class="no_margin"><a href="/pcsubstance/?term=ML291[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML291</a> Probe solubility is 3.9 μg/mL, (9.4 μM) see <a class="figpopup" href="/books/NBK133431/table/ml291.t3/?report=objectonly" target="object" rid-figpopup="figml291t3" rid-ob="figobml291t3">Table 3</a></p></div></dd></dl></dl></div></div></div></article><article data-type="table-wrap" id="figobml291t3"><div id="ml291.t3" class="table"><h3><span class="label">Table 3</span><span class="title">Summary of <i>in vitro</i> ADME Properties of UPR CHOP Activator probe <a href="/pcsubstance/?term=ML291[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML291</a></span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK133431/table/ml291.t3/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml291.t3_lrgtbl__"><table class="no_margin"><tbody><tr><td colspan="2" rowspan="1" style="text-align:left;vertical-align:middle;"><b>Aqueous Solubility</b> in pION’s buffer (μg/mL) <i>[μM]</i><sup>a</sup> pH 5.0/6.2/7.4</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3.6/3.8/4.0 <i>[8.7/9.2/9.7]</i></td></tr><tr><td colspan="2" rowspan="1" style="text-align:left;vertical-align:middle;"><b>Aqueous Solubility</b> in 1× PBS, pH 7.4 (μg/mL) <i>[μM]</i><sup>a</sup></td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3.9 <i>[9.4]</i></td></tr><tr><td colspan="2" rowspan="1" style="text-align:left;vertical-align:middle;"><b>PAMPA Permeability</b>, P<sub>e</sub> (×10<sup>−6</sup> cm/s) Donor pH: 5.0/6.2/7.4 Acceptor pH: 7.4</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">291/329/245</td></tr><tr><td rowspan="2" colspan="1" style="text-align:left;vertical-align:middle;"><b>Plasma Protein Binding</b> (% Bound)</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Human 1 μM/10 μM</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">99.75/99.63</td></tr><tr><td rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Mouse 1 μM/10 μM</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">84.47/84.35</td></tr><tr><td colspan="2" rowspan="1" style="text-align:left;vertical-align:middle;"><b>Plasma Stability</b> (%Remaining at 3 hrs @ 37°C) Human/Mouse</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">85.58/52.31</td></tr><tr><td colspan="2" rowspan="1" style="text-align:left;vertical-align:middle;"><b>Hepatic Microsome Stability</b> (% Remaining after 1 hr @ 37°C) Human/Mouse</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.49/0.02</td></tr><tr><td colspan="2" rowspan="1" style="text-align:left;vertical-align:middle;"><b>Toxicity</b> Towards Fa2N-4 Immortalized Human Hepatocytes LC<sub>50</sub> (μM)</td><td rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">11.4</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt>a</dt><dd><div id="ml291.tfn6"><p class="no_margin">Solubility also expressed in molar units (μM) as indicated in <i>italicized [bracketed values],</i> in addition to more traditional μg/mL units.</p></div></dd></dl></dl></div></div></div></article><article data-type="fig" id="figobml291f1"><div id="ml291.f1" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK133431/bin/ml291f1.jpg" alt="Figure 1. Stability of ML291 over 48 h in PBS and 1:1 PBS:acetonitrile." /></div><h3><span class="label">Figure 1</span><span class="title">Stability of <a href="/pcsubstance/?term=ML291[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML291</a> over 48 h in PBS and 1:1 PBS:acetonitrile</span></h3><div class="caption"><p>Apparent instability in PBS is actually due to poor solubility of <a href="/pcsubstance/?term=ML291[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML291</a>.</p></div></div></article><article data-type="fig" id="figobml291f2"><div id="ml291.f2" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%202.%20Chemical%20stability%20of%20ML291%2C%20represented%20by%20percent%20of%20parent%20remaining%20over%20time%2C%20in%20the%20presence%20of%20five-fold%20molar%20equivalent%20of%20GSH%20or%20DTT%2C%20incubated%20at%20room%20temperature%20in%201%3A1%20ACN%3APBS%2C%20pH%207.4%2C%201%25%20(v%2Fv)%20DMSO.&p=BOOKS&id=133431_ml291f2.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK133431/bin/ml291f2.jpg" alt="Figure 2. Chemical stability of ML291, represented by percent of parent remaining over time, in the presence of five-fold molar equivalent of GSH or DTT, incubated at room temperature in 1:1 ACN:PBS, pH 7.4, 1% (v/v) DMSO." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 2</span><span class="title">Chemical stability of <a href="/pcsubstance/?term=ML291[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML291</a>, represented by percent of parent remaining over time, in the presence of five-fold molar equivalent of GSH or DTT, incubated at room temperature in 1:1 ACN:PBS, pH 7.4, 1% (v/v) DMSO</span></h3></div></article><article data-type="fig" id="figobml291f5"><div id="ml291.f5" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK133431/bin/ml291f5.jpg" alt="Scheme 1" /></div><h3><span class="label">Scheme 1</span></h3></div></article><article data-type="fig" id="figobml291fu3"><div id="ml291.fu3" class="figure"><div class="graphic"><img data-src="/books/NBK133431/bin/ml291fu3.jpg" alt="Image ml291fu3" /></div></div></article><article data-type="fig" id="figobml291fu4"><div id="ml291.fu4" class="figure"><div class="graphic"><img data-src="/books/NBK133431/bin/ml291fu4.jpg" alt="Image ml291fu4" /></div></div></article><article data-type="fig" id="figobml291fu5"><div id="ml291.fu5" class="figure"><div class="graphic"><img data-src="/books/NBK133431/bin/ml291fu5.jpg" alt="Image ml291fu5" /></div></div></article><article data-type="fig" id="figobml291f3"><div id="ml291.f3" class="figure bk_fig"><div class="graphic"><img data-src="/books/NBK133431/bin/ml291f3.jpg" alt="Figure 3. Activation of luciferase reporters driven by UPR sub-pathway promoters for the apoptotic (CHOP) and adaptive (XBP1) arms." /></div><h3><span class="label">Figure 3</span><span class="title">Activation of luciferase reporters driven by UPR sub-pathway promoters for the apoptotic (CHOP) and adaptive (XBP1) arms</span></h3><div class="caption"><p>Engineered CHO-K1 cell were incubated with <a href="/pcsubstance/?term=ML291[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML291</a> for overnight (~16 hr) and luciferase induction measured with SteadyGlo™</p></div></div></article><article data-type="fig" id="figobml291f4"><div id="ml291.f4" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%204.%20Cellular%20Efficacy%20of%20ML291%20for%20Activating%20the%20CHOP%20Pathway%20Induced%20cytotoxicity%20in%20MEF%20with%20wt-CHOP%20vs.%20CHOP-KO.&p=BOOKS&id=133431_ml291f4.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK133431/bin/ml291f4.jpg" alt="Figure 4. Cellular Efficacy of ML291 for Activating the CHOP Pathway Induced cytotoxicity in MEF with wt-CHOP vs. CHOP-KO." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure 4</span><span class="title">Cellular Efficacy of <a href="/pcsubstance/?term=ML291[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML291</a> for Activating the CHOP Pathway Induced cytotoxicity in MEF with wt-CHOP <i>vs.