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<div class="pre-content"><div><div class="bk_prnt"><p class="small">NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.</p><p>Probe Reports from the NIH Molecular Libraries Program [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2010-. </p></div><div class="iconblock clearfix whole_rhythm no_top_margin bk_noprnt"><a class="img_link icnblk_img" title="Table of Contents Page" href="/books/n/mlprobe/"><img class="source-thumb" src="/corehtml/pmc/pmcgifs/bookshelf/thumbs/th-mlprobe-lrg.png" alt="Cover of Probe Reports from the NIH Molecular Libraries Program" height="100px" width="80px" /></a><div class="icnblk_cntnt eight_col"><h2>Probe Reports from the NIH Molecular Libraries Program [Internet].</h2><a data-jig="ncbitoggler" href="#__NBK280040_dtls__">Show details</a><div style="display:none" class="ui-widget" id="__NBK280040_dtls__"><div>Bethesda (MD): National Center for Biotechnology Information (US); 2010-.</div></div><div class="half_rhythm"><ul class="inline_list"><li style="margin-right:1em"><a class="bk_cntns" href="/books/n/mlprobe/">Contents</a></li></ul></div><div class="bk_noprnt"><form method="get" action="/books/n/mlprobe/" id="bk_srch"><div class="bk_search"><label for="bk_term" class="offscreen_noflow">Search term</label><input type="text" title="Search this book" id="bk_term" name="term" value="" data-jig="ncbiclearbutton" /> <input type="submit" class="jig-ncbibutton" value="Search this book" submit="false" style="padding: 0.1em 0.4em;" /></div></form></div></div><div class="icnblk_cntnt two_col"><div class="pagination bk_noprnt"><a class="active page_link prev" href="/books/n/mlprobe/ml381/" title="Previous page in this title">< Prev</a><a class="active page_link next" href="/books/n/mlprobe/ml388/" title="Next page in this title">Next ></a></div></div></div></div></div>
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<div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><h1 id="_NBK280040_"><span class="title" itemprop="name">Discovery and characterization of a small molecule allosteric agonist of MrgX1</span></h1><p class="contrib-group"><span itemprop="author">Wandong Wen</span>, <span itemprop="author">Yan Wang</span>, <span itemprop="author">Owen McManus</span>, <span itemprop="author">Meng Wu</span>, <span itemprop="author">Min Li</span>, <span itemprop="author">Craig W. Lindsley</span>, <span itemprop="author">Xinzhong Dong</span>, and <span itemprop="author">Corey R. Hopkins</span>.</p><a data-jig="ncbitoggler" href="#__NBK280040_ai__" style="border:0;text-decoration:none">Author Information and Affiliations</a><div style="display:none" class="ui-widget" id="__NBK280040_ai__"><p class="contrib-group"><h4>Authors</h4><span itemprop="author">Wandong Wen</span>, <span itemprop="author">Yan Wang</span>, <span itemprop="author">Owen McManus</span>, <span itemprop="author">Meng Wu</span>, <span itemprop="author">Min Li</span>, <span itemprop="author">Craig W. Lindsley</span>, <span itemprop="author">Xinzhong Dong</span>, and <span itemprop="author">Corey R. Hopkins</span>.</p><h4>Affiliations</h4><div class="affiliation"><sup>1</sup> Vanderbilt Specialized Chemistry Center for Accelerated Probe Development and Johns Hopkins Ion Chanel Center</div></div><p class="small">Received: <span itemprop="datePublished">December 15, 2013</span>; Last Update: <span itemprop="dateModified">February 11, 2015</span>.</p></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="_abs_rndgid_" itemprop="description"><p>Previous studies have shown that activation of mouse MrgprC11, a G-protein coupled receptor, by its peptide ligand BAM8-22 can inhibit chronic pain. A large scale screen has been carried out to isolate small molecule allosteric agonists of MrgprX1, the human homologue of MrgprC11. The goal of this study is to improve the efficacy and potency of the allosteric agonists with therapeutic implications of anti-chronic pain. From compounds identified through the high-throughput screening effort, a structure-activity relationship of a series of arylsulfonamides led to the discovery of the first allosteric agonist of MrgprX1, <a href="/pcsubstance/?term=ML382[synonym]" ref="pagearea=abstract&targetsite=entrez&targetcat=term&targettype=pubchem">ML382</a>.</p></div><div class="h2"></div><p><b>Assigned Assay Grant #:</b> R03 DA033176-01</p><p><b>Screening Center Name & PI:</b> Johns Hopkins Ion Channel Center, Min Li</p><p><b>Chemistry Center Name & PI:</b> Vanderbilt Specialized Chemistry Center for Accelerated Probe Development, Craig W. Lindsley</p><p><b>Assay Submitter & Institution:</b> Xinzhong Dong, Johns Hopkins University</p><p><b>PubChem Summary Bioassay Identifier (AID):</b>
