(3R,4S)-3-[4-(4-Fluorophenyl)-4-hydroxypiperidin-1-yl]chroman-4,7-diol: A Conformationally Restricted Analogue of the NR2B Subtype-Selective NMDA Antagonist (1S,2S)-1-(4-Hydroxyphenyl)-2- (4-hydroxy-4-phenylpiperidino)-1-propanol
(1S,2S)-1-(4-Hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol (CP-101,606, 1) is a recently described antagonist of N-methyl-d-aspartate (NMDA) receptors containing the NR2B subunit. In the present study, the optimal orientation of compounds of this structural type for their receptor was e...
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| Veröffentlicht in: | Journal of medicinal chemistry 1998-03, Vol.41 (7), p.1172-1184 |
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| creator | Butler, Todd W Blake, James F Bordner, Jon Butler, Paul Chenard, Bertrand L Collins, Mary A DeCosta, Debra Ducat, Mary J Eisenhard, Michael E Menniti, Frank S Pagnozzi, Martin J Sands, Steven B Segelstein, Barbara E Volberg, Walter White, W. Frost Zhao, Dayao |
| description | (1S,2S)-1-(4-Hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol (CP-101,606, 1) is a recently described antagonist of N-methyl-d-aspartate (NMDA) receptors containing the NR2B subunit. In the present study, the optimal orientation of compounds of this structural type for their receptor was explored. Tethering of the pendent methyl group of 1 to the phenolic aromatic ring via an oxygen atom prevents rotation about the central portion of the molecule. Several of the new chromanol compounds have high affinity for the racemic [3H]CP-101,606 binding site on the NMDA receptor and protect against glutamate toxicity in cultured hippocampal neurons. The new ring caused a change in the stereochemical preference of the receptorcis (erythro) compounds had better affinity for the receptor than the trans isomers. Computational studies suggest that steric interactions between the pendent methyl group and the phenol ring in the acyclic series determine which structures can best fit the receptor. The chromanol analogue, (3R,4S)-3-[4-(4-fluorophenyl)-4-hydroxypiperidin-1-yl]chroman-4,7-diol (12a, CP-283,097), was found to possess potency and selectivity comparable to CP-101,606. Thus 12a is a new tool to explore the function of the NR2B-containing NMDA receptors. |
| doi_str_mv | 10.1021/jm9707986 |
| format | Article |
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Frost ; Zhao, Dayao</creator><creatorcontrib>Butler, Todd W ; Blake, James F ; Bordner, Jon ; Butler, Paul ; Chenard, Bertrand L ; Collins, Mary A ; DeCosta, Debra ; Ducat, Mary J ; Eisenhard, Michael E ; Menniti, Frank S ; Pagnozzi, Martin J ; Sands, Steven B ; Segelstein, Barbara E ; Volberg, Walter ; White, W. Frost ; Zhao, Dayao</creatorcontrib><description>(1S,2S)-1-(4-Hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol (CP-101,606, 1) is a recently described antagonist of N-methyl-d-aspartate (NMDA) receptors containing the NR2B subunit. In the present study, the optimal orientation of compounds of this structural type for their receptor was explored. Tethering of the pendent methyl group of 1 to the phenolic aromatic ring via an oxygen atom prevents rotation about the central portion of the molecule. Several of the new chromanol compounds have high affinity for the racemic [3H]CP-101,606 binding site on the NMDA receptor and protect against glutamate toxicity in cultured hippocampal neurons. The new ring caused a change in the stereochemical preference of the receptorcis (erythro) compounds had better affinity for the receptor than the trans isomers. Computational studies suggest that steric interactions between the pendent methyl group and the phenol ring in the acyclic series determine which structures can best fit the receptor. The chromanol analogue, (3R,4S)-3-[4-(4-fluorophenyl)-4-hydroxypiperidin-1-yl]chroman-4,7-diol (12a, CP-283,097), was found to possess potency and selectivity comparable to CP-101,606. Thus 12a is a new tool to explore the function of the NR2B-containing NMDA receptors.