</i> CHOP-KO</span></h3><div class="caption"><p>(After 16 hr exposure to probe)</p></div></div></article><article data-type="fig" id="figobml291f6"><div id="ml291.f6" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%20A6A.%20Proton%201H%20NMR%20spectra%20for%20ML291%20(SID%20123083137%2C%20CID%2052940465).&p=BOOKS&id=133431_ml291f6.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK133431/bin/ml291f6.jpg" alt="Figure A6A. Proton 1H NMR spectra for ML291 (SID 123083137, CID 52940465)." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure A6A</span><span class="title">Proton <sup>1</sup>H NMR spectra for <a href="/pcsubstance/?term=ML291[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML291</a> (<a href="https://pubchem.ncbi.nlm.nih.gov/substance/123083137" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 123083137</a>, CID 52940465)</span></h3></div></article><article data-type="fig" id="figobml291f7"><div id="ml291.f7" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%20A6B.%20Carbon%2013C-NMR%20data%20for%20ML291%20(SID%20123083137%2C%20CID%2052940465).&p=BOOKS&id=133431_ml291f7.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK133431/bin/ml291f7.jpg" alt="Figure A6B. Carbon 13C-NMR data for ML291 (SID 123083137, CID 52940465)." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure A6B</span><span class="title">Carbon <sup>13</sup>C-NMR data for <a href="/pcsubstance/?term=ML291[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML291</a> (<a href="https://pubchem.ncbi.nlm.nih.gov/substance/123083137" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 123083137</a>, CID 52940465)</span></h3></div></article><article data-type="fig" id="figobml291f8"><div id="ml291.f8" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%20A6C.%20LCMS%20purity%20data%20at%20214%20nm%20for%20ML291%201st%20batch%20(SID%20123083137%2C%20CID%2052940465)%3B%20LCMS%20retention%20time%3A%203.074%20min%3B%20purity%20at%20214%20nm%20%3D%2095.4%25.&p=BOOKS&id=133431_ml291f8.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK133431/bin/ml291f8.jpg" alt="Figure A6C. LCMS purity data at 214 nm for ML291 1st batch (SID 123083137, CID 52940465); LCMS retention time: 3.074 min; purity at 214 nm = 95.4%." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure A6C</span><span class="title">LCMS purity data at 214 nm for <a href="/pcsubstance/?term=ML291[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML291</a> 1<sup>st</sup> batch (<a href="https://pubchem.ncbi.nlm.nih.gov/substance/123083137" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 123083137</a>, CID 52940465); LCMS retention time: 3.074 min; purity at 214 nm = 95.4%</span></h3></div></article><article data-type="fig" id="figobml291f9"><div id="ml291.f9" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%20A6D.%20HRMS%20data%20for%20ML291%201st%20batch%20(SID%20123083137%2C%20CID%2052940465)%3B%20HRMS%20m%2Fz%20calculated%20for%20C16H17ClN3O6S%20%5BM%20%2B%20H%2B%5D%3A%20414.0521%2C%20found%20414.0527.&p=BOOKS&id=133431_ml291f9.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK133431/bin/ml291f9.jpg" alt="Figure A6D. HRMS data for ML291 1st batch (SID 123083137, CID 52940465); HRMS m/z calculated for C16H17ClN3O6S [M + H+]: 414.0521, found 414.0527." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure A6D</span><span class="title">HRMS data for <a href="/pcsubstance/?term=ML291[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML291</a> 1<sup>st</sup> batch (<a href="https://pubchem.ncbi.nlm.nih.gov/substance/123083137" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 123083137</a>, CID 52940465); HRMS <i>m</i>/<i>z</i> calculated for C<sub>16</sub>H<sub>17</sub>ClN<sub>3</sub>O<sub>6</sub>S [M + H<sup>+</sup>]: 414.0521, found 414.0527</span></h3></div></article><article data-type="fig" id="figobml291f10"><div id="ml291.f10" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%20A6E.%20LCMS%20purity%20data%20at%20214%20nm%20for%20ML291%202nd%20batch%20%02013submitted%20to%20the%20MLSMR%20(SID%20134228465%2C%20CID%2052940465)%3B%20LCMS%20retention%20time%3A%203.125%20min%3B%20purity%20at%20214%20nm%20%3D%2097.5%25.&p=BOOKS&id=133431_ml291f10.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK133431/bin/ml291f10.jpg" alt="Figure A6E. LCMS purity data at 214 nm for ML291 2nd batch –submitted to the MLSMR (SID 134228465, CID 52940465); LCMS retention time: 3.125 min; purity at 214 nm = 97.5%." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure A6E</span><span class="title">LCMS purity data at 214 nm for <a href="/pcsubstance/?term=ML291[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML291</a> 2<sup>nd</sup> batch –submitted to the MLSMR (<a href="https://pubchem.ncbi.nlm.nih.gov/substance/134228465" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 134228465</a>, CID 52940465); LCMS retention time: 3.125 min; purity at 214 nm = 97.5%</span></h3></div></article><article data-type="fig" id="figobml291f11"><div id="ml291.f11" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Figure%20A6F.%20HRMS%20data%20for%20ML291%202nd%20batch%20%02013submitted%20to%20the%20MLSMR%20(SID%20134228465%2C%20CID%2052940465)%3B%20HRMS%20m%2Fz%20calculated%20for%20C16H17ClN3O6S%20%5BM%20%2B%20H%2B%5D%3A%20414.0521%2C%20found%20414.0522.&p=BOOKS&id=133431_ml291f11.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK133431/bin/ml291f11.jpg" alt="Figure A6F. HRMS data for ML291 2nd batch –submitted to the MLSMR (SID 134228465, CID 52940465); HRMS m/z calculated for C16H17ClN3O6S [M + H+]: 414.0521, found 414.0522." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="label">Figure A6F</span><span class="title">HRMS data for <a href="/pcsubstance/?term=ML291[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML291</a> 2<sup>nd</sup> batch –submitted to the MLSMR (<a href="https://pubchem.ncbi.nlm.nih.gov/substance/134228465" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 134228465</a>, CID 52940465); HRMS <i>m</i>/<i>z</i> calculated for C<sub>16</sub>H<sub>17</sub>ClN<sub>3</sub>O<sub>6</sub>S [M + H<sup>+</sup>]: 414.0521, found 414.0522</span></h3></div></article><article data-type="table-wrap" id="figobml291tu2"><div id="ml291.tu2" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK133431/table/ml291.tu2/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml291.tu2_lrgtbl__"><table><thead><tr><th id="hd_h_ml291.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Cat #</th><th id="hd_h_ml291.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Assay Name</th><th id="hd_h_ml291.tu2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Species</th><th id="hd_h_ml291.tu2_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Conc.</th><th id="hd_h_ml291.tu2_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">% Inh.</th></tr></thead><tbody><tr><td headers="hd_h_ml291.