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<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588700" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">588700</a></p><div id="ml382.s1"><h2 id="_ml382_s1_">Probe Structure & Characteristics</h2><div id="ml382.f1" class="figure bk_fig"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=ML382.&p=BOOKS&id=280040_ml382f1.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/NBK280040/bin/ml382f1.jpg" alt="ML382." class="tileshop" title="Click on image to zoom" /></a></div><h3><span class="title">ML382</span></h3></div><div id="ml382.t1" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK280040/table/ml382.t1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml382.t1_lrgtbl__"><table><thead><tr><th id="hd_h_ml382.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CID/ML#</th><th id="hd_h_ml382.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Target Name</th><th id="hd_h_ml382.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">EC<sub>50</sub>/(nM)<br />[SID, AID]</th><th id="hd_h_ml382.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Anti-target Name(s)</th><th id="hd_h_ml382.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">IC<sub>50</sub> (μM) [SID, AID]</th><th id="hd_h_ml382.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Fold Selective</th><th id="hd_h_ml382.t1_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Secondary Assay(s) Name:<br />IC<sub>50</sub>/EC<sub>50</sub> (nM)<br />[SID, AID]</th></tr></thead><tbody><tr><td headers="hd_h_ml382.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">CID 71598556/<a href="/pcsubstance/?term=ML382[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML382</a></td><td headers="hd_h_ml382.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MrgX1</td><td headers="hd_h_ml382.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">190 nM<br />[<a href="https://pubchem.ncbi.nlm.nih.gov/substance/163679225" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 163679225</a>; <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/743016" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 743016</a>]</td><td headers="hd_h_ml382.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MrgX2 [<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/414291" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 414291</a>]</td><td headers="hd_h_ml382.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">>30 μM</td><td headers="hd_h_ml382.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">>100-fold</td><td headers="hd_h_ml382.t1_1_1_1_7" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">MrgX2 (>30 μM);<br />[<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/414291" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 414291</a>]</td></tr></tbody></table></div></div></div><div id="ml382.s2"><h2 id="_ml382_s2_">Recommendations for scientific use of the probe</h2><p><a href="/pcsubstance/?term=ML382[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML382</a> (CID 71598556) is a potent allosteric agonist of MrgprX1 when tested in cell based Ca2+ imaging assay (EC<sub>50</sub> = 190 nM; using 10 nM BAM8-22 as an agonist of MrgprX1). The action of <a href="/pcsubstance/?term=ML382[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML382</a> on enhancing MrgprX1 activation by BAM8-22 is highly selective since it did not have any effect on MrgprX2, a closely related gene to MrgprX1. Since this is the first allosteric agonist of MrgprX1, <a href="/pcsubstance/?term=ML382[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML382</a> is an invaluable research tool to study the role of MrgprX1 in chronic pain. The expected effect of this compound is to inhibit chronic pain.</p></div><div id="ml382.s3"><h2 id="_ml382_s3_">2. Materials and Methods</h2><p><b>Cell based Ca2+ imaging assay to detect MrgX1 activation.</b> The purpose of this assay is to identify test compounds that act as an allosteric agonist for MrgX1. This assay employs a HEK293 cell line that stably expresses MrgX1 protein. The cells, which loaded with fluorescent dye-Flou4, are treated with test compounds, followed by measurement of calcium flux. Those HEK293 cells stably expressing MrgX1 were plated into 96-well plates. On the following day, cells were incubated with Fluo4 solution at 37 °C for 30min and at RT for 30 min after removing media. 10 μM compounds were added to the assay buffer with dye for 80 sec followed by adding 10 nM BAM8-22 for 75 sec and recorded the change of fluorescence by Flexstation3 imaging plate reader. Compound effect was evaluated by the calculated fluorescence ratio. If the compound causes more than 3 times the standard deviation of the B-scores of the library compounds, the compound is then considered to be active as an agonist of the MrgX1 protein.</p><p><b>DMPK Methods.</b>
