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<meta name="robots" content="INDEX,FOLLOW,NOARCHIVE" /><meta name="citation_inbook_title" content="Probe Reports from the NIH Molecular Libraries Program [Internet]" /><meta name="citation_title" content="Probe Report for NPY-Y2 Receptor Antagonists" /><meta name="citation_publisher" content="National Center for Biotechnology Information (US)" /><meta name="citation_date" content="2010/08/06" /><meta name="citation_author" content="SA Saldanha" /><meta name="citation_author" content="SP Brothers" /><meta name="citation_author" content="T Spicer" /><meta name="citation_author" content="M Cameron" /><meta name="citation_author" content="BA Mercer" /><meta name="citation_author" content="P Chase" /><meta name="citation_author" content="P McDonald" /><meta name="citation_author" content="C Wahlestedt" /><meta name="citation_author" content="PS Hodder" /><meta name="citation_pmid" content="21433370" /><meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK47354/" /><link rel="schema.DC" href="http://purl.org/DC/elements/1.0/" /><meta name="DC.Title" content="Probe Report for NPY-Y2 Receptor Antagonists" /><meta name="DC.Type" content="Text" /><meta name="DC.Publisher" content="National Center for Biotechnology Information (US)" /><meta name="DC.Contributor" content="SA Saldanha" /><meta name="DC.Contributor" content="SP Brothers" /><meta name="DC.Contributor" content="T Spicer" /><meta name="DC.Contributor" content="M Cameron" /><meta name="DC.Contributor" content="BA Mercer" /><meta name="DC.Contributor" content="P Chase" /><meta name="DC.Contributor" content="P McDonald" /><meta name="DC.Contributor" content="C Wahlestedt" /><meta name="DC.Contributor" content="PS Hodder" /><meta name="DC.Date" content="2010/08/06" /><meta name="DC.Identifier" content="https://www.ncbi.nlm.nih.gov/books/NBK47354/" /><meta name="description" content="Due to its expression profile and biological action, neuropeptide Y (NPY)-Y2 receptor (Y2R) is an attractive G protein-coupled receptor (GPCR) target for anxiolytic research. Additionally, NPY-Y2R is predicted to be a therapeutic target in alcoholism. Four different compounds, ML075 (CID-2936384), ML074 (CID-2228302), ML073 (CID-3236979) and ML072 (CID-4460128) are claimed as novel antagonist probes to the NPY-Y2R, producing increased cAMP (3',5'-cyclic-AMP phosphodiesterase) levels. These probes demonstrate submicromolar affinity to the Y2 receptor, do not antagonize NPY-Y1R, do not present significant cytotoxicity, and are blood-brain barrier penetrant. 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These probes demonstrate submicromolar affinity to the Y2 receptor, do not antagonize NPY-Y1R, do not present significant cytotoxicity, and are blood-brain barrier penetrant. 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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="#__NBK47354_dtls__">Show details</a><div style="display:none" class="ui-widget" id="__NBK47354_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/ml076/" title="Previous page in this title">< Prev</a><a class="active page_link next" href="/books/n/mlprobe/ml071/" 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="_NBK47354_"><span class="title" itemprop="name">Probe Report for NPY-Y2 Receptor Antagonists</span></h1><p class="contrib-group"><span itemprop="author">SA Saldanha</span>, <span itemprop="author">SP Brothers</span>, <span itemprop="author">T Spicer</span>, <span itemprop="author">M Cameron</span>, <span itemprop="author">BA Mercer</span>, <span itemprop="author">P Chase</span>, <span itemprop="author">P McDonald</span>, <span itemprop="author">C Wahlestedt</span>, and <span itemprop="author">PS Hodder</span>.</p><p class="small">Received: <span itemprop="datePublished">January 13, 2009</span>; Last Update: <span itemprop="dateModified">August 6, 2010</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>Due to its expression profile and biological action, neuropeptide Y (NPY)-Y2 receptor (Y2R) is an attractive G protein-coupled receptor (GPCR) target for anxiolytic research. Additionally, NPY-Y2R is predicted to be a therapeutic target in alcoholism. Four different compounds, ML075 (CID-2936384), ML074 (CID-2228302), ML073 (CID-3236979) and ML072 (CID-4460128) are claimed as novel antagonist probes to the NPY-Y2R, producing increased cAMP (3',5'-cyclic-AMP phosphodiesterase) levels. These probes demonstrate submicromolar affinity to the Y2 receptor, do not antagonize NPY-Y1R, do not present significant cytotoxicity, and are blood-brain barrier penetrant. Hence, these probes represent an improvement over previously described NPY-Y2R antagonists and offer greater promise to serve as valuable in vivo pharmacological probes for elucidating the Y2R signaling pathway.</p></div><div class="h2"></div><p><b>Assigned Assay Grant #:</b> 1 R21 NS056950-01</p><p><b>Screening Center Name & PI:</b> Scripps Research Institute Molecular
|
||
Screening Center (SRIMSC); Hugh Rosen</p><p><b>Chemistry Center Name & PI:</b> SRIMSC; Hugh Rosen</p><p><b>Assay Submitter & Institution:</b> Claes Wahlestedt, The Scripps
|
||
Research Institute (TSRI)</p><p><b>PubChem Summary Bioassay Identifier (AID):</b>
|
||
<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1791" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1791</a></p><div id="ml075.s1"><h2 id="_ml075_s1_">Probe Structure & Characteristics</h2><p>Four different compounds are claimed as novel antagonist probes to the NPY-Y2
|
||
receptor. These four probes demonstrate sub-micromolar affinity to the Y2 receptor,
|
||
do not antagonize the Y1R receptor, and do not present significant cytotoxicity.