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">220320</td><td headers="hd_h_ml291.tu2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Transporter, Dopamine (DAT)</td><td headers="hd_h_ml291.tu2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml291.tu2_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">10 μM</td><td headers="hd_h_ml291.tu2_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">68</td></tr></tbody></table></div></div></article><article data-type="table-wrap" id="figobml291tu3"><div id="ml291.tu3" class="table"><h3><span class="title">EXPERIMENTAL RESULTS FOR <a href="https://pubchem.ncbi.nlm.nih.gov/substance/123083137" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 123083137</a> ON OTHER TARGETS</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK133431/table/ml291.tu3/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml291.tu3_lrgtbl__"><table class="no_margin"><thead><tr><th id="hd_h_ml291.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Cat #</th><th id="hd_h_ml291.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Assay Name</th><th id="hd_h_ml291.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">Batch<sup>*</sup></th><th id="hd_h_ml291.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:bottom;">Spec.</th><th id="hd_h_ml291.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">Rep.</th><th id="hd_h_ml291.tu3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">Cone.</th><th id="hd_h_ml291.tu3_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">% Inh.</th></tr></thead><tbody><tr><td headers="hd_h_ml291.tu3_1_1_1_1 hd_h_ml291.tu3_1_1_1_2 hd_h_ml291.tu3_1_1_1_3 hd_h_ml291.tu3_1_1_1_4 hd_h_ml291.tu3_1_1_1_5 hd_h_ml291.tu3_1_1_1_6 hd_h_ml291.tu3_1_1_1_7" colspan="7" rowspan="1" style="text-align:left;vertical-align:top;"><b>Compound: <a href="https://pubchem.ncbi.nlm.nih.gov/substance/123083137" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID123083137</a>, PT #: 1158789</b></td></tr><tr><td headers="hd_h_ml291.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">200510</td><td headers="hd_h_ml291.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Adenosine A<sub>1</sub></td><td headers="hd_h_ml291.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">310992</td><td headers="hd_h_ml291.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml291.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml291.tu3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml291.tu3_1_1_1_7" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">12</td></tr><tr><td headers="hd_h_ml291.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">200610</td><td headers="hd_h_ml291.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Adenosine A<sub>2A</sub></td><td headers="hd_h_ml291.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">310993</td><td headers="hd_h_ml291.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml291.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml291.tu3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml291.tu3_1_1_1_7" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">8</td></tr><tr><td headers="hd_h_ml291.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">200720</td><td headers="hd_h_ml291.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Adenosine A<sub>3</sub></td><td headers="hd_h_ml291.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">310976</td><td headers="hd_h_ml291.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml291.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml291.tu3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml291.tu3_1_1_1_7" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">6</td></tr><tr><td headers="hd_h_ml291.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">203100</td><td headers="hd_h_ml291.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Adrenergic α<sub>1A</sub></td><td headers="hd_h_ml291.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">310901</td><td headers="hd_h_ml291.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">rat</td><td headers="hd_h_ml291.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml291.tu3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml291.tu3_1_1_1_7" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">19</td></tr><tr><td headers="hd_h_ml291.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">203200</td><td headers="hd_h_ml291.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Adrenergic α<sub>1B</sub></td><td headers="hd_h_ml291.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">310902</td><td headers="hd_h_ml291.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">rat</td><td headers="hd_h_ml291.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml291.tu3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml291.tu3_1_1_1_7" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">13</td></tr><tr><td headers="hd_h_ml291.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">203400</td><td headers="hd_h_ml291.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Adrenergic α<sub>1D</sub></td><td headers="hd_h_ml291.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">310903</td><td headers="hd_h_ml291.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml291.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml291.tu3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml291.tu3_1_1_1_7" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">8</td></tr><tr><td headers="hd_h_ml291.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">203620</td><td headers="hd_h_ml291.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Adrenergic α<sub>2A</sub></td><td headers="hd_h_ml291.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">310904</td><td headers="hd_h_ml291.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml291.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml291.tu3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml291.tu3_1_1_1_7" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">11</td></tr><tr><td headers="hd_h_ml291.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">204010</td><td headers="hd_h_ml291.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Adrenergic β<sub>1</sub></td><td headers="hd_h_ml291.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">310974</td><td headers="hd_h_ml291.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml291.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml291.tu3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml291.tu3_1_1_1_7" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">1</td></tr><tr><td headers="hd_h_ml291.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">204110</td><td headers="hd_h_ml291.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Adrenergic β<sub>2</sub></td><td headers="hd_h_ml291.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">310983</td><td headers="hd_h_ml291.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml291.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml291.tu3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml291.tu3_1_1_1_7" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">17</td></tr><tr><td headers="hd_h_ml291.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">285010</td><td headers="hd_h_ml291.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Androgen (Testosterone) AR</td><td headers="hd_h_ml291.