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<u>In vitro:</u> The metabolism of <a href="/pcsubstance/?term=ML382[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML382</a> was investigated in human, rat and mouse hepatic microsomes (BD Biosciences, Billerica, MA) using substrate depletion methodology (% test article remaining). A potassium phosphate-buffered reaction mixture (0.1 M, pH 7.4) of test article (1 μM) and microsomes (0.5 mg/mL) was pre-incubated (5 min) at 37°C prior to the addition of NADPH (1 mM). The incubations, performed in 96-well plates, were continued at 37 °C under ambient oxygenation and aliquots (80 μL) were removed at selected time intervals (0, 3, 7, 15, 25 and 45 min). Protein was precipitated by the addition of chilled acetonitrile (160 μL), containing glyburide as an internal standard (50 ng/mL), and centrifuged at 3000 rpm (4°C) for 10 min. Resulting supernatants were transferred to new 96-well plates in preparation for LC/MS/MS analysis. The in vitro half-life (<i>t</i><sub>1/2</sub>, min, <a href="#ml382.eq1">Eq. 1</a>), intrinsic clearance (CL<sub>int</sub>, mL/min/kg, <a href="#ml382.eq2">Eq. 2</a>) and subsequent predicted hepatic clearance (CL<sub>hep</sub>, mL/min/kg, <a href="#ml382.eq3">Eq. 3</a>) were determined employing the following equations:</p><div class="pmc_disp_formula whole_rhythm clearfix" id="ml382.eq1"><div class="inline_block pmc_inline_block pmc_va_middle pmc_hide_overflow eleven_col">
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<i>t</i><sub>1/2</sub> = Ln(2) / <i>k</i> ; where <i>k</i> represents the slope from linear regression analysis (% test article remaining)</div><div class="inline_block pmc_inline_block pmc_va_middle pmc_hide_overflow last bk_equ_label "><div><span class="nowrap">1</span></div></div></div><div class="pmc_disp_formula whole_rhythm clearfix" id="ml382.eq2"><div class="inline_block pmc_inline_block pmc_va_middle pmc_hide_overflow eleven_col">
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CL<sub>int</sub> = (0.693 / <i>t</i><sub>1/2</sub>) (rxn volume / mg of microsomes) (45 mg microsomes / gram of liver) (20<i><sup>a</sup></i> gm of liver / kg body weight); <i><sup>a</sup></i>scale-up factors of 20 (human) and 45 (rat)</div><div class="inline_block pmc_inline_block pmc_va_middle pmc_hide_overflow last bk_equ_label "><div><span class="nowrap">2</span></div></div></div><div class="pmc_disp_formula whole_rhythm clearfix" id="ml382.eq3"><div class="inline_block pmc_inline_block pmc_va_middle pmc_hide_overflow eleven_col">
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<math id="ml382.m1" display="block"><mrow><mtext mathvariant="italic">CLhep</mtext><mo>=</mo><mfrac><mrow><mi>Q</mi><mo>·</mo><mtext mathvariant="italic">CL</mtext><mtext>int</mtext></mrow><mrow><mi>Q</mi><mo>+</mo><mtext mathvariant="italic">CL</mtext><mtext>int</mtext></mrow></mfrac></mrow></math></div><div class="inline_block pmc_inline_block pmc_va_middle pmc_hide_overflow last bk_equ_label "><div><span class="nowrap">3</span></div></div></div><p><b>Plasma Protein Binding.</b> Protein binding of <a href="/pcsubstance/?term=ML382[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML382</a> was determined in human, rat and mouse plasma via equilibrium dialysis employing Single-Use RED Plates with inserts (ThermoFisher Scientific, Rochester, NY). Briefly plasma (220 μL) was added to the 96 well plate containing test article (5 μL) and mixed thoroughly. Subsequently, 200 μL of the plasma-test article mixture was transferred to the <i>cis</i> chamber (red) of the RED plate, with an accompanying 350 μL of phosphate buffer (25 mM, pH 7.4) in the <i>trans</i> chamber. The RED plate was sealed and incubated 4 h at 37 °C with shaking. At completion, 50 μL aliquots from each chamber were diluted 1:1 (50 μL) with either plasma (<i>cis</i>) or buffer (<i>trans</i>) and transferred to a new 96 well plate, at which time ice-cold acetonitrile (2 volumes) was added to extract the matrices. The plate was centrifuged (3000 rpm, 10 min) and supernatants transferred to a new 96 well plate. The sealed plate was stored at -20 °C until LC/MS/MS analysis.</p><p><b>Liquid Chromatography/Mass Spectrometry Analysis</b>. <i>In vitro experiments.</i>