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm9707986</identifier><identifier>PMID: 9544217</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Animals ; Biological and medical sciences ; Chromans - chemical synthesis ; Chromans - pharmacology ; Dose-Response Relationship, Drug ; Glutamatergic system (aspartate and other excitatory aminoacids) ; Male ; Medical sciences ; Models, Molecular ; Neuropharmacology ; Neurotransmitters. Neurotransmission. Receptors ; Pharmacology. Drug treatments ; Piperidines - chemical synthesis ; Piperidines - pharmacology ; Rats ; Rats, Sprague-Dawley ; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors ; Structure-Activity Relationship</subject><ispartof>Journal of medicinal chemistry, 1998-03, Vol.41 (7), p.1172-1184</ispartof><rights>Copyright © 1998 American Chemical Society</rights><rights>1998 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a309t-b9ba06a7cca6bada11a494a12d904e5356ce8f7cece5395c1a9427b55f1610633</citedby><cites>FETCH-LOGICAL-a309t-b9ba06a7cca6bada11a494a12d904e5356ce8f7cece5395c1a9427b55f1610633</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm9707986$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm9707986$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>315,781,785,2766,27081,27929,27930,56743,56793</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=2209653$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/9544217$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Butler, Todd W</creatorcontrib><creatorcontrib>Blake, James F</creatorcontrib><creatorcontrib>Bordner, Jon</creatorcontrib><creatorcontrib>Butler, Paul</creatorcontrib><creatorcontrib>Chenard, Bertrand L</creatorcontrib><creatorcontrib>Collins, Mary A</creatorcontrib><creatorcontrib>DeCosta, Debra</creatorcontrib><creatorcontrib>Ducat, Mary J</creatorcontrib><creatorcontrib>Eisenhard, Michael E</creatorcontrib><creatorcontrib>Menniti, Frank S</creatorcontrib><creatorcontrib>Pagnozzi, Martin J</creatorcontrib><creatorcontrib>Sands, Steven B</creatorcontrib><creatorcontrib>Segelstein, Barbara E</creatorcontrib><creatorcontrib>Volberg, Walter</creatorcontrib><creatorcontrib>White, W. Frost</creatorcontrib><creatorcontrib>Zhao, Dayao</creatorcontrib><title>(3R,4S)-3-[4-(4-Fluorophenyl)-4-hydroxypiperidin-1-yl]chroman-4,7-diol: A Conformationally Restricted Analogue of the NR2B Subtype-Selective NMDA Antagonist (1S,2S)-1-(4-Hydroxyphenyl)-2- (4-hydroxy-4-phenylpiperidino)-1-propanol</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>(1S,2S)-1-(4-Hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol (CP-101,606, 1) is a recently described antagonist of N-methyl-d-aspartate (NMDA) receptors containing the NR2B subunit. In the present study, the optimal orientation of compounds of this structural type for their receptor was explored. Tethering of the pendent methyl group of 1 to the phenolic aromatic ring via an oxygen atom prevents rotation about the central portion of the molecule. Several of the new chromanol compounds have high affinity for the racemic [3H]CP-101,606 binding site on the NMDA receptor and protect against glutamate toxicity in cultured hippocampal neurons. The new ring caused a change in the stereochemical preference of the receptorcis (erythro) compounds had better affinity for the receptor than the trans isomers. Computational studies suggest that steric interactions between the pendent methyl group and the phenol ring in the acyclic series determine which structures can best fit the receptor. The chromanol analogue, (3R,4S)-3-[4-(4-fluorophenyl)-4-hydroxypiperidin-1-yl]chroman-4,7-diol (12a, CP-283,097), was found to possess potency and selectivity comparable to CP-101,606. Thus 12a is a new tool to explore the function of the NR2B-containing NMDA receptors.