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">311022</td><td headers="hd_h_ml291.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">rat</td><td headers="hd_h_ml291.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml291.tu3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml291.tu3_1_1_1_7" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">8</td></tr><tr><td headers="hd_h_ml291.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">212510</td><td headers="hd_h_ml291.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Bradykinin B<sub>1</sub></td><td headers="hd_h_ml291.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">311038</td><td headers="hd_h_ml291.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml291.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml291.tu3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml291.tu3_1_1_1_7" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">11</td></tr><tr><td headers="hd_h_ml291.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">212620</td><td headers="hd_h_ml291.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Bradykinin B<sub>2</sub></td><td headers="hd_h_ml291.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">311061</td><td headers="hd_h_ml291.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml291.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml291.tu3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml291.tu3_1_1_1_7" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">4</td></tr><tr><td headers="hd_h_ml291.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">214510</td><td headers="hd_h_ml291.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Calcium Channel L-Type, Benzothiazepine</td><td headers="hd_h_ml291.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">310999</td><td headers="hd_h_ml291.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">rat</td><td headers="hd_h_ml291.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml291.tu3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml291.tu3_1_1_1_7" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">6</td></tr><tr><td headers="hd_h_ml291.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">214600</td><td headers="hd_h_ml291.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Calcium Channel L-Type, Dihydropyridine</td><td headers="hd_h_ml291.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">310998</td><td headers="hd_h_ml291.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">rat</td><td headers="hd_h_ml291.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml291.tu3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml291.tu3_1_1_1_7" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">24</td></tr><tr><td headers="hd_h_ml291.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">216000</td><td headers="hd_h_ml291.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Calcium Channel N-Type</td><td headers="hd_h_ml291.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">310899</td><td headers="hd_h_ml291.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">rat</td><td headers="hd_h_ml291.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml291.tu3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml291.tu3_1_1_1_7" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">18</td></tr><tr><td headers="hd_h_ml291.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">217030</td><td headers="hd_h_ml291.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Cannabinoid CB<sub>1</sub></td><td headers="hd_h_ml291.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">311000</td><td headers="hd_h_ml291.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml291.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml291.tu3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml291.tu3_1_1_1_7" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">20</td></tr><tr><td headers="hd_h_ml291.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">219500</td><td headers="hd_h_ml291.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Dopamine D<sub>1</sub></td><td headers="hd_h_ml291.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">310984</td><td headers="hd_h_ml291.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml291.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml291.tu3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml291.tu3_1_1_1_7" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">−2</td></tr><tr><td headers="hd_h_ml291.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">219700</td><td headers="hd_h_ml291.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Dopamine D<sub>2S</sub></td><td headers="hd_h_ml291.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">310985</td><td headers="hd_h_ml291.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml291.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml291.tu3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml291.tu3_1_1_1_7" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">21</td></tr><tr><td headers="hd_h_ml291.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">219800</td><td headers="hd_h_ml291.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Dopamine D<sub>3</sub></td><td headers="hd_h_ml291.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">311010</td><td headers="hd_h_ml291.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml291.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml291.tu3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml291.tu3_1_1_1_7" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">9</td></tr><tr><td headers="hd_h_ml291.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">219900</td><td headers="hd_h_ml291.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Dopamine D<sub>4.2</sub></td><td headers="hd_h_ml291.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">310959</td><td headers="hd_h_ml291.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml291.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml291.tu3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml291.tu3_1_1_1_7" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">1</td></tr><tr><td headers="hd_h_ml291.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">224010</td><td headers="hd_h_ml291.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Endothelin ET<sub>A</sub></td><td headers="hd_h_ml291.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">311036</td><td headers="hd_h_ml291.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml291.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml291.tu3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml291.tu3_1_1_1_7" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">−10</td></tr><tr><td headers="hd_h_ml291.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">224110</td><td headers="hd_h_ml291.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Endothelin ET<sub>B</sub></td><td headers="hd_h_ml291.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">311037</td><td headers="hd_h_ml291.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml291.