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<a href="/pcsubstance/?term=ML382[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML382</a> was analyzed via electrospray ionization (ESI) on an AB Sciex API-4000 (Foster City, CA) triple-quadrupole instrument that was coupled with Shimadzu LC-10AD pumps (Columbia, MD) and a Leap Technologies CTC PAL auto-sampler (Carrboro, NC). Analytes were separated by gradient elution using a Fortis C18 2.1 × 50 mm, 3.5 μm column (Fortis Technologies Ltd, Cheshire, UK) thermostated at 40 °C. HPLC mobile phase A was 0.1% NH<sub>4</sub>OH (pH unadjusted), mobile phase B was acetonitrile. The gradient started at 30% B after a 0.2 min hold and was linearly increased to 90% B over 0.8 min; held at 90% B for 0.5 min and returned to 30% B in 0.1 min followed by a re-equilibration (0.9 min). The total run time was 2.5 min and the HPLC flow rate was 0.5 mL/min. The source temperature was set at 500°C and mass spectral analyses were performed using multiple reaction monitoring (MRM) utilizing a Turbo-Ionspray® source in positive ionization mode (5.0 kV spray voltage). LC/MS/MS analysis was performed employing a TSQ Quantum<sup>ULTRA</sup> that was coupled to a ThermoSurveyor LC system (Thermoelectron Corp., San Jose, CA) and a Leap Technologies CTC PAL auto-sampler (Carrboro, NC). Chromatographic separation of analytes was achieved with an Acquity BEH C18 2.1 × 50 mm, 1.7 μm column (Waters, Taunton, MA).</p><div id="ml382.s4"><h3>2.1. Assays</h3><dl class="temp-labeled-list"><dt>2.1.1.</dt><dd><p class="no_top_margin"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588700" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 588700</a> – Summary</p></dd><dt>2.1.2.</dt><dd><p class="no_top_margin"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/588675" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 588675</a> – Primary cell-based high-throughput screening for identification of compounds that allosterically activate MrgX1 receptor signaling</p></dd><dt>2.1.3.</dt><dd><p class="no_top_margin"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/624114" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 624114</a> – Counterscreen for MrgX1 small molecule allosteric agonist false positives in parental HEK293 cell line</p></dd><dt>2.1.4.</dt><dd><p class="no_top_margin"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/743016" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 743016</a> – Dose responses of compounds that allosterically activate MrgX1 receptor signaling</p></dd><dt>2.1.5.</dt><dd><p class="no_top_margin"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/74250" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID 74250</a> – Activity against human MrgX2 counterscreen</p></dd></dl></div><div id="ml382.s5"><h3>2.2. Probe Chemical Characterization</h3><p>Probe compound <a href="/pcsubstance/?term=ML382[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML382</a> (CID: 71598556, SID: <a href="https://pubchem.ncbi.nlm.nih.gov/substance/164175119" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">164175119</a>) was prepared according to <a class="figpopup" href="/books/NBK280040/figure/ml382.f2/?report=objectonly" target="object" rid-figpopup="figml382f2" rid-ob="figobml382f2">scheme 1</a> and had the following characterization. <b>2-(cyclopropanesulfonamido)-N-(2-ethoxyphenyl)benzamide,</b>
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<a href="/pcsubstance/?term=ML382[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML382</a><b>.</b> LCMS: R<sub>T</sub> = 1.13 min, >98% @ 215 and 254 nm, m/z = 360.9 [M]<sup>+</sup>. <sup>1</sup>H NMR (400.1 MHz, CDCl<sub>3</sub>): δ 10.45 (s, 1H), 8.67 (s, 1H), 8.45-8.43 (m, 1H), 7.85 (d, <i>J</i> = 8.38 Hz, 1H), 7.64 (d, <i>J</i> = 8.02 Hz, 1H), 7.56-7.52 (m, 1H), 7.28-7.22 (m, 1H), 7.15-7.11 (m, 1H), 7.06-7.02 (m, 1H), 6.96-6.94 (m, 1H), 4.22-4.16 (m, 2H), 2.56-2.50 (m, 1H), 1.51 (t, <i>J</i> = 6.97 Hz, 3H), 1.27-1.25 (m, 2H), 0.95-0.92 (m, 2H).</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml382f2" co-legend-rid="figlgndml382f2"><a href="/books/NBK280040/figure/ml382.f2/?report=objectonly" target="object" title="Scheme 1" class="img_link icnblk_img figpopup" rid-figpopup="figml382f2" rid-ob="figobml382f2"><img class="small-thumb" src="/books/NBK280040/bin/ml382f2.gif" src-large="/books/NBK280040/bin/ml382f2.jpg" alt="Scheme 1. Chemical characterization of Probe ML382." /></a><div class="icnblk_cntnt" id="figlgndml382f2"><h4 id="ml382.f2"><a href="/books/NBK280040/figure/ml382.f2/?report=objectonly" target="object" rid-ob="figobml382f2">Scheme 1</a></h4><p class="float-caption no_bottom_margin">Chemical characterization of Probe ML382. </p></div></div><p><b>Solubility.</b> Solubility for <a href="/pcsubstance/?term=ML382[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML382</a> in PBS was determined to be 73.0 ± 3.5 μM, which is ∼380-fold higher than the cellular EC<sub>50</sub> for MrgX1 activation.</p><p><b>Stability.