Comparative Molecular Field Analysis-Based Prediction of Drug Affinities at Recombinant D1A Dopamine Receptors
Determination of quantitative structure−activity relationships (QSAR) for affinity at particular dopamine (DA) receptors has become an even greater priority with the cloning of five DA receptor subtypes. The use of agonist affinity at recombinant receptors selectively expressed in clonal cells as th...
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Veröffentlicht in: | Journal of medicinal chemistry 1996-02, Vol.39 (4), p.850-859 |
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description | Determination of quantitative structure−activity relationships (QSAR) for affinity at particular dopamine (DA) receptors has become an even greater priority with the cloning of five DA receptor subtypes. The use of agonist affinity at recombinant receptors selectively expressed in clonal cells as the dependent variable in QSAR presents a unique opportunity for accuracy and precision in measurement of biological values. Bound conformations of 11 agonists (for which both affinity data at the recombinant D1A DA receptor and stereochemical configurations were available) were determined by alignment with a template compound, SKF38393, which shows high affinity and selectivity for D1A receptors and is fairly rigid in structure. These aligned structures suggested a 3-point pharmacophore map (one cationic nitrogen and two electronegative centers) of the D1A DA receptor. This map shows both similarities and differences when compared with a previously reported D2 DA receptor pharmacophore map based on biological data from rat brain and with a recently published map of the native D1 DA receptor using several semirigid compounds. Log(1/K d) values at recombinant D1A DA receptors were used as the target property for a CoMFA (comparative molecular field analysis) of the 11 aligned structures. The resulting CoMFA model yielded a cross-validated r 2 (q 2) value of 0.829 and a simple r 2 = 0.96. In contrast, when a CoMFA model was developed for 10 of these compounds using striatal D1 K d values, the q 2 value was reduced to 0.178. These results are consistent with the idea that drug affinity data obtained from clonal cells expressing recombinant receptors may be superior to that obtained using heterogeneous mixtures of native receptors prepared from brain membranes. The predictive utility of the CoMFA model was evaluated using several high-affinity dopamine agonists and m- and p-tyramine, two compounds with a single hydroxyl group on the aromatic ring. Predictions were fairly accurate for all compounds but the two tyramines. |
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The use of agonist affinity at recombinant receptors selectively expressed in clonal cells as the dependent variable in QSAR presents a unique opportunity for accuracy and precision in measurement of biological values. Bound conformations of 11 agonists (for which both affinity data at the recombinant D1A DA receptor and stereochemical configurations were available) were determined by alignment with a template compound, SKF38393, which shows high affinity and selectivity for D1A receptors and is fairly rigid in structure. These aligned structures suggested a 3-point pharmacophore map (one cationic nitrogen and two electronegative centers) of the D1A DA receptor. This map shows both similarities and differences when compared with a previously reported D2 DA receptor pharmacophore map based on biological data from rat brain and with a recently published map of the native D1 DA receptor using several semirigid compounds. Log(1/K d) values at recombinant D1A DA receptors were used as the target property for a CoMFA (comparative molecular field analysis) of the 11 aligned structures. The resulting CoMFA model yielded a cross-validated r 2 (q 2) value of 0.829 and a simple r 2 = 0.96. In contrast, when a CoMFA model was developed for 10 of these compounds using striatal D1 K d values, the q 2 value was reduced to 0.178. These results are consistent with the idea that drug affinity data obtained from clonal cells expressing recombinant receptors may be superior to that obtained using heterogeneous mixtures of native receptors prepared from brain membranes. The predictive utility of the CoMFA model was evaluated using several high-affinity dopamine agonists and m- and p-tyramine, two compounds with a single hydroxyl group on the aromatic ring. Predictions were fairly accurate for all compounds but the two tyramines.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm950447w</identifier><identifier>PMID: 8632409</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Animals ; Cell Line ; Cercopithecus aethiops ; Computer Graphics ; Dopamine - analogs & derivatives ; Dopamine - chemistry ; Dopamine - metabolism ; Dopamine Agonists - chemistry ; Dopamine Agonists - metabolism ; Glioma ; Humans ; Kinetics ; Models, Molecular ; Receptors, Dopamine D1 - metabolism ; Recombinant Proteins - metabolism ; Structure-Activity Relationship ; Tumor Cells, Cultured</subject><ispartof>Journal of medicinal chemistry, 1996-02, Vol.39 (4), p.850-859</ispartof><rights>Copyright © 1996 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a348t-71717b469ba5603500c645ef21a9bbfba0258a70d5b9d36c2e406400d45f6ffa3</citedby><cites>FETCH-LOGICAL-a348t-71717b469ba5603500c645ef21a9bbfba0258a70d5b9d36c2e406400d45f6ffa3</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/jm950447w$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm950447w$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,777,781,2752,27057,27905,27906,56719,56769</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/8632409$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Brusniak, Mi-Youn Kim</creatorcontrib><creatorcontrib>Pearlman, Robert S</creatorcontrib><creatorcontrib>Neve, Kim