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml291.tu3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml291.tu3_1_1_1_7" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">3</td></tr><tr><td headers="hd_h_ml291.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">225510</td><td headers="hd_h_ml291.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Epidermal Growth Factor (EGF)</td><td headers="hd_h_ml291.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">310884</td><td headers="hd_h_ml291.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml291.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml291.tu3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml291.tu3_1_1_1_7" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">−5</td></tr><tr><td headers="hd_h_ml291.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">226010</td><td headers="hd_h_ml291.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Estrogen ERα.</td><td headers="hd_h_ml291.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">310897</td><td headers="hd_h_ml291.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml291.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml291.tu3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml291.tu3_1_1_1_7" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">0</td></tr><tr><td headers="hd_h_ml291.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">226600</td><td headers="hd_h_ml291.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">GABA<sub>A</sub>, Flunitrazepam, Central</td><td headers="hd_h_ml291.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">310986</td><td headers="hd_h_ml291.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">rat</td><td headers="hd_h_ml291.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml291.tu3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml291.tu3_1_1_1_7" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">21</td></tr><tr><td headers="hd_h_ml291.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">226500</td><td headers="hd_h_ml291.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">GABA<sub>A</sub>, Muscimol, Central</td><td headers="hd_h_ml291.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">311011</td><td headers="hd_h_ml291.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">rat</td><td headers="hd_h_ml291.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml291.tu3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml291.tu3_1_1_1_7" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">21</td></tr><tr><td headers="hd_h_ml291.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">228610</td><td headers="hd_h_ml291.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">GABA<sub>B1A</sub></td><td headers="hd_h_ml291.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">310896</td><td headers="hd_h_ml291.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml291.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml291.tu3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml291.tu3_1_1_1_7" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">5</td></tr><tr><td headers="hd_h_ml291.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">232030</td><td headers="hd_h_ml291.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Glucocorticoid</td><td headers="hd_h_ml291.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">311064</td><td headers="hd_h_ml291.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml291.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml291.tu3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml291.tu3_1_1_1_7" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">19</td></tr><tr><td headers="hd_h_ml291.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">232700</td><td headers="hd_h_ml291.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Glutamate, Kainate</td><td headers="hd_h_ml291.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">311034</td><td headers="hd_h_ml291.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">rat</td><td headers="hd_h_ml291.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml291.tu3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml291.tu3_1_1_1_7" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">−9</td></tr><tr><td headers="hd_h_ml291.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">232810</td><td headers="hd_h_ml291.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Glutamate, NMDA, Agonism</td><td headers="hd_h_ml291.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">311035</td><td headers="hd_h_ml291.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">rat</td><td headers="hd_h_ml291.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml291.tu3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml291.tu3_1_1_1_7" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">4</td></tr><tr><td headers="hd_h_ml291.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">232910</td><td headers="hd_h_ml291.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Glutamate, NMDA, Glycine</td><td headers="hd_h_ml291.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">310895</td><td headers="hd_h_ml291.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">rat</td><td headers="hd_h_ml291.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml291.tu3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml291.tu3_1_1_1_7" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">2</td></tr><tr><td headers="hd_h_ml291.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">233000</td><td headers="hd_h_ml291.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Glutamate, NMDA, Phencyclidine</td><td headers="hd_h_ml291.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">311003</td><td headers="hd_h_ml291.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">rat</td><td headers="hd_h_ml291.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml291.tu3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml291.tu3_1_1_1_7" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">−3</td></tr><tr><td headers="hd_h_ml291.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">239610</td><td headers="hd_h_ml291.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Histamine H<sub>1</sub></td><td headers="hd_h_ml291.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">310934</td><td headers="hd_h_ml291.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml291.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml291.tu3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml291.tu3_1_1_1_7" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">−2</td></tr><tr><td headers="hd_h_ml291.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">239710</td><td headers="hd_h_ml291.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Histamine H<sub>2</sub></td><td headers="hd_h_ml291.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">310975</td><td headers="hd_h_ml291.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml291.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml291.tu3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml291.tu3_1_1_1_7" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">10</td></tr><tr><td headers="hd_h_ml291.