</b> Stability was determined for <a href="/pcsubstance/?term=ML382[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML382</a> at 23 °C in PBS (no antioxidants or other protectorants and DMSO concentration below 0.1%). After 48 hours, ∼91% of the initial concentration of <a href="/pcsubstance/?term=ML382[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML382</a> remained in solution, signifying that <a href="/pcsubstance/?term=ML382[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML382</a> is a stable compound under these conditions.</p><div id="ml382.t2" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK280040/table/ml382.t2/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml382.t2_lrgtbl__"><table><thead><tr><th id="hd_h_ml382.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"></th><th id="hd_h_ml382.t2_1_1_1_2" colspan="6" rowspan="1" style="text-align:center;vertical-align:middle;">Percent Remaining (%)</th></tr><tr><th headers="hd_h_ml382.t2_1_1_1_1" id="hd_h_ml382.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Compound</th><th headers="hd_h_ml382.t2_1_1_1_2" id="hd_h_ml382.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1 min</th><th headers="hd_h_ml382.t2_1_1_1_2" id="hd_h_ml382.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">18 min</th><th headers="hd_h_ml382.t2_1_1_1_2" id="hd_h_ml382.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">34 min</th><th headers="hd_h_ml382.t2_1_1_1_2" id="hd_h_ml382.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">90 min</th><th headers="hd_h_ml382.t2_1_1_1_2" id="hd_h_ml382.t2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">24 Hour</th><th headers="hd_h_ml382.t2_1_1_1_2" id="hd_h_ml382.t2_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">48 Hour</th></tr></thead><tbody><tr><td headers="hd_h_ml382.t2_1_1_1_1 hd_h_ml382.t2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="/pcsubstance/?term=ML347[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML347</a>, CID 44577753</td><td headers="hd_h_ml382.t2_1_1_1_2 hd_h_ml382.t2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">100 ± 0.0</td><td headers="hd_h_ml382.t2_1_1_1_2 hd_h_ml382.t2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">98.2 ± 0.2</td><td headers="hd_h_ml382.t2_1_1_1_2 hd_h_ml382.t2_1_1_2_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">97.8 ± 0.3</td><td headers="hd_h_ml382.t2_1_1_1_2 hd_h_ml382.t2_1_1_2_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">97.1 ± 1.0</td><td headers="hd_h_ml382.t2_1_1_1_2 hd_h_ml382.t2_1_1_2_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">93.9 ± 3.9</td><td headers="hd_h_ml382.t2_1_1_1_2 hd_h_ml382.t2_1_1_2_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">91.2 ± 4.6</td></tr></tbody></table></div></div><div id="ml382.f3" class="figure"><div class="graphic"><a href="/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Image%20ml382f3&p=BOOKS&id=280040_ml382f3.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/NBK280040/bin/ml382f3.jpg" alt="Image ml382f3" class="tileshop" title="Click on image to zoom" /></a></div></div><p><b>Compounds added to the SMR collection (MLS#s):</b> MLS005527261 (<a href="/pcsubstance/?term=ML382[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML382</a>, CID 71598556, 23.5 mg); MLS005527262 (CID 2712184, 7.5 mg); MLS005527263 (CID 951628, 7.7 mg); MLS005527264 (CID 71598554, 7.6 mg); MLS005527265 (CID 838665, 7.0 mg); MLS005527266 (CID 1260775, 6.1 mg).</p></div><div id="ml382.s6"><h3>2.3. Probe Preparation</h3><p>Probe compound <a href="/pcsubstance/?term=ML382[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML382</a> (CID 71598556, <a href="https://pubchem.ncbi.nlm.nih.gov/substance/164175119" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID 164175119</a>) was prepared according to <a class="figpopup" href="/books/NBK280040/figure/ml382.f4/?report=objectonly" target="object" rid-figpopup="figml382f4" rid-ob="figobml382f4">scheme 2</a> and had the following characterization. <b>2-(cyclopropanesulfonamido)-N-(2-ethoxyphenyl)benzamide,</b>
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<a href="/pcsubstance/?term=ML382[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML382</a><b>.</b></p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figml382f4" co-legend-rid="figlgndml382f4"><a href="/books/NBK280040/figure/ml382.f4/?report=objectonly" target="object" title="Scheme 2" class="img_link icnblk_img figpopup" rid-figpopup="figml382f4" rid-ob="figobml382f4"><img class="small-thumb" src="/books/NBK280040/bin/ml382f4.gif" src-large="/books/NBK280040/bin/ml382f4.jpg" alt="Scheme 2. Preparation of Probe ML382." /></a><div class="icnblk_cntnt" id="figlgndml382f4"><h4 id="ml382.f4"><a href="/books/NBK280040/figure/ml382.f4/?report=objectonly" target="object" rid-ob="figobml382f4">Scheme 2</a></h4><p class="float-caption no_bottom_margin">Preparation of Probe ML382. </p></div></div><p><b>2-amino-N-(2-ethoxyphenyl)benzamide (3).