|
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Additionally, they are all blood-brain barrier penetrant. In this regard they all
|
||
represent an improvement over the current NPY Y2 antagonist probe, BIIE 0246. The
|
||
four probes are illustrated below:</p><div id="ml075.fu1" class="figure bk_fig"><div class="graphic"><img src="/books/NBK47354/bin/ml075fu1.jpg" alt="Scaffold 1 (Piperidine carbothioamide) [ML075]." /></div><h3><span class="title">Scaffold 1 (Piperidine carbothioamide) [ML075]</span></h3></div><div id="ml075.fu2" class="figure bk_fig"><div class="graphic"><img src="/books/NBK47354/bin/ml075fu2.jpg" alt="Scaffold 2 (Arysulfamoyl benzamide) [ML074]." /></div><h3><span class="title">Scaffold 2 (Arysulfamoyl benzamide) [ML074]</span></h3></div><div id="ml075.fu3" class="figure bk_fig"><div class="graphic"><img src="/books/NBK47354/bin/ml075fu3.jpg" alt="Scaffold 3 (Aryl-1,2,4-oxadiazole) [ML073]." /></div><h3><span class="title">Scaffold 3 (Aryl-1,2,4-oxadiazole) [ML073]</span></h3></div><div id="ml075.fu4" class="figure bk_fig"><div class="graphic"><img src="/books/NBK47354/bin/ml075fu4.jpg" alt="Scaffold 4 (Dimethylisoxazole) [ML072]." /></div><h3><span class="title">Scaffold 4 (Dimethylisoxazole) [ML072]</span></h3></div><div id="ml075.tu1" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK47354/table/ml075.tu1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml075.tu1_lrgtbl__"><table><thead><tr><th id="hd_h_ml075.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Scaffold ID</th><th id="hd_h_ml075.tu1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Scaffold Name</th><th id="hd_h_ml075.tu1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">CID/ML</th><th id="hd_h_ml075.tu1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">SID</th><th id="hd_h_ml075.tu1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Target (NPY Y2) IC<sub>50</sub>
|
||
(μM)</th><th id="hd_h_ml075.tu1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Anti-Target (NPY Y1) IC<sub>50</sub>
|
||
(μM)</th><th id="hd_h_ml075.tu1_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Secondary Assay CC<sub>50</sub>
|
||
(μM)</th><th id="hd_h_ml075.tu1_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">Brain Penetrance (ng/mL)</th></tr></thead><tbody><tr><td headers="hd_h_ml075.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1</td><td headers="hd_h_ml075.tu1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Piperidine carbothioamide</td><td headers="hd_h_ml075.tu1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2936384/<a href="/pcsubstance/?term=ML075[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML075</a></td><td headers="hd_h_ml075.tu1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/17507305" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">17507305</a></td><td headers="hd_h_ml075.tu1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.220
|
||
[<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1272" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1272</a>]</td><td headers="hd_h_ml075.tu1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>35
|
||
[<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1279" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1279</a>]</td><td headers="hd_h_ml075.tu1_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">74</td><td headers="hd_h_ml075.tu1_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1656 ± 749</td></tr><tr><td headers="hd_h_ml075.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2</td><td headers="hd_h_ml075.tu1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Arysulfamoylbenzamide</td><td headers="hd_h_ml075.tu1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2228302/<a href="/pcsubstance/?term=ML074[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML074</a></td><td headers="hd_h_ml075.tu1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/17413392" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">17413392</a></td><td headers="hd_h_ml075.tu1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.428
|
||
[<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1272" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1272</a>]</td><td headers="hd_h_ml075.tu1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>35.4
|
||
[<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1279" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1279</a>]</td><td headers="hd_h_ml075.tu1_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">20.6</td><td headers="hd_h_ml075.tu1_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">395 ± 16</td></tr><tr><td headers="hd_h_ml075.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3</td><td headers="hd_h_ml075.tu1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Aryl-1,2,4-oxadiazole</td><td headers="hd_h_ml075.tu1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3236979/<a href="/pcsubstance/?term=ML073[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML073</a></td><td headers="hd_h_ml075.tu1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/4242079" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">4242079</a></td><td headers="hd_h_ml075.tu1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.733 [<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1272" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1272</a>]</td><td headers="hd_h_ml075.tu1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>35 [<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1279" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1279</a>]</td><td headers="hd_h_ml075.tu1_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>99</td><td headers="hd_h_ml075.tu1_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">1860 ± 135</td></tr><tr><td headers="hd_h_ml075.tu1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4</td><td headers="hd_h_ml075.tu1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Dimethylisoxazole</td><td headers="hd_h_ml075.tu1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4460128/<a href="/pcsubstance/?term=ML072[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML072</a></td><td headers="hd_h_ml075.tu1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/substance/22413249" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">22413249</a></td><td headers="hd_h_ml075.tu1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3.917 [<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1272" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1272</a>]</td><td headers="hd_h_ml075.tu1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>35.4 [<a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1279" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1279</a>]</td><td headers="hd_h_ml075.tu1_1_1_1_7" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">>99</td><td headers="hd_h_ml075.tu1_1_1_1_8" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">513 ± 57</td></tr></tbody></table></div></div></div><div id="ml075.s2"><h2 id="_ml075_s2_">Recommendations for the scientific use of this probe</h2><p>These probes are useful for assays aiming to block cellular NPY Y2 receptor (Y2R)
|
||
signaling, leading to increased cAMP levels, without inhibiting NPY Y1 receptor
|
||
(Y1R) activity. The representative (“best-in-class”)
|
||
compounds from scaffold 1 (<b><a href="https://pubchem.ncbi.nlm.nih.gov/substance/17507305" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID-17507305</a></b>), scaffold 2
|
||
(<b><a href="https://pubchem.ncbi.nlm.nih.gov/substance/17413392" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID-17413392</a></b>), scaffold 3 (<b><a href="https://pubchem.ncbi.nlm.nih.gov/substance/4242079" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID-4242079</a></b>), and scaffold
|
||
4 (<b><a href="https://pubchem.ncbi.nlm.nih.gov/substance/22413249" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID-22413249</a></b>) displace agonist from the Y2R with high affinity. These
|
||
probes bind to fewer off-target receptors than BIIE 0246, currently the most widely
|
||
used Y2R antagonist. Most importantly, and in contrast to BIIE 0246, these
|
||
best-in-class probes are brain penetrant and thus able to reach Y2R binding sites in
|
||
both the periphery and brain. Additional information regarding the compounds and
|
||
assays employed in this probe development campaign can be found in (<a class="bk_pop" href="#ml075.r1">1</a>).</p></div><div id="ml075.s3"><h2 id="_ml075_s3_">1. Scientific Rationale for Project</h2><p>Due to its expression profile and biological action, NPY Y2 is an attractive GPCR
|
||
target for anxiolytic research. Additionally, Y2 is predicted to be a therapeutic
|
||
target in alcoholism. It has been reported, however, that the complex structure and
|
||
high molecular weight of BIIE 0246 (the current NPY Y2 antagonist) limit its
|
||
usefulness as an <i>in vivo</i> pharmacological tool (<a class="bk_pop" href="#ml075.r2">2</a>). It is therefore necessary to produce brain penetrant,
|
||
high affinity selective ligands for the Y2 receptor.</p></div><div id="ml075.s4"><h2 id="_ml075_s4_">2. Project Description</h2><div id="ml075.s2b"><h3>a. Information for each Assay Implemented and Screening Run</h3><div id="ml075.s2bi"><h4>i. PubChem Bioassay Name(s), AID(s), Assay-Type (Primary, DR, Counterscreen,
|
||
Secondary)</h4><div id="ml075.t1" class="table"><h3><span class="label">Table 2</span><span class="title">PubChem BioAssay</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK47354/table/ml075.t1/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml075.t1_lrgtbl__"><table class="no_top_margin"><thead><tr><th id="hd_h_ml075.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">AID</th><th id="hd_h_ml075.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Assay Name</th><th id="hd_h_ml075.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Assay Type</th><th id="hd_h_ml075.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Target</th><th id="hd_h_ml075.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Powder Sample</th><th id="hd_h_ml075.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Compound Concentration</th></tr></thead><tbody><tr><td headers="hd_h_ml075.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/793" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">793</a></td><td headers="hd_h_ml075.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Primary cell based
|
||
high-throughput screening assay for antagonists of
|
||
neuropeptide Y receptor Y2.</td><td headers="hd_h_ml075.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Primary Assay (1X
|
||
%INH)</td><td headers="hd_h_ml075.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">NPY-Y2</td><td headers="hd_h_ml075.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">No</td><td headers="hd_h_ml075.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2.7μM</td></tr><tr><td headers="hd_h_ml075.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1256" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1256</a></td><td headers="hd_h_ml075.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Counterscreen assay for
|
||
antagonists of neuropeptide Y receptor Y2 (NPY-Y2):
|
||
Cell-based high throughput assay to measure NPY-Y1
|
||
antagonism.</td><td headers="hd_h_ml075.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Counterscreen Assay (3X
|
||