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">239820</td><td headers="hd_h_ml291.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Histamine H<sub>3</sub></td><td headers="hd_h_ml291.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">311012</td><td headers="hd_h_ml291.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml291.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml291.tu3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml291.tu3_1_1_1_7" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">−5</td></tr><tr><td headers="hd_h_ml291.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">241000</td><td headers="hd_h_ml291.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Imidazoline I<sub>2</sub>, Central</td><td headers="hd_h_ml291.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">311006</td><td headers="hd_h_ml291.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">rat</td><td headers="hd_h_ml291.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml291.tu3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml291.tu3_1_1_1_7" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">−3</td></tr><tr><td headers="hd_h_ml291.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">243520</td><td headers="hd_h_ml291.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Interleukin IL-1</td><td headers="hd_h_ml291.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">311266</td><td headers="hd_h_ml291.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">mouse</td><td headers="hd_h_ml291.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml291.tu3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml291.tu3_1_1_1_7" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">−4</td></tr><tr><td headers="hd_h_ml291.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">250460</td><td headers="hd_h_ml291.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Leukotriene, Cysteinyl CysLT<sub>1</sub></td><td headers="hd_h_ml291.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">311007</td><td headers="hd_h_ml291.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml291.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml291.tu3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml291.tu3_1_1_1_7" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">11</td></tr><tr><td headers="hd_h_ml291.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">251600</td><td headers="hd_h_ml291.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Melatonin MT<sub>1</sub></td><td headers="hd_h_ml291.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">310969</td><td headers="hd_h_ml291.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml291.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml291.tu3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml291.tu3_1_1_1_7" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">8</td></tr><tr><td headers="hd_h_ml291.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">252610</td><td headers="hd_h_ml291.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Muscarinic M<sub>1</sub></td><td headers="hd_h_ml291.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">311151</td><td headers="hd_h_ml291.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml291.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml291.tu3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10μM</td><td headers="hd_h_ml291.tu3_1_1_1_7" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">2</td></tr><tr><td headers="hd_h_ml291.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">252710</td><td headers="hd_h_ml291.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Muscarinic M<sub>2</sub></td><td headers="hd_h_ml291.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">310988</td><td headers="hd_h_ml291.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml291.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml291.tu3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml291.tu3_1_1_1_7" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">10</td></tr><tr><td headers="hd_h_ml291.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">252810</td><td headers="hd_h_ml291.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Muscarinic M<sub>3</sub></td><td headers="hd_h_ml291.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">310989</td><td headers="hd_h_ml291.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml291.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml291.tu3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml291.tu3_1_1_1_7" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">13</td></tr><tr><td headers="hd_h_ml291.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">257010</td><td headers="hd_h_ml291.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Neuropeptide Y Y<sub>1</sub></td><td headers="hd_h_ml291.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">310893</td><td headers="hd_h_ml291.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml291.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml291.tu3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml291.tu3_1_1_1_7" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">7</td></tr><tr><td headers="hd_h_ml291.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">257110</td><td headers="hd_h_ml291.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Neuropeptide Y Y<sub>2</sub></td><td headers="hd_h_ml291.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">310894</td><td headers="hd_h_ml291.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml291.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml291.tu3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml291.tu3_1_1_1_7" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">4</td></tr><tr><td headers="hd_h_ml291.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">258590</td><td headers="hd_h_ml291.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Nicotinic Acetylcholine</td><td headers="hd_h_ml291.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">310971</td><td headers="hd_h_ml291.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml291.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml291.tu3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml291.tu3_1_1_1_7" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">−1</td></tr><tr><td headers="hd_h_ml291.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">258700</td><td headers="hd_h_ml291.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Nicotinic Acetylcholine α, Bungarotoxin</td><td headers="hd_h_ml291.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">310972</td><td headers="hd_h_ml291.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml291.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml291.tu3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml291.tu3_1_1_1_7" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">−1</td></tr><tr><td headers="hd_h_ml291.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">260130</td><td headers="hd_h_ml291.