</description><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Chromans - chemical synthesis</subject><subject>Chromans - pharmacology</subject><subject>Dose-Response Relationship, Drug</subject><subject>Glutamatergic system (aspartate and other excitatory aminoacids)</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Models, Molecular</subject><subject>Neuropharmacology</subject><subject>Neurotransmitters. Neurotransmission. Receptors</subject><subject>Pharmacology. Drug treatments</subject><subject>Piperidines - chemical synthesis</subject><subject>Piperidines - pharmacology</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors</subject><subject>Structure-Activity Relationship</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1998</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkcuO0zAUhi0EGsrAggdAygKkVqrBtyQ1u06ZC1K5qBlWCEUnjjNNSeLITtBkN1tekxWPgatGWbGyfM5nn8_-EXpJyVtKGH13qGVMYrmKHqEZDRnBYkXEYzQjhDHMIsafomfOHQghnDJ-hs5kKASj8Qz9nfPdUiQLzPF3gecCX1W9sabd62aoFljg_ZBbcz-0ZattmZcNpniofqi9NTU0WCxjnJemev_n4XewDjamKYytoStNA1U1BDvtOluqTufB2lfMXa8DUwTdXgefd-wiSPqsG1qNE11p1ZW_fPnTh7VnO7gzTem6YE6TJfN-9Ch3M8qMdgwH88nQu57qk6o5nmr9Y6Ax1XP0pIDK6Rfjeo6-XV3ebm7w9sv1x816i4ET2eFMZkAiiJWCKIMcKAUhBVCWSyJ0yMNI6VURK638RoaKghQszsKwoBElEefnaHG6V1njnNVF2tqyBjuklKTHsNIpLM--OrFtn9U6n8gxHd9_PfbBKagKC40q3YQxRmQUHkfiE-b_S99PbbA_0yjmcZjefk3S7eaC77b0OpWef3PiQbn0YHrrk3H_0fsHVv-20w</recordid><startdate>19980326</startdate><enddate>19980326</enddate><creator>Butler, Todd W</creator><creator>Blake, James F</creator><creator>Bordner, Jon</creator><creator>Butler, Paul</creator><creator>Chenard, Bertrand L</creator><creator>Collins, Mary A</creator><creator>DeCosta, Debra</creator><creator>Ducat, Mary J</creator><creator>Eisenhard, Michael E</creator><creator>Menniti, Frank S</creator><creator>Pagnozzi, Martin J</creator><creator>Sands, Steven B</creator><creator>Segelstein, Barbara E</creator><creator>Volberg, Walter</creator><creator>White, W. Frost</creator><creator>Zhao, Dayao</creator><general>American Chemical Society</general><scope>BSCLL</scope><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope></search><sort><creationdate>19980326</creationdate><title>(3R,4S)-3-[4-(4-Fluorophenyl)-4-hydroxypiperidin-1-yl]chroman-4,7-diol: A Conformationally Restricted Analogue of the NR2B Subtype-Selective NMDA Antagonist (1S,2S)-1-(4-Hydroxyphenyl)-2- (4-hydroxy-4-phenylpiperidino)-1-propanol</title><author>Butler, Todd W ; Blake, James F ; Bordner, Jon ; Butler, Paul ; Chenard, Bertrand L ; Collins, Mary A ; DeCosta, Debra ; Ducat, Mary J ; Eisenhard, Michael E ; Menniti, Frank S ; Pagnozzi, Martin J ; Sands, Steven B ; Segelstein, Barbara E ; Volberg, Walter ; White, W. Frost ; Zhao, Dayao</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a309t-b9ba06a7cca6bada11a494a12d904e5356ce8f7cece5395c1a9427b55f1610633</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1998</creationdate><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Chromans - chemical synthesis</topic><topic>Chromans - pharmacology</topic><topic>Dose-Response Relationship, Drug</topic><topic>Glutamatergic system (aspartate and other excitatory aminoacids)</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Models, Molecular</topic><topic>Neuropharmacology</topic><topic>Neurotransmitters. Neurotransmission. Receptors</topic><topic>Pharmacology. Drug treatments</topic><topic>Piperidines - chemical synthesis</topic><topic>Piperidines - pharmacology</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Butler, Todd W</creatorcontrib><creatorcontrib>Blake, James F</creatorcontrib><creatorcontrib>Bordner, Jon</creatorcontrib><creatorcontrib>Butler, Paul</creatorcontrib><creatorcontrib>Chenard, Bertrand L</creatorcontrib><creatorcontrib>Collins, Mary A</creatorcontrib><creatorcontrib>DeCosta, Debra</creatorcontrib><creatorcontrib>Ducat, Mary