%INH)</td><td headers="hd_h_ml075.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">NPY-Y1</td><td headers="hd_h_ml075.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">No</td><td headers="hd_h_ml075.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3.6 μM</td></tr><tr><td headers="hd_h_ml075.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1257" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1257</a></td><td headers="hd_h_ml075.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Cell-based high throughput
|
||
confirmation assay for antagonists of neuropeptide Y
|
||
receptor.</td><td headers="hd_h_ml075.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Confirmation Assay (3X
|
||
%INH)</td><td headers="hd_h_ml075.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">NPY-Y2</td><td headers="hd_h_ml075.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">No</td><td headers="hd_h_ml075.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">2.7 μM</td></tr><tr><td headers="hd_h_ml075.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1272" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1272</a></td><td headers="hd_h_ml075.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Dose response cell-based
|
||
screening assay for antagonists of neuropeptide Y receptor
|
||
Y2.</td><td headers="hd_h_ml075.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Dose Response (3X
|
||
IC<sub>50</sub>)</td><td headers="hd_h_ml075.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">NPY-Y2</td><td headers="hd_h_ml075.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">No</td><td headers="hd_h_ml075.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">10-point, 1:3 dilution
|
||
starting at 35 μM</td></tr><tr><td headers="hd_h_ml075.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1040" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1040</a></td><td headers="hd_h_ml075.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Primary cell-based
|
||
high-throughput screening assay for antagonists of
|
||
NPY-Y1</td><td headers="hd_h_ml075.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Primary Assay (1X
|
||
%INH)</td><td headers="hd_h_ml075.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">NPY-Y1</td><td headers="hd_h_ml075.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">No</td><td headers="hd_h_ml075.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3.6 μM</td></tr><tr><td headers="hd_h_ml075.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1279" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1279</a></td><td headers="hd_h_ml075.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Dose response counterscreen for
|
||
neuropeptide Y receptor Y2 (NPY-Y2): Cell-based high
|
||
throughput assay to measure NPY-Y1 antagonism.</td><td headers="hd_h_ml075.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Dose Response Counterscreen
|
||
(3X IC<sub>50</sub>)</td><td headers="hd_h_ml075.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">NPY-Y1</td><td headers="hd_h_ml075.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">No</td><td headers="hd_h_ml075.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">10-point, 1:3 dilution
|
||
starting at 35 μM</td></tr><tr><td headers="hd_h_ml075.t1_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2142" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2142</a></td><td headers="hd_h_ml075.t1_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Late stage results from the
|
||
probe development effort to identify antagonists of
|
||
neuropeptide Y receptor Y2 (NPY-Y2)</td><td headers="hd_h_ml075.t1_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Various (Cytotoxicity and
|
||
Brain Penetrance assays)</td><td headers="hd_h_ml075.t1_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">NPY-Y2</td><td headers="hd_h_ml075.t1_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Yes</td><td headers="hd_h_ml075.t1_1_1_1_6" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Various</td></tr></tbody></table></div></div></div><div id="ml075.s6"><h4>ii. Assay Rationale & Description</h4><div id="ml075.t2" class="table"><h3><span class="label">Table 3</span><span class="title">Assay Rationale and Description</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK47354/table/ml075.t2/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml075.t2_lrgtbl__"><table class="no_top_margin"><thead><tr><th id="hd_h_ml075.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">AID</th><th id="hd_h_ml075.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">Assay Rationale</th><th id="hd_h_ml075.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:bottom;">Assay Description</th><th id="hd_h_ml075.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Z′</th><th id="hd_h_ml075.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">S:B</th></tr></thead><tbody><tr><td headers="hd_h_ml075.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/793" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">793</a></td><td headers="hd_h_ml075.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">The purpose of this assay is to
|
||
determine the ability of test compounds to inhibit NPY Y2
|
||
activity.</td><td headers="hd_h_ml075.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">In this assay test compounds are
|
||
screened for their ability to increase agonist-mediated cAMP
|
||
levels in a cell line transfected with the NPY-Y2 receptor
|
||
and a cyclic-nucleotide gated channel (CNG). The cells are
|
||
treated with isoproterenol to activate adenylate cyclase and
|
||
open the CNG channel, leading to a change in membrane
|
||
potential that is measured using a fluorescent probe. The
|
||
addition of the agonist NPY peptide counteracts cAMP
|
||
accumulation induced by isoproterenol. As designed, test
|
||
compounds that act as NPY-Y2 receptor antagonists will
|
||
reverse the reduction in well fluorescence.</td><td headers="hd_h_ml075.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.78+/− 0.04</td><td headers="hd_h_ml075.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">5.09
|
||
+/− 0.33</td></tr><tr><td headers="hd_h_ml075.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1256" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1256</a></td><td headers="hd_h_ml075.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">The purpose of this assay is to
|
||
determine the ability of test compounds to inhibit NPY Y1
|
||
activity.</td><td headers="hd_h_ml075.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Same as <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/793" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-793</a>, except that
|
||
test compounds are tested in triplicate and are incubated
|
||
with a cell line that is transfected with the NPY-Y1
|
||
receptor.</td><td headers="hd_h_ml075.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.79
|
||
+/− 0.01</td><td headers="hd_h_ml075.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4.28
|
||
+/− 0.04</td></tr><tr><td headers="hd_h_ml075.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1257" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1257</a></td><td headers="hd_h_ml075.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">The purpose of this assay is to
|
||
confirm activity of compounds previously identified as
|
||
active in a previous set of experiments (PubChem AID
|
||
793).</td><td headers="hd_h_ml075.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Same as <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/793" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-793</a>, except that
|
||
compounds are tested in triplicate..</td><td headers="hd_h_ml075.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.81+/− 0.02</td><td headers="hd_h_ml075.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3.99
|
||
+/− 0.13</td></tr><tr><td headers="hd_h_ml075.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1272" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1272</a></td><td headers="hd_h_ml075.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">The purpose of this assay is to
|
||
determine dose response curves for compounds identified as
|
||
active in a previous set of experiments entitled, "Primary
|
||
cell-based high-throughput screening assay for antagonists
|
||
of neuropeptide Y receptor Y2 (NPY-Y2)," (PubChem AID
|
||
793).</td><td headers="hd_h_ml075.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Same as <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/793" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-793</a>, except that
|
||
test compounds were assayed in triplicate in a 10-point, 1:3
|
||
dilution series starting at a nominal test concentration of
|
||
35 μM.</td><td headers="hd_h_ml075.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.84
|
||
+/− 0.02</td><td headers="hd_h_ml075.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">4.04
|
||
+/− 0.19</td></tr><tr><td headers="hd_h_ml075.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1040" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1040</a></td><td headers="hd_h_ml075.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">The purpose of this assay is to
|
||
determine the ability of test compounds to inhibit NPY Y1
|
||
activity.</td><td headers="hd_h_ml075.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Same as <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1256" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1256</a>, except that
|
||
test compounds are incubated with a cell line that is
|
||
transfected with the NPY-Y1 receptor.</td><td headers="hd_h_ml075.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.65+/− 0.06</td><td headers="hd_h_ml075.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3.35
|
||
+/− 0.28</td></tr><tr><td headers="hd_h_ml075.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1279" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1279</a></td><td headers="hd_h_ml075.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">The purpose of this assay is to
|
||
determine whether compounds identified as active in a
|
||
previous set of experiments (PubChem <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/793" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-793</a>) were
|
||
nonselective due to inhibition of the NPY Y1 receptor.</td><td headers="hd_h_ml075.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Same as <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1272" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">AID-1272</a>, except that
|
||
test compounds are incubated with a cell line that is
|
||
transfected with the NPY-Y1 receptor.</td><td headers="hd_h_ml075.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">0.70+/− 0.10</td><td headers="hd_h_ml075.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">3.56+/−0.09</td></tr><tr><td headers="hd_h_ml075.t2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2142" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2142</a></td><td headers="hd_h_ml075.t2_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">The purpose of this assay is to
|
||
determine whether probe candidates were cytotoxic and brain
|
||
penetrant.</td><td headers="hd_h_ml075.t2_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">The purpose of this assay is to
|
||
determine whether compounds of interest reduce cell
|
||
viability. Y2R HEK293-CNG cells were seeded at 500 cells per
|
||
well in 1536-well plates in 5 uL growth media. Compounds (in
|
||
DMSO) were prepared as 10-point, 1:3 serial dilutions
|
||
starting at 11 µM final concentration were added to cells.