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Opiate δ<sub>1</sub> (OP1, DOP)</td><td headers="hd_h_ml291.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">310879</td><td headers="hd_h_ml291.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml291.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml291.tu3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml291.tu3_1_1_1_7" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">−13</td></tr><tr><td headers="hd_h_ml291.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">260210</td><td headers="hd_h_ml291.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Opiate κ(OP2, KOP)</td><td headers="hd_h_ml291.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">310880</td><td headers="hd_h_ml291.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml291.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml291.tu3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml291.tu3_1_1_1_7" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">7</td></tr><tr><td headers="hd_h_ml291.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">260410</td><td headers="hd_h_ml291.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Opiate μ(OP3, MOP)</td><td headers="hd_h_ml291.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">310881</td><td headers="hd_h_ml291.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml291.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml291.tu3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml291.tu3_1_1_1_7" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">1</td></tr><tr><td headers="hd_h_ml291.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">264500</td><td headers="hd_h_ml291.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Phorbol Ester</td><td headers="hd_h_ml291.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">310990</td><td headers="hd_h_ml291.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">mouse</td><td headers="hd_h_ml291.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml291.tu3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml291.tu3_1_1_1_7" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">9</td></tr><tr><td headers="hd_h_ml291.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">265010</td><td headers="hd_h_ml291.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Platelet Activating Factor (PAF)</td><td headers="hd_h_ml291.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">310876</td><td headers="hd_h_ml291.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml291.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml291.tu3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml291.tu3_1_1_1_7" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">39</td></tr><tr><td headers="hd_h_ml291.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">265600</td><td headers="hd_h_ml291.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Potassium Channel [K<sub>ATP</sub>]</td><td headers="hd_h_ml291.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">310991</td><td headers="hd_h_ml291.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">ham</td><td headers="hd_h_ml291.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml291.tu3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml291.tu3_1_1_1_7" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">11</td></tr><tr><td headers="hd_h_ml291.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">265900</td><td headers="hd_h_ml291.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Potassium Channel hERG</td><td headers="hd_h_ml291.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">310905</td><td headers="hd_h_ml291.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml291.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml291.tu3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml291.tu3_1_1_1_7" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">32</td></tr><tr><td headers="hd_h_ml291.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">268420</td><td headers="hd_h_ml291.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Prostanoid EP<sub>4</sub></td><td headers="hd_h_ml291.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">311013</td><td headers="hd_h_ml291.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml291.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml291.tu3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml291.tu3_1_1_1_7" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">−2</td></tr><tr><td headers="hd_h_ml291.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">268700</td><td headers="hd_h_ml291.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Purinergic P<sub>2X</sub></td><td headers="hd_h_ml291.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">311014</td><td headers="hd_h_ml291.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">rabbit</td><td headers="hd_h_ml291.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml291.tu3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml291.tu3_1_1_1_7" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">−12</td></tr><tr><td headers="hd_h_ml291.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">268810</td><td headers="hd_h_ml291.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Purinergic P<sub>2Y</sub></td><td headers="hd_h_ml291.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">311015</td><td headers="hd_h_ml291.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">rat</td><td headers="hd_h_ml291.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml291.tu3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml291.tu3_1_1_1_7" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">9</td></tr><tr><td headers="hd_h_ml291.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">270000</td><td headers="hd_h_ml291.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Rolipram</td><td headers="hd_h_ml291.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">311177</td><td headers="hd_h_ml291.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">rat</td><td headers="hd_h_ml291.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml291.tu3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml291.tu3_1_1_1_7" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">12</td></tr><tr><td headers="hd_h_ml291.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">271110</td><td headers="hd_h_ml291.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serotonin (5-Hydroxytryptamine) 5-HT<sub>2A</sub></td><td headers="hd_h_ml291.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">311017</td><td headers="hd_h_ml291.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml291.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml291.tu3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml291.tu3_1_1_1_7" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">4</td></tr><tr><td headers="hd_h_ml291.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">271700</td><td headers="hd_h_ml291.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serotonin (5-Hydroxytryptamine) 5-HT<sub>2B</sub></td><td headers="hd_h_ml291.