</b> To a dry argon-filled flask was added anthrinilic acid, <b>1</b>, (1 eq), and 3 drops of dimethylformamide (DMF) and ether as solvent. To the solution, thionyl chloride (2 eq) was added dropwise at 0 °C. The mixture was refluxed for 2 hours. On completion, ether and remaining thionyl chloride were removed under reduced pressure. The mixture was cooled to 0 °C, followed by addition of 0.5 ml pyridine, 2,4-dimethoxyaniline, <b>2</b>, (1.2 eq) and ether as solvent. The solution was allowed to warm up to room temperature and stir for 2 h. After removing solvents under reduced pressure, the crude product was purified via reverse phase preparative chromatography (Gilson, Acetonitrile-0.5% NH<sub>4</sub>OH in water), which yielded 2-amino-N-(2-ethoxyphenyl)benzamide, <b>3</b>, as yellow solid, 77% yield. 1H NMR (400.1 MHz, CDCl<sub>3</sub>): δ 8.48-8.46 (m, 1H), 7.52-7.50 (m, 1H), 7.30-7.26 (m, 1H), 7.10-7.00 (m, 2H), 6.94-6.92 (m, 1H), 6.75 (t, 2H, <i>J</i> = 6.87 Hz), 5.62 (s, 2H), 4.18-4.13 (m, 2H), 1.50 (t, 3H, <i>J</i> = 6.94 Hz) <sup>13</sup>C NMR (100.6 MHz, CDCl<sub>3</sub>): δ 167.3, 149.3, 147.7, 132.6, 128.0, 127.2, 123.7, 121.0, 119.9, 117.6, 116.9, 116.7, 111.0, 64.3, 15.0. LCMS: R<sub>T</sub> = 1.01 min, >98% @ 215 and 254 nm, <i>m/z</i> = 257.0 [M + H]<sup>+</sup>.</p><p><b>2-(cyclopropanesulfonamido)-N-(2-ethoxyphenyl)benzamide,</b>
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<a href="/pcsubstance/?term=ML382[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML382</a><b>.</b> To dry vial was added 2-amino-N-(2-ethoxyphenyl)benzamide, <b>3</b>, (1 eq), cyclopropanesulfonyl chloride (2 eq), pyridine (4 eq) and DCM as solvent. The mixture was stirred for 16 h at room temperature. On completion, the crude product was purified by reverse phase preparative chromatography (Gilson, Acetonitrile-0.5% NH<sub>4</sub>OH in water). LCMS: R<sub>T</sub> = 1.13 min, >95% @ 215 and 254 nm, m/z = 360.9 [M]<sup>+</sup>. <sup>1</sup>H NMR (400.1 MHz, CDCl<sub>3</sub>): δ 10.45 (s, 1H), 8.67 (s, 1H), 8.45-8.43 (m, 1H), 7.85 (d, <i>J</i> = 8.38 Hz, 1H), 7.64 (d, <i>J</i> = 8.02 Hz, 1H), 7.56-7.52 (m, 1H), 7.28-7.22 (m, 1H), 7.15-7.11 (m, 1H), 7.06-7.02 (m, 1H), 6.96-6.94 (m, 1H), 4.22-4.16 (m, 2H), 2.56-2.50 (m, 1H), 1.51 (t, <i>J</i> = 6.97 Hz, 3H), 1.27-1.25 (m, 2H), 0.95-0.92 (m, 2H).</p></div></div><div id="ml382.s7"><h2 id="_ml382_s7_">3. Results</h2><div id="ml382.s8"><h3>3.1. Dose Response Curves for Probe</h3><div id="ml382.f5" class="figure bk_fig"><div class="graphic"><img src="/books/NBK280040/bin/ml382f5.jpg" alt="Figure 1. In vitro molecular pharmacology characterization of ML382." /></div><h3><span class="label">Figure 1</span><span class="title">In vitro molecular pharmacology characterization of ML382</span></h3><div class="caption"><p>Concentration-response curves of <a href="/pcsubstance/?term=ML382[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML382</a> in Ca2+ imaging assay in HEK293 cells expressing either MrgX1 (black squares) or MrgX2 (open cicle). EC50 of <a href="/pcsubstance/?term=ML382[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML382</a> enhancing MrgX1 activation by BAM8-22 is 190 nM. 5μM <a href="/pcsubstance/?term=ML382[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML382</a> did not produce a significant increase in activation of MrgX2 by its specific agonist peptide PAMP (5μM).</p></div></div></div><div id="ml382.s9"><h3>3.2. Cellular Activity</h3><p>The primary screening assay for MrgX1 is a cell-based assay, indicating that <a href="/pcsubstance/?term=ML382[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML382</a> can gain access to its molecular target when applied to cells. The compound did not exhibit acute toxicity in cell based assays at concentrations up to 10 μM.</p></div><div id="ml382.s10"><h3>3.3. Profiling Assays</h3><p>To more fully characterize this potent, selective MrgX1 allosteric agonist, <a href="/pcsubstance/?term=ML382[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML382</a> was tested using EuroFin's (formerly MDS Pharma's) Lead Profiling Screen (binding assay panel of 68 GPCRs, ion channels and transporters screened at 10 μM). Included in the EuroFin screening panel are a number of ion channels (Calcium Channel, L-Type and N-Type; Potassium channel [K<sub>ATP</sub>]; Potassium channel [hERG]) and class A GPCRs (D<sub>1-5</sub>, H<sub>1-3</sub>, etc…). <a href="/pcsubstance/?term=ML382[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML382</a> did not inhibit 67 of the 68 targets conducted (inhibition of radio ligand binding > 50% at 10 μM), highlighting a clean ancillary pharmacology profile. The only target that showed any inhibition was the serotonin (5-hydroxytryptamine), 5-HT2B which showed 63% at 10 μM. Table 5 highlights calculated properties for <a href="/pcsubstance/?term=ML382[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML382</a>, which compares favorably with the MDDR.