|
||
Plates were incubated for 24, 48 or 72 h at 37 C. After
|
||
incubation, 5 uL of CellTiter-Glo (Promega, Madison, WI)
|
||
were added to each well and the plates were allowed to
|
||
incubate for 15 min at room temperature. Luminescence was
|
||
then measured (ViewLux plate reader, PerkinElmer, Turku,
|
||
Finland). Viability was measured as a percentage relative to
|
||
control cells treated with DMSO alone (0%
|
||
cytotoxicity) and cells treated with 100 µM Doxorubicin
|
||
(100% cytotoxicity).<br /><br />Plasma and
|
||
brain levels of the compounds were assessed in C57Bl6 mice
|
||
30 minutes after dosing 10 mg/kg intraperitoneally. Samples
|
||
were formulated at 2 mg/mL in 10/10/80 DMSO/tween/water.
|
||
Blood was collected into EDTA containing tubes at 30 min and
|
||
plasma was generated using standard centrifugation
|
||
techniques. Brain samples were frozen upon collection and
|
||
all samples were stored at −80 C until analyzed.
|
||
Brain tissue was not perfused prior to freezing to prevent
|
||
diffusion of the compound out of the tissue during the
|
||
process. Plasma samples were analyzed by treating 25
|
||
μL of plasma with 125 μL of
|
||
acetonitrile containing an internal standard (propanolol)
|
||
and filtering through a Millipore Multiscreen Solvinter 0.45
|
||
μm low binding PTFE hydrophilic filter. The
|
||
filtrate was analyzed by LC- MS/MS using an API Sciex 4000.
|
||
MRM methods were developed in positive ion mode and
|
||
concentrations were determined using a standard curve
|
||
between 2 to 2000 ng/mL. Samples with concentrations outside
|
||
of the curve were diluted with blank plasma and reanalyzed.
|
||
Similar conditions were used to determine brain levels
|
||
except the samples were weighed and acetonitrile was added
|
||
(10x, weight by volume). The samples were sonicated to
|
||
extract the compound from the brain matrix and then filtered
|
||
as described above. A density of 1 g/mL was used to convert
|
||
compound per mg tissue into molar equivalents.</td><td headers="hd_h_ml075.t2_1_1_1_4" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"></td><td headers="hd_h_ml075.t2_1_1_1_5" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"></td></tr></tbody></table></div></div><div id="ml075.t3" class="table"><h3><span class="label">Table 4</span><span class="title">Reagents and Source</span></h3><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK47354/table/ml075.t3/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml075.t3_lrgtbl__"><table class="no_top_margin"><thead><tr><th id="hd_h_ml075.t3_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">AID</th><th id="hd_h_ml075.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Reagent (Source)</th></tr></thead><tbody><tr><td headers="hd_h_ml075.t3_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
|
||
<b><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/793" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">793</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1256" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1256</a>, <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1257" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1257</a>, and <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1272" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1272</a></b>
|
||
</td><td headers="hd_h_ml075.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Neuropeptide Y receptor Y2
|
||
HEK293-CNG cells (BD Biosciences, part 344870)<br /> 10x
|
||
ACTOne Membrane Potential Assay Kit (BD Biosciences, part
|
||
<a href="/nuccore/92255785" class="bk_tag" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=nuccore">BD354663</a>)<br /> Phosphate Buffered Saline (Invitrogen,
|
||
part 10010-023)<br /> DMEM (Invitrogen, part
|
||
11965-092)<br /> Fetal Bovine Serum (Invitrogen, part
|
||
16140-071)<br /> Trypsin-EDTA solution (Invitrogen, part
|
||
25200-056)<br /> Geneticin (Invitrogen, part
|
||
10131-027)<br /> Puromycin (Sigma, part P9620)<br />
|
||
Isoproterenol (Sigma, part I6504)<br /> Ro 20-1724 (Sigma,
|
||
part B8279)<br /> Neuropeptide Y (American Peptide, part
|
||
60-1-11B)<br /> BIIE 0246 (Tocris, part 1700)<br />
|
||
1536-well plates (Greiner, part 789072)<br /> T-175 tissue
|
||
culture flasks (Corning, part 431)</td></tr><tr><td headers="hd_h_ml075.t3_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">
|
||
<b><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1040" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1040</a> and <a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/1279" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">1279</a></b>
|
||
</td><td headers="hd_h_ml075.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">As above, with the
|
||
following changes: Neuropeptide Y receptor
|
||
Y1 HEK293-CNG cells (BD Biosciences, part 344869) (replaces
|
||
Y2 cells)</td></tr><tr><td headers="hd_h_ml075.t3_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;"><a href="https://pubchem.ncbi.nlm.nih.gov/bioassay/2142" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">2142</a></td><td headers="hd_h_ml075.t3_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Y2R HEK293-CNG cells ;
|
||
CellTiter-Glo (Promega, Madison, WI); DMSO; Doxorubicin
|
||
DMSO/tween/water; EDTA; acetonitrile containing an internal
|
||
standard (propanolol)</td></tr></tbody></table></div></div></div><div id="ml075.s7"><h4>iii. Summary of Results</h4><p>Compared to previously described Y2R antagonists, the compounds described
|
||
herein offer greater promise for elucidating the Y2R signaling pathway.</p></div></div><div id="ml075.s8"><h3>b. Probe Optimization</h3></div><div id="ml075.s9"><h3>i. Description of SAR & chemistry strategy (including structure and
|
||
data) that led to the probe.</h3><p>Since receptor subtype selective antagonists were desired, compounds worth
|
||
follow-up from the Primary, Confirmation and Counterscreening were required to
|
||
exhibit an IC<sub>50</sub> value of less than 10 μM at Y2R and
|
||
greater than 35 μM at Y1 in dose response assays. Structures and
|
||
data for each probe can be found in the SAR tables. The chemistry strategy that
|
||
lead to each scaffold is described below:</p><p><b>Scaffold 1:</b> Based on the above criteria, one compound belonging
|
||
to the piperidine-carbothioamide scaffold was identified:
|
||
<b><a href="https://pubchem.ncbi.nlm.nih.gov/substance/17507305" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID-17507305</a></b>. This compound does not share structural
|
||
similarities with the known NPY-Y2 antagonist BIIE 0246 or JNJ-5207787.