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">311019</td><td headers="hd_h_ml291.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml291.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml291.tu3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml291.tu3_1_1_1_7" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">8</td></tr><tr><td headers="hd_h_ml291.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">271910</td><td headers="hd_h_ml291.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Serotonin (5-Hydroxytryptamine) 5-HT<sub>3</sub></td><td headers="hd_h_ml291.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">310891</td><td headers="hd_h_ml291.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml291.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml291.tu3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml291.tu3_1_1_1_7" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">−13</td></tr><tr><td headers="hd_h_ml291.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">278110</td><td headers="hd_h_ml291.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Sigma σ<sub>1</sub></td><td headers="hd_h_ml291.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">311021</td><td headers="hd_h_ml291.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml291.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml291.tu3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml291.tu3_1_1_1_7" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">38</td></tr><tr><td headers="hd_h_ml291.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">255520</td><td headers="hd_h_ml291.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Tachykinin NK<sub>1</sub></td><td headers="hd_h_ml291.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">311044</td><td headers="hd_h_ml291.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml291.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml291.tu3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml291.tu3_1_1_1_7" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">3</td></tr><tr><td headers="hd_h_ml291.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">285900</td><td headers="hd_h_ml291.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Thyroid Hormone</td><td headers="hd_h_ml291.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">310909</td><td headers="hd_h_ml291.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">rat</td><td headers="hd_h_ml291.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml291.tu3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml291.tu3_1_1_1_7" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">7</td></tr><tr><td headers="hd_h_ml291.tu3_1_1_1_1" rowspan="1" colspan="1" style="background-color:#E0E0E0;text-align:left;vertical-align:top;">220320</td><td headers="hd_h_ml291.tu3_1_1_1_2" rowspan="1" colspan="1" style="background-color:#E0E0E0;text-align:left;vertical-align:top;">Transporter, Dopamine (DAT)</td><td headers="hd_h_ml291.tu3_1_1_1_3" rowspan="1" colspan="1" style="background-color:#E0E0E0;text-align:center;vertical-align:top;">310996</td><td headers="hd_h_ml291.tu3_1_1_1_4" rowspan="1" colspan="1" style="background-color:#E0E0E0;text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml291.tu3_1_1_1_5" rowspan="1" colspan="1" style="background-color:#E0E0E0;text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml291.tu3_1_1_1_6" rowspan="1" colspan="1" style="background-color:#E0E0E0;text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml291.tu3_1_1_1_7" rowspan="1" colspan="1" style="background-color:#E0E0E0;text-align:right;vertical-align:top;">68</td></tr><tr><td headers="hd_h_ml291.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">226400</td><td headers="hd_h_ml291.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Transporter, GABA</td><td headers="hd_h_ml291.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">311002</td><td headers="hd_h_ml291.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">rat</td><td headers="hd_h_ml291.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml291.tu3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml291.tu3_1_1_1_7" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">17</td></tr><tr><td headers="hd_h_ml291.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">204410</td><td headers="hd_h_ml291.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Transporter, Norepinephrine (NET)</td><td headers="hd_h_ml291.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">310995</td><td headers="hd_h_ml291.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml291.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml291.tu3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml291.tu3_1_1_1_7" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">28</td></tr><tr><td headers="hd_h_ml291.tu3_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">274030</td><td headers="hd_h_ml291.tu3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Transporter, Serotonin (5-Hydroxytryptamine) (SERT)</td><td headers="hd_h_ml291.tu3_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">311020</td><td headers="hd_h_ml291.tu3_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">hum</td><td headers="hd_h_ml291.tu3_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td><td headers="hd_h_ml291.tu3_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">10 μM</td><td headers="hd_h_ml291.tu3_1_1_1_7" rowspan="1" colspan="1" style="text-align:right;vertical-align:top;">5</td></tr></tbody></table></div><div class="tblwrap-foot"><div><dl class="temp-labeled-list small"><dl class="bkr_refwrap"><dt></dt><dd><div id="ml291.tfn10"><p class="no_margin">Note: Items meeting criteria for significance (≥50% stimulation or inhibition) are highlighted.</p></div></dd></dl><dl class="bkr_refwrap"><dt>*</dt><dd><div id="ml291.tfn7"><p class="no_margin">Batch: Represents compounds tested concurrently in the same assay(s).</p></div></dd></dl><dl class="bkr_refwrap"><dt></dt><dd><div id="ml291.tfn8"><p class="no_margin">R=See Remarks (if any) at end of this section.</p></div></dd></dl><dl class="bkr_refwrap"><dt></dt><dd><div id="ml291.tfn9"><p class="no_margin">ham=Hamster; hum=Human</p></div></dd></dl></dl></div></div></div></article><article data-type="fig" id="figobml291fu6"><div id="ml291.fu6" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ml291fu6a&p=BOOKS&id=133431_ml291fu6a.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK133431/bin/ml291fu6a.jpg" alt="Image ml291fu6a" class="tileshop" title="Click on image to zoom" /></a></div><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ml291fu6b&p=BOOKS&id=133431_ml291fu6b.jpg" target="tileshopwindow" class="inline_block pmc_inline_block ts_canvas img_link" title="Click on image to zoom"><div class="ts_bar small" title="Click on image to zoom"></div><img data-src="/books/NBK133431/bin/ml291fu6b.jpg" alt="Image ml291fu6b" class="tileshop" title="Click on image to zoom" /></a></div></div></article><article data-type="fig" id="figobml291fu7"><div id="ml291.fu7" class="figure"><div class="graphic"><a 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