</p></div></div><div id="ml382.s11"><h2 id="_ml382_s11_">4. Discussion</h2><div id="ml382.s12"><h3>4.1. Comparison to existing art and how the new probe is an improvement</h3><p><a href="/pcsubstance/?term=ML382[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML382</a> (CID 71598556) is a potent allosteric agonist of MrgprX1 (EC<sub>50</sub> = 190 nM; using 10 nM BAM8-22 as an agonist of MrgprX1). There are no known allosteric agonists of MrgprX1. It is highly selective for MrgprX1 over other MrgprX receptors such as MrgprX2.</p></div><div id="ml382.s13"><h3>4.2. Mechanism of Action Studies</h3><p><a href="/pcsubstance/?term=ML382[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML382</a> acts as an allosteric agonist of MrgprX1 since it only elicits the enhancing effect on MrgprX1 in the presence of the true agonist BAM8-22. This suggests that <a href="/pcsubstance/?term=ML382[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML382</a> and BAM8-22 have two different binding sites on MrgprX1. In addition, <a href="/pcsubstance/?term=ML382[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML382</a> has no effect on MrgprC11, the mouse homologue of MrgprX1 which indicates the compound is also species selective.</p></div><div id="ml382.s14"><h3>4.3. Efficacy in Cell-Based Assays</h3><p>The primary MrgprX1 assay is a cell based functional assay. <a href="/pcsubstance/?term=ML382[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML382</a> displays no cytotoxicity in any assays.</p></div></div><div id="ml382.s15"><h2 id="_ml382_s15_">5. References</h2><dl class="temp-labeled-list"><dt>1.</dt><dd><div class="bk_ref" id="ml382.r1">Dong X, Han S-k, Zylka MJ, Simon MI, Anderson DJ. A diverse family of GPCRs expressed in specific subsets of nociceptive sensory neurons. <span><span class="ref-journal">Cell. </span>2001;<span class="ref-vol">106</span>:619–632.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/11551509" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11551509</span></a>]</div></dd><dt>2.</dt><dd><div class="bk_ref" id="ml382.r2">Han S-k, Dong X, Hwang J-I, Zylka MJ, Anderson DJ, Simon MI. Orphan G protein-coupled receptors MrgA1 and MrgC11 are distinctively activated by RF-amide-related peptides through Gα<sub>q/11</sub> pathway. <span><span class="ref-journal">Proc. Nat. Acad. Sci. </span>2002;<span class="ref-vol">99</span>:14740–14745.</span> [<a href="/pmc/articles/PMC137489/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC137489</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/12397184" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12397184</span></a>]</div></dd><dt>3.</dt><dd><div class="bk_ref" id="ml382.r3">Lembo PMC, Grazzini E, Groblewski T, O'Donnell D, Roy M-O, Zhang J, Hoffert C, Cao J, Schmidt R, Pelletier M, Labarre M, Gosselin M, Fortin Y, Banville D, Shen SH, Ström P, Payza K, Dray A, Walker P, Ahmad S. Proenkephalin A gene products activate a new family of sensory neuron-specific GPCRs. <span><span class="ref-journal">Nature Neuroscience. </span>2002;<span class="ref-vol">5</span>:201–209.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/11850634" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11850634</span></a>]</div></dd><dt>4.</dt><dd><div class="bk_ref" id="ml382.r4">Guan Y, Liu Q, Tang Z, Raja SN, Anderson DJ, Dong X. Mas-related G-protein-coupled receptors inhibit pathological pain in mice. <span><span class="ref-journal">Proc. Nat. Acad. Sci. </span>2010;<span class="ref-vol">107</span>:15933–15938.</span> [<a href="/pmc/articles/PMC2936626/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2936626</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/20724664" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 20724664</span></a>]</div></dd><dt>5.</dt><dd><div class="bk_ref" id="ml382.r5">Malik L, Kelly NM, Ma J-N, Currier EA, Burstein ES, Olsson R. Discovery of non-peptidergic MrgX1 and MrgX2 receptor agonists and exploration of an initial SAR using solid-phase synthesis. <span><span class="ref-journal">Bioorg. Med. Chem. Lett. </span>2009;<span class="ref-vol">19</span>:1729–1732.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/19230660" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19230660</span></a>]</div></dd><dt>6.</dt><dd><div class="bk_ref" id="ml382.r6">Wroblowski B, Wigglesworth MJ, Szekeres PG, Smith GD, Rahman SS, Nicholson NH, Muir AI, Hall A, Heer JP, Garland SL, Coates WJ. The discovery of a selective, small molecule agonist for the Mas-related gene X1 receptor. <span><span class="ref-journal">J. Med. Chem. </span>2009;<span class="ref-vol">52</span>:818–825.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/19146417" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19146417</span></a>]</div></dd></dl></div><div id="bk_toc_contnr"></div></div></div>