|
||
Analogs were purchased in powder form or reordered from the MLSMR in liquid
|
||
form and tested in dose response assays against both receptors. Results for
|
||
these analogs are summarized in the SAR table below.</p><p><b>Scaffold 2:</b> Based on the above criteria, a compound belonging to
|
||
the arysulfamoyl benzamide scaffold was identified:
|
||
<b><a href="https://pubchem.ncbi.nlm.nih.gov/substance/17413392" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID-17413392</a></b>. This compound does not share structural
|
||
similarities with the known NPY-Y2 antagonist BIIE0246 or JNJ-5207787.
|
||
Analogs were purchased in powder form or re-ordered from the MLSMR in liquid
|
||
form and tested in dose response assays against both receptors. Results for
|
||
these analogs are summarized in the SAR table below.</p><p><b>Scaffold 3:</b> Based on the above criteria, a compound belonging to
|
||
the aryl-1,2,4-oxadiazole scaffold was identified: <b><a href="https://pubchem.ncbi.nlm.nih.gov/substance/4242079" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID-4242079</a></b>.
|
||
This compound does not share structural similarities with the known NPY-Y2
|
||
antagonist BIIE0246 or JNJ-5207787. Analogs were purchased in powder form or
|
||
re-ordered from the MLSMR in liquid form and tested in dose response assays
|
||
against both receptors. Results for these analogs are summarized in the SAR
|
||
table below.</p><p><b>Scaffold 4:</b> Based on the above criteria, a compound belonging to
|
||
the dimethylisoxazole scaffold was identified: <b><a href="https://pubchem.ncbi.nlm.nih.gov/substance/22413249" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID-22413249</a></b>.
|
||
This compound does not share structural similarities with the known NPY-Y2
|
||
antagonist BIIE0246 or JNJ-5207787. Analogs were purchased in powder form or
|
||
re-ordered from the MLSMR in liquid form and tested in dose response assays
|
||
against both receptors. Results for these analogs are summarized in the SAR
|
||
table below.</p></div></div><div id="ml075.s10"><h2 id="_ml075_s10_">3. Probe</h2><div id="ml075.s11"><h3>a. Chemical name</h3><p><b>Scaffold 1:</b>
|
||
N-(4-ethoxyphenyl)-4-[hydroxy(diphenyl)methyl]piperidine-1-
|
||
carbothioamide [<a href="/pcsubstance/?term=ML075[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML075</a>]</p><p><b>Scaffold 2:</b>
|
||
4-chloro-3-[(2,5-dimethylphenyl)sulfamoyl]-N-(2-phenylphenyl)benzamide
|
||
[<a href="/pcsubstance/?term=ML074[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML074</a>]</p><p><b>Scaffold 3:</b>
|
||
2-(2-methoxyphenyl)-N-[4-[5-(3-methoxyphenyl)-1,2,
|
||
4-oxadiazol-3-yl]phenyl]acetamide
|
||
[<a href="/pcsubstance/?term=ML073[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML073</a>]</p><p><b>Scaffold 4:</b>
|
||
3,5-dimethyl-4-[(4-methylphenyl)sulfonyl-phenylmethyl]-1,2-oxazole
|
||
[<a href="/pcsubstance/?term=ML072[synonym]" ref="pagearea=body&targetsite=entrez&targetcat=term&targettype=pubchem">ML072</a>]</p></div><div id="ml075.s12"><h3>b. Probe chemical structure</h3><div id="ml075.fu6" class="figure bk_fig"><div class="graphic"><img src="/books/NBK47354/bin/ml075fu1.jpg" alt="Scaffold 1 (Piperidine carbothioamide) [ML075]." /></div><h3><span class="title">Scaffold 1 (Piperidine carbothioamide) [ML075]</span></h3></div><div id="ml075.fu7" class="figure bk_fig"><div class="graphic"><img src="/books/NBK47354/bin/ml075fu2.jpg" alt="Scaffold 2 (Arysulfamoyl benzamide) [ML074]." /></div><h3><span class="title">Scaffold 2 (Arysulfamoyl benzamide) [ML074]</span></h3></div><div id="ml075.fu8" class="figure bk_fig"><div class="graphic"><img src="/books/NBK47354/bin/ml075fu3.jpg" alt="Scaffold 3 (Aryl-1,2,4-oxadiazole) [ML073]." /></div><h3><span class="title">Scaffold 3 (Aryl-1,2,4-oxadiazole) [ML073]</span></h3></div><div id="ml075.fu9" class="figure bk_fig"><div class="graphic"><img src="/books/NBK47354/bin/ml075fu4.jpg" alt="Scaffold 4 (Dimethylisoxazole) [ML072]." /></div><h3><span class="title">Scaffold 4 (Dimethylisoxazole) [ML072]</span></h3></div></div><div id="ml075.s13"><h3>c. Structural Verification Information of probe SID</h3><p>LCMS</p></div><div id="ml075.s14"><h3>d. PubChem CID (corresponding to the SID)</h3><p><b>Scaffold 1:</b> CID-2936384</p><p><b>Scaffold 2:</b> CID-2228302</p><p><b>Scaffold 3:</b> CID-3236979</p><p><b>Scaffold 4:</b> CID-4460128</p></div><div id="ml075.s15"><h3>e. Availabilty from vendor</h3><p><b>Scaffold 1:</b> Asinex, catalog number BAS 01915526</p><p><b>Scaffold 2:</b> ChemBridge, catalog number 7955494</p><p><b>Scaffold 3:</b> ChemDiv, catalog number K907-0250</p><p><b>Scaffold 4:</b> Specs, catalog number AM970/41069539</p></div><div id="ml075.s16"><h3>f. Mode of action for biological activity of probe</h3><p><b>Scaffold 1:</b> Using cell-based <sup>125</sup>I-PYY binding assays, the
|
||
Assay Provider has determined that <b><a href="https://pubchem.ncbi.nlm.nih.gov/substance/17507305" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID-17507305</a></b> competes with
|
||
agonist for binding to the NPY Y2 receptor. In cells expressing NPY Y2, this
|
||
compound exhibited a K<sub>i</sub> value of 1.55 nM (<a class="bk_pop" href="#ml075.r1">1</a>). No significant blockade of <sup>125</sup>I-PYY
|
||
binding in cells expressing NPY Y1 was detected, even at concentrations up to 50
|
||
μM. These results suggest that this probe binds to the NPY Y2
|
||
receptor and does not bind to the Y1 receptor subtype.</p><p><b>Scaffold 2:</b> Using cell-based <sup>125</sup>I-PYY binding assays, the
|
||
Assay Provider has determined that <b><a href="https://pubchem.ncbi.nlm.nih.gov/substance/17413392" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID-17413392</a></b> competes with
|
||
agonist for binding to the NPY Y2 receptor. In cells expressing NPY Y2, this
|
||
compound exhibited a K<sub>i</sub> value of 1.93 nM (<a class="bk_pop" href="#ml075.r1">1</a>). No significant blockade of <sup>125</sup>I-PYY
|
||
binding in cells expressing NPY Y1 was detected, even at concentrations up to 50
|
||
μM. These results suggest that this probe binds to the NPY Y2
|
||
receptor and does not bind to the Y1 receptor subtype.</p><p><b>Scaffold 3:</b> Using cell-based <sup>125</sup>I-PYY binding assays, the
|
||
Assay Provider has determined that <b><a href="https://pubchem.ncbi.nlm.nih.gov/substance/4242079" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID-4242079</a></b> competes with agonist
|
||
for binding to the NPY Y2 receptor. In cells expressing NPY Y2, this compound
|
||
exhibited a K<sub>i</sub> value of 6.0 nM (<a class="bk_pop" href="#ml075.r1">1</a>). No significant blockade of <sup>125</sup>I-PYY binding in cells
|
||
expressing NPY Y1 was detected, even at concentrations up to 50 μM.