J</creatorcontrib><creatorcontrib>Eisenhard, Michael E</creatorcontrib><creatorcontrib>Menniti, Frank S</creatorcontrib><creatorcontrib>Pagnozzi, Martin J</creatorcontrib><creatorcontrib>Sands, Steven B</creatorcontrib><creatorcontrib>Segelstein, Barbara E</creatorcontrib><creatorcontrib>Volberg, Walter</creatorcontrib><creatorcontrib>White, W. Frost</creatorcontrib><creatorcontrib>Zhao, Dayao</creatorcontrib><collection>Istex</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Butler, Todd W</au><au>Blake, James F</au><au>Bordner, Jon</au><au>Butler, Paul</au><au>Chenard, Bertrand L</au><au>Collins, Mary A</au><au>DeCosta, Debra</au><au>Ducat, Mary J</au><au>Eisenhard, Michael E</au><au>Menniti, Frank S</au><au>Pagnozzi, Martin J</au><au>Sands, Steven B</au><au>Segelstein, Barbara E</au><au>Volberg, Walter</au><au>White, W. Frost</au><au>Zhao, Dayao</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>(3R,4S)-3-[4-(4-Fluorophenyl)-4-hydroxypiperidin-1-yl]chroman-4,7-diol: A Conformationally Restricted Analogue of the NR2B Subtype-Selective NMDA Antagonist (1S,2S)-1-(4-Hydroxyphenyl)-2- (4-hydroxy-4-phenylpiperidino)-1-propanol</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>1998-03-26</date><risdate>1998</risdate><volume>41</volume><issue>7</issue><spage>1172</spage><epage>1184</epage><pages>1172-1184</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>(1S,2S)-1-(4-Hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol (CP-101,606, 1) is a recently described antagonist of N-methyl-d-aspartate (NMDA) receptors containing the NR2B subunit. In the present study, the optimal orientation of compounds of this structural type for their receptor was explored. Tethering of the pendent methyl group of 1 to the phenolic aromatic ring via an oxygen atom prevents rotation about the central portion of the molecule. Several of the new chromanol compounds have high affinity for the racemic [3H]CP-101,606 binding site on the NMDA receptor and protect against glutamate toxicity in cultured hippocampal neurons. The new ring caused a change in the stereochemical preference of the receptorcis (erythro) compounds had better affinity for the receptor than the trans isomers. Computational studies suggest that steric interactions between the pendent methyl group and the phenol ring in the acyclic series determine which structures can best fit the receptor. The chromanol analogue, (3R,4S)-3-[4-(4-fluorophenyl)-4-hydroxypiperidin-1-yl]chroman-4,7-diol (12a, CP-283,097), was found to possess potency and selectivity comparable to CP-101,606. Thus 12a is a new tool to explore the function of the NR2B-containing NMDA receptors.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>9544217</pmid><doi>10.1021/jm9707986</doi><tpages>13</tpages></addata></record> |
| fulltext | fulltext |
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| ispartof | Journal of medicinal chemistry, 1998-03, Vol.41 (7), p.1172-1184 |
| issn | 0022-2623 1520-4804 |
| language | eng |
| recordid | cdi_crossref_primary_10_1021_jm9707986 |
| source | MEDLINE; ACS Publications |
| subjects | Animals Biological and medical sciences Chromans - chemical synthesis Chromans - pharmacology Dose-Response Relationship, Drug Glutamatergic system (aspartate and other excitatory aminoacids) Male Medical sciences Models, Molecular Neuropharmacology Neurotransmitters. Neurotransmission. Receptors Pharmacology. Drug treatments Piperidines - chemical synthesis Piperidines - pharmacology Rats Rats, Sprague-Dawley Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors Structure-Activity Relationship |
| title | (3R,4S)-3-[4-(4-Fluorophenyl)-4-hydroxypiperidin-1-yl]chroman-4,7-diol: A Conformationally Restricted Analogue of the NR2B Subtype-Selective NMDA Antagonist (1S,2S)-1-(4-Hydroxyphenyl)-2- (4-hydroxy-4-phenylpiperidino)-1-propanol |
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