A</creatorcontrib><creatorcontrib>Wilcox, Richard E</creatorcontrib><title>Comparative Molecular Field Analysis-Based Prediction of Drug Affinities at Recombinant D1A Dopamine Receptors</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Determination of quantitative structure−activity relationships (QSAR) for affinity at particular dopamine (DA) receptors has become an even greater priority with the cloning of five DA receptor subtypes. The use of agonist affinity at recombinant receptors selectively expressed in clonal cells as the dependent variable in QSAR presents a unique opportunity for accuracy and precision in measurement of biological values. Bound conformations of 11 agonists (for which both affinity data at the recombinant D1A DA receptor and stereochemical configurations were available) were determined by alignment with a template compound, SKF38393, which shows high affinity and selectivity for D1A receptors and is fairly rigid in structure. These aligned structures suggested a 3-point pharmacophore map (one cationic nitrogen and two electronegative centers) of the D1A DA receptor. This map shows both similarities and differences when compared with a previously reported D2 DA receptor pharmacophore map based on biological data from rat brain and with a recently published map of the native D1 DA receptor using several semirigid compounds. Log(1/K d) values at recombinant D1A DA receptors were used as the target property for a CoMFA (comparative molecular field analysis) of the 11 aligned structures. The resulting CoMFA model yielded a cross-validated r 2 (q 2) value of 0.829 and a simple r 2 = 0.96. In contrast, when a CoMFA model was developed for 10 of these compounds using striatal D1 K d values, the q 2 value was reduced to 0.178. These results are consistent with the idea that drug affinity data obtained from clonal cells expressing recombinant receptors may be superior to that obtained using heterogeneous mixtures of native receptors prepared from brain membranes. The predictive utility of the CoMFA model was evaluated using several high-affinity dopamine agonists and m- and p-tyramine, two compounds with a single hydroxyl group on the aromatic ring. Predictions were fairly accurate for all compounds but the two tyramines.</description><subject>Animals</subject><subject>Cell Line</subject><subject>Cercopithecus aethiops</subject><subject>Computer Graphics</subject><subject>Dopamine - analogs & derivatives</subject><subject>Dopamine - chemistry</subject><subject>Dopamine - metabolism</subject><subject>Dopamine Agonists - chemistry</subject><subject>Dopamine Agonists - metabolism</subject><subject>Glioma</subject><subject>Humans</subject><subject>Kinetics</subject><subject>Models, Molecular</subject><subject>Receptors, Dopamine D1 - metabolism</subject><subject>Recombinant Proteins - metabolism</subject><subject>Structure-Activity Relationship</subject><subject>Tumor Cells, Cultured</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1996</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkE1v1DAQhi1EVZbCgR-A5AtIHALjzyTH7S6llYootFy4WJPERl6SONgOpf-eVLvaE5rDHN5n3pEeQl4xeM-Asw-7oVYgZXn_hKyY4lDICuRTsgLgvOCai2fkeUo7ABCMi1NyWmnBJdQrMm7CMGHE7P9Y-jn0tp17jPTC276j6xH7h-RTcY7JdvQm2s632YeRBke3cf5J18750WdvE8VMv9k2DI0fccx0y9Z0GyYc_GgfAzvlENMLcuKwT_blYZ-R7xcf7zaXxfWXT1eb9XWBQla5KNkyjdR1g0qDUACtlso6zrBuGtcgcFVhCZ1q6k7ollsJWgJ0UjntHIoz8nbfO8Xwe7Ypm8Gn1vY9jjbMyZQVLAdMLOC7PdjGkFK0zkzRDxgfDAPz6NYc3S7s60Pp3Ay2O5IHmUte7HOfsv17jDH-MroUpTJ3N7emFBv99cft1rCFf7PnsU1mF-a46E7_-fsPkL-PVQ</recordid><startdate>19960216</startdate><enddate>19960216</enddate><creator>Brusniak, Mi-Youn Kim</creator><creator>Pearlman, Robert S</creator><creator>Neve, Kim A</creator><creator>Wilcox, Richard E</creator><general>American Chemical Society</general><scope>BSCLL</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><scope>7X8</scope></search><sort><creationdate>19960216</creationdate><title>Comparative Molecular Field Analysis-Based Prediction of Drug Affinities at Recombinant D1A Dopamine Receptors</title><author>Brusniak, Mi-Youn Kim ; Pearlman, Robert S ; Neve, Kim A ; Wilcox, Richard E</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a348t-71717b469ba5603500c645ef21a9bbfba0258a70d5b9d36c2e406400d45f6ffa3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1996</creationdate><topic>Animals</topic><topic>Cell Line</topic><topic>Cercopithecus aethiops</topic><topic>Computer Graphics</topic><topic>Dopamine - analogs & derivatives</topic><topic>Dopamine - chemistry</topic><topic>Dopamine - metabolism</topic><topic>Dopamine Agonists - chemistry</topic><topic>Dopamine Agonists - metabolism</topic><topic>Glioma</topic><topic>Humans</topic><topic>Kinetics</topic><topic>Models, Molecular</topic><topic>Receptors, Dopamine D1 - metabolism</topic><topic>Recombinant Proteins - metabolism</topic><topic>Structure-Activity Relationship</topic><topic>Tumor Cells, Cultured</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Brusniak, Mi-Youn Kim</creatorcontrib><creatorcontrib>Pearlman, Robert S</creatorcontrib><creatorcontrib>Neve, Kim A</creatorcontrib><creatorcontrib>Wilcox, Richard E</creatorcontrib><collection>Istex</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Brusniak, Mi-Youn Kim</au><au>Pearlman, Robert S</au><au>Neve, Kim A</au><au>Wilcox, Richard E</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Comparative Molecular Field Analysis-Based Prediction of Drug Affinities at Recombinant D1A Dopamine Receptors</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>1996-02-16</date><risdate>1996</risdate><volume>39</volume><issue>4</issue><spage>850</spage><epage>859</epage><pages>850-859</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>Determination of quantitative structure−activity relationships (QSAR) for affinity at particular dopamine (DA) receptors has