|
||
These results suggest that this probe binds to the NPY Y2 receptor and does not
|
||
bind to the Y1 receptor subtype.</p><p><b>Scaffold 4:</b> Using cell-based <sup>125</sup>I-PYY binding assays, the
|
||
Assay Provider has determined that <b><a href="https://pubchem.ncbi.nlm.nih.gov/substance/22413249" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID-22413249</a></b> competes with
|
||
agonist for binding to the NPY Y2 receptor. In cells expressing NPY Y2, this
|
||
compound exhibited a K<sub>i</sub> value of 60.3 nM (<a class="bk_pop" href="#ml075.r1">1</a>). No significant blockade of <sup>125</sup>I-PYY
|
||
binding in cells expressing NPY Y1 was detected, even at concentrations up to 50
|
||
μM. These results suggest that this probe binds to the NPY Y2
|
||
receptor and does not bind to the Y1 receptor subtype.</p></div><div id="ml075.s17"><h3>g. Detailed synthetic pathway for making probe</h3><p>Not applicable</p></div><div id="ml075.s18"><h3>h. Probe properties</h3><p><b>Scaffold 1:</b> Aqueous solubility, −8.47; ADMET BBB, 0.803;
|
||
ADMET BBB level, 0; ADMET absorption level, 0; ADMET solubility,
|
||
−5.463; ADMET solubility level, 2</p><p><b>Scaffold 2:</b> Aqueous solubility, −9.18; ADMET BBB, ND;
|
||
ADMET BBB level, 4; ADMET absorption level, 2; ADMET solubility,
|
||
−7.195; ADMET solubility level, 1</p><p><b>Scaffold 3:</b> Aqueous solubility, −6.86; ADMET BBB,
|
||
−.253; ADMET BBB level, 2; ADMET absorption level, 0; ADMET
|
||
solubility, −4.849; ADMET solubility level, 2</p><p><b>Scaffold 4:</b> Aqueous solubility, −6.11; ADMET BBB, .133;
|
||
ADMET BBB level, 1; ADMET absorption level, 0; ADMET solubility,
|
||
−5.237; ADMET solubility level, 2</p></div><div id="ml075.s19"><h3>i. A tabular presentation summarizing known probe properties</h3><p>Please see Tables of <a class="figpopup" href="/books/NBK47354/table/ml075.t4/?report=objectonly" target="object" rid-figpopup="figml075t4" rid-ob="figobml075t4">Probe
|
||
Properties</a> and <a class="figpopup" href="/books/NBK47354/table/ml075.t5/?report=objectonly" target="object" rid-figpopup="figml075t5" rid-ob="figobml075t5">Probe Names</a>.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml075t4"><a href="/books/NBK47354/table/ml075.t4/?report=objectonly" target="object" title="Table 5" class="img_link icnblk_img figpopup" rid-figpopup="figml075t4" rid-ob="figobml075t4"><img class="small-thumb" src="/books/NBK47354/table/ml075.t4/?report=thumb" src-large="/books/NBK47354/table/ml075.t4/?report=previmg" alt="Table 5. Probe Properties." /></a><div class="icnblk_cntnt"><h4 id="ml075.t4"><a href="/books/NBK47354/table/ml075.t4/?report=objectonly" target="object" rid-ob="figobml075t4">Table 5</a></h4><p class="float-caption no_bottom_margin">Probe Properties. </p></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml075t5"><a href="/books/NBK47354/table/ml075.t5/?report=objectonly" target="object" title="Table 6" class="img_link icnblk_img figpopup" rid-figpopup="figml075t5" rid-ob="figobml075t5"><img class="small-thumb" src="/books/NBK47354/table/ml075.t5/?report=thumb" src-large="/books/NBK47354/table/ml075.t5/?report=previmg" alt="Table 6. Probe Names." /></a><div class="icnblk_cntnt"><h4 id="ml075.t5"><a href="/books/NBK47354/table/ml075.t5/?report=objectonly" target="object" rid-ob="figobml075t5">Table 6</a></h4><p class="float-caption no_bottom_margin">Probe Names. </p></div></div></div></div><div id="ml075.s20"><h2 id="_ml075_s20_">4. Appendices</h2><ol class="lower-alpha"><li class="half_rhythm"><div>
|
||
<b>Comparative data on (<a class="bk_pop" href="#ml075.r1">1</a>)
|
||
probes, (<a class="bk_pop" href="#ml075.r2">2</a>) similar compound
|
||
structures (establishing SAR) and (<a class="bk_pop" href="#ml075.r3">3</a>) prior probes</b>
|
||
</div></li><li class="half_rhythm"><div>
|
||
<b>Comparative data showing probe specificity for target</b>
|
||
</div></li></ol><p>See Tables <a class="figpopup" href="/books/NBK47354/table/ml075.t6/?report=objectonly" target="object" rid-figpopup="figml075t6" rid-ob="figobml075t6">7a</a>-<a class="figpopup" href="/books/NBK47354/table/ml075.t9/?report=objectonly" target="object" rid-figpopup="figml075t9" rid-ob="figobml075t9">d</a></p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml075t6"><a href="/books/NBK47354/table/ml075.t6/?report=objectonly" target="object" title="Table 7(a)" class="img_link icnblk_img figpopup" rid-figpopup="figml075t6" rid-ob="figobml075t6"><img class="small-thumb" src="/books/NBK47354/table/ml075.t6/?report=thumb" src-large="/books/NBK47354/table/ml075.t6/?report=previmg" alt="Table 7(a). SAR Scaffold 1: Piperidine-carbothioamide." /></a><div class="icnblk_cntnt"><h4 id="ml075.t6"><a href="/books/NBK47354/table/ml075.t6/?report=objectonly" target="object" rid-ob="figobml075t6">Table 7(a)</a></h4><p class="float-caption no_bottom_margin">SAR Scaffold 1: Piperidine-carbothioamide. </p></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml075t7"><a href="/books/NBK47354/table/ml075.t7/?report=objectonly" target="object" title="Table 7(b)" class="img_link icnblk_img figpopup" rid-figpopup="figml075t7" rid-ob="figobml075t7"><img class="small-thumb" src="/books/NBK47354/table/ml075.t7/?report=thumb" src-large="/books/NBK47354/table/ml075.t7/?report=previmg" alt="Table 7(b). SAR Scaffold 2: Arylsulfamoylbenzamide." /></a><div class="icnblk_cntnt"><h4 id="ml075.t7"><a href="/books/NBK47354/table/ml075.t7/?report=objectonly" target="object" rid-ob="figobml075t7">Table 7(b)</a></h4><p class="float-caption no_bottom_margin">SAR Scaffold 2: Arylsulfamoylbenzamide. </p></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml075t8"><a href="/books/NBK47354/table/ml075.t8/?report=objectonly" target="object" title="Table 7(c)" class="img_link icnblk_img figpopup" rid-figpopup="figml075t8" rid-ob="figobml075t8"><img class="small-thumb" src="/books/NBK47354/table/ml075.t8/?report=thumb" src-large="/books/NBK47354/table/ml075.t8/?report=previmg" alt="Table 7(c). SAR Scaffold 3: Aryl-1,2,4-oxadiazole." /></a><div class="icnblk_cntnt"><h4 id="ml075.t8"><a