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<div class="post-content"><div><div class="half_rhythm"><a href="/books/about/copyright/">Copyright Notice</a></div><div class="small"><span class="label">Bookshelf ID: NBK280040</span><span class="label">PMID: <a href="https://pubmed.ncbi.nlm.nih.gov/25834894" title="PubMed record of this page" ref="pagearea=meta&targetsite=entrez&targetcat=link&targettype=pubmed">25834894</a></span></div><div style="margin-top:2em" class="bk_noprnt"><a class="bk_cntns" href="/books/n/mlprobe/">Contents</a><div class="pagination bk_noprnt"><a class="active page_link prev" href="/books/n/mlprobe/ml381/" title="Previous page in this title">< Prev</a><a class="active page_link next" href="/books/n/mlprobe/ml388/" title="Next page in this title">Next ></a></div></div></div></div>
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<div xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Views</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="PDF_download" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="/books/NBK280040/?report=reader">PubReader</a></li><li><a href="/books/NBK280040/?report=printable">Print View</a></li><li><a data-jig="ncbidialog" href="#_ncbi_dlg_citbx_NBK280040" data-jigconfig="width:400,modal:true">Cite this Page</a><div id="_ncbi_dlg_citbx_NBK280040" style="display:none" title="Cite this Page"><div class="bk_tt">Wen W, Wang Y, McManus O, et al. Discovery and characterization of a small molecule allosteric agonist of MrgX1. 2013 Dec 15 [Updated 2015 Feb 11]. In: Probe Reports from the NIH Molecular Libraries Program [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 2010-. <span class="bk_cite_avail"></span></div></div></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>In this Page</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="page-toc" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="#ml382.s1" ref="log$=inpage&link_id=inpage">Probe Structure & Characteristics</a></li><li><a href="#ml382.s2" ref="log$=inpage&link_id=inpage">Recommendations for scientific use of the probe</a></li><li><a href="#ml382.s3" ref="log$=inpage&link_id=inpage">Materials and Methods</a></li><li><a href="#ml382.s7" ref="log$=inpage&link_id=inpage">Results</a></li><li><a href="#ml382.s11" ref="log$=inpage&link_id=inpage">Discussion</a></li><li><a href="#ml382.s15" ref="log$=inpage&link_id=inpage">References</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Related information</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="discovery_db_links" id="Shutter"></a></div><div class="portlet_content"><ul><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=pmc&DbFrom=books&Cmd=Link&LinkName=books_pmc_refs&IdsFromResult=3413776" ref="log$=recordlinks">PMC</a><div class="brieflinkpop offscreen_noflow">PubMed Central citations</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=pcsubstance&DbFrom=books&Cmd=Link&LinkName=books_pcsubstance&IdsFromResult=3413776" ref="log$=recordlinks">PubChem Substance</a><div class="brieflinkpop offscreen_noflow">Related PubChem Substances</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=pubmed&DbFrom=books&Cmd=Link&LinkName=books_pubmed_refs&IdsFromResult=3413776" ref="log$=recordlinks">PubMed</a><div class="brieflinkpop offscreen_noflow">Links to PubMed</div></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Similar articles in PubMed</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="PBooksDiscovery_RA" id="Shutter"></a></div><div class="portlet_content"><ul><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/25209672" ref="ordinalpos=1&linkpos=1&log$=relatedarticles&logdbfrom=pubmed">Discovery and characterization of 2-(cyclopropanesulfonamido)-N-(2-ethoxyphenyl)benzamide, ML382: a potent and selective positive allosteric modulator of MrgX1.</a><span class="source">[ChemMedChem. 2015]</span><div class="brieflinkpop offscreen_noflow">Discovery and characterization of 2-(cyclopropanesulfonamido)-N-(2-ethoxyphenyl)benzamide, ML382: a potent and selective positive allosteric modulator of MrgX1.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Wen W, Wang Y, Li Z, Tseng PY, McManus OB, Wu M, Li M, Lindsley CW, Dong X, Hopkins CR. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">ChemMedChem. 2015 Jan; 10(1):57-61. 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