href="/books/NBK47354/table/ml075.t8/?report=objectonly" target="object" rid-ob="figobml075t8">Table 7(c)</a></h4><p class="float-caption no_bottom_margin">SAR Scaffold 3: Aryl-1,2,4-oxadiazole. </p></div></div><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figml075t9"><a href="/books/NBK47354/table/ml075.t9/?report=objectonly" target="object" title="Table 7(d)" class="img_link icnblk_img figpopup" rid-figpopup="figml075t9" rid-ob="figobml075t9"><img class="small-thumb" src="/books/NBK47354/table/ml075.t9/?report=thumb" src-large="/books/NBK47354/table/ml075.t9/?report=previmg" alt="Table 7(d). SAR Scaffold 4: Dimethylisoxazole." /></a><div class="icnblk_cntnt"><h4 id="ml075.t9"><a href="/books/NBK47354/table/ml075.t9/?report=objectonly" target="object" rid-ob="figobml075t9">Table 7(d)</a></h4><p class="float-caption no_bottom_margin">SAR Scaffold 4: Dimethylisoxazole. </p></div></div></div><div id="ml075.bib"><h2 id="_ml075_bib_">5. Bibliography</h2><dl class="temp-labeled-list"><dt>1.</dt><dd><div class="bk_ref" id="ml075.r1">Saldanha SA, Brothers SP, Spicer T, Cameron M, Mercer BA, Chase P, McDonald P, Wahlestedt C, Hodder PS. Selective and Brain Penetrant Neuropeptide Y Y2 Receptor
|
||
Antagonists Discovered through Whole-Cell High Throughput
|
||
Screening. <span></span> Submitted. [<a href="/pmc/articles/PMC2802430/" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pmc">PMC free article<span class="bk_prnt">: PMC2802430</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/19837904" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 19837904</span></a>]</div></dd><dt>2.</dt><dd><div class="bk_ref" id="ml075.r2">Bonaventure P, Nepomuceno D, Mazur C, Lord B, Rudolph DA, Jablonowski JA, Carruthers NI, Lovenberg TW. Characterization of
|
||
N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-3-(3-cyanophenyl)-N-[1-(2-cyclopentyl-ethyl)-piperidin-4yl]acrylamide
|
||
(JNJ-5207787), a small molecule antagonist of the neuropeptide Y Y 2
|
||
receptor. <span><span class="ref-journal">J Pharmacol Exp Ther. </span>2004 Mar;<span class="ref-vol">308</span>(3:):1130–7.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/14617685" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 14617685</span></a>]</div></dd><dt>3.</dt><dd><div class="bk_ref" id="ml075.r3">Tetko IV, Tanchuk VY, Kasheva TN, Villa AE. Estimation of aqueous solubility of chemical compounds using
|
||
E-state indices. <span><span class="ref-journal">J Chem Inf Comput Sci. </span>2001;<span class="ref-vol">41</span>:1488–1493.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/11749573" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11749573</span></a>]</div></dd><dt>4.</dt><dd><div class="bk_ref" id="ml075.r4">Egan WJ, Merz KM Jr, Baldwin JJ. Prediction of drug absorption using multivariate
|
||
statistics. <span><span class="ref-journal">J Med Chem. </span>2000;<span class="ref-vol">43</span>:3867–3877.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/11052792" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11052792</span></a>]</div></dd><dt>5.</dt><dd><div class="bk_ref" id="ml075.r5">Egan WJ, Lauri G. Prediction of intestinal permeability. <span><span class="ref-journal">Adv Drug Deliv Rev. </span>2002;<span class="ref-vol">54</span>:273–289.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/11922948" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 11922948</span></a>]</div></dd><dt>6.</dt><dd><div class="bk_ref" id="ml075.r6">Cheng A, Merz KM Jr. Prediction of aqueous solubility of a diverse set of
|
||
compounds using quantitative structure-property
|
||
relationships. <span><span class="ref-journal">J Med Chem. </span>2003;<span class="ref-vol">46</span>:3572–3580.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12904062" ref="pagearea=cite-ref&targetsite=entrez&targetcat=link&targettype=pubmed">PubMed<span class="bk_prnt">: 12904062</span></a>]</div></dd></dl></div><div id="ml075.s21"><h2 id="_ml075_s21_">Brain Penetrance Data</h2><p>In order to determine whether the identified Y2R antagonists were brain-penetrant,
|
||
selected compounds were injected intraperitoneally into adult mice at 10 mg/kg and
|
||
levels in the brain tissue and plasma were measured after thirty minutes. BIIE 0246,
|
||
the current NPY Y2 antagonist probe, exhibited poor penetration (only 2%
|
||
of plasma levels). All probes demonstrated a higher brain penetrance than BIIE
|
||
0246.</p><div id="ml075.tu2" class="table"><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK47354/table/ml075.tu2/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__ml075.tu2_lrgtbl__"><table><thead><tr><th id="hd_h_ml075.tu2_1_1_1_1" rowspan="2" colspan="1" headers="hd_h_ml075.tu2_1_1_1_1" style="text-align:center;vertical-align:middle;">ID</th><th id="hd_h_ml075.tu2_1_1_1_2" colspan="3" rowspan="1" style="text-align:center;vertical-align:middle;">Brain Penetration
|
||
Studies<span class="hr"></span></th></tr><tr><th headers="hd_h_ml075.tu2_1_1_1_2" id="hd_h_ml075.tu2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Plasma Concentration
|
||
(μM)</th><th headers="hd_h_ml075.tu2_1_1_1_2" id="hd_h_ml075.tu2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Brain Concentration
|
||
(μM)</th><th headers="hd_h_ml075.tu2_1_1_1_2" id="hd_h_ml075.tu2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:middle;">Ratio
|
||
[B]/[P]
|
||
(%)</th></tr></thead><tbody><tr><td headers="hd_h_ml075.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
|
||
<b><a href="https://pubchem.ncbi.nlm.nih.gov/substance/17507305" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID-17507305</a></b>
|
||
</td><td headers="hd_h_ml075.tu2_1_1_1_2 hd_h_ml075.tu2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">8.5 ± 3.3</td><td headers="hd_h_ml075.tu2_1_1_1_2 hd_h_ml075.tu2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">3.7 ± 1.7</td><td headers="hd_h_ml075.tu2_1_1_1_2 hd_h_ml075.tu2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">44</td></tr><tr><td headers="hd_h_ml075.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
|
||
<b><a href="https://pubchem.ncbi.nlm.nih.gov/substance/17413392" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID-17413392</a></b>
|
||
</td><td headers="hd_h_ml075.tu2_1_1_1_2 hd_h_ml075.tu2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">1.1 ± 0.1</td><td headers="hd_h_ml075.tu2_1_1_1_2 hd_h_ml075.tu2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.4 ± 0.03</td><td headers="hd_h_ml075.tu2_1_1_1_2 hd_h_ml075.tu2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">36</td></tr><tr><td headers="hd_h_ml075.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
|
||
<b><a href="https://pubchem.ncbi.nlm.nih.gov/substance/17413034" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID-17413034</a></b>
|
||
</td><td headers="hd_h_ml075.tu2_1_1_1_2 hd_h_ml075.tu2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">1.6 ± 0.6</td><td headers="hd_h_ml075.tu2_1_1_1_2 hd_h_ml075.tu2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">1.7 ± 0.6</td><td headers="hd_h_ml075.tu2_1_1_1_2 hd_h_ml075.tu2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">106</td></tr><tr><td headers="hd_h_ml075.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
|
||
<b><a href="https://pubchem.ncbi.nlm.nih.gov/substance/4242079" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID-4242079</a></b>
|
||
</td><td headers="hd_h_ml075.tu2_1_1_1_2 hd_h_ml075.tu2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">9.0 ± 0.7</td><td headers="hd_h_ml075.tu2_1_1_1_2 hd_h_ml075.tu2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">4.5 ± 0.3</td><td headers="hd_h_ml075.tu2_1_1_1_2 hd_h_ml075.tu2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">50</td></tr><tr><td headers="hd_h_ml075.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
|
||
<b><a href="https://pubchem.ncbi.nlm.nih.gov/substance/22413249" ref="pagearea=body&targetsite=entrez&targetcat=link&targettype=pubchem">SID-22413249</a></b>
|
||
</td><td headers="hd_h_ml075.tu2_1_1_1_2 hd_h_ml075.tu2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">1.3 ± 0.3</td><td headers="hd_h_ml075.tu2_1_1_1_2 hd_h_ml075.tu2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">1.5 ± 0.2</td><td headers="hd_h_ml075.tu2_1_1_1_2 hd_h_ml075.tu2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">115</td></tr><tr><td headers="hd_h_ml075.tu2_1_1_1_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">
|
||
<b>BIIE-0246</b>
|
||
</td><td headers="hd_h_ml075.tu2_1_1_1_2 hd_h_ml075.tu2_1_1_2_1" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">12 ± 2</td><td headers="hd_h_ml075.tu2_1_1_1_2 hd_h_ml075.tu2_1_1_2_2" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">0.2 ± 0.1</td><td headers="hd_h_ml075.tu2_1_1_1_2 hd_h_ml075.tu2_1_1_2_3" rowspan="1" colspan="1" style="text-align:center;vertical-align:top;">2</td></tr></tbody></table></div></div></div><div id="bk_toc_contnr"></div></div></div>
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<div xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Views</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="PDF_download" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="/books/NBK47354/?report=reader">PubReader</a></li><li><a href="/books/NBK47354/?report=printable">Print View</a></li><li><a data-jig="ncbidialog" href="#_ncbi_dlg_citbx_NBK47354" data-jigconfig="width:400,modal:true">Cite this Page</a><div id="_ncbi_dlg_citbx_NBK47354" style="display:none" title="Cite this Page"><div class="bk_tt">Saldanha SA, Brothers SP, Spicer T, et al. Probe Report for NPY-Y2 Receptor Antagonists. 2009 Jan 13 [Updated 2010 Aug 6]. 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><li><a href="/books/NBK47354/pdf/Bookshelf_NBK47354.pdf">PDF version of this page</a> (400K)</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="#ml075.s1" ref="log$=inpage&link_id=inpage">Probe Structure & Characteristics</a></li><li><a href="#ml075.s2" ref="log$=inpage&link_id=inpage">Recommendations for the scientific use of this probe</a></li><li><a href="#ml075.s3" ref="log$=inpage&link_id=inpage">Scientific Rationale for Project</a></li><li><a href="#ml075.s4" ref="log$=inpage&link_id=inpage">Project Description</a></li><li><a href="#ml075.s10" ref="log$=inpage&link_id=inpage">Probe</a></li><li><a href="#ml075.s20" ref="log$=inpage&link_id=inpage">Appendices</a></li><li><a href="#ml075.bib" ref="log$=inpage&link_id=inpage">Bibliography</a></li><li><a href="#ml075.s21" ref="log$=inpage&link_id=inpage">Brain Penetrance Data</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=2359688" ref="log$=recordlinks">PMC</a><div class="brieflinkpop offscreen_noflow">PubMed Central citations</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=pcassay&DbFrom=books&Cmd=Link&LinkName=books_pcassay_probe&IdsFromResult=2359688" ref="log$=recordlinks">PubChem BioAssay for Chemical Probe</a><div class="brieflinkpop offscreen_noflow">PubChem BioAssay records reporting screening data for the development of the chemical probe(s) described in this book chapter</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=pcsubstance&DbFrom=books&Cmd=Link&LinkName=books_pcsubstance&IdsFromResult=2359688" ref="log$=recordlinks">PubChem Substance</a><div class="brieflinkpop offscreen_noflow">Related PubChem Substances</div></li><li class="brieflinkpopper"><a class="brieflinkpopperctrl" href="/books/?Db=pubmed&DbFrom=books&Cmd=Link&LinkName=books_pubmed_refs&IdsFromResult=2359688" ref="log$=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/19837904" ref="ordinalpos=1&linkpos=1&log$=relatedarticles&logdbfrom=pubmed">Selective and brain penetrant neuropeptide y y2 receptor antagonists discovered by whole-cell high-throughput screening.</a><span class="source">[Mol Pharmacol. 2010]</span><div class="brieflinkpop offscreen_noflow">Selective and brain penetrant neuropeptide y y2 receptor antagonists discovered by whole-cell high-throughput screening.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Brothers SP, Saldanha SA, Spicer TP, Cameron M, Mercer BA, Chase P, McDonald P, Wahlestedt C, Hodder PS. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">Mol Pharmacol. 2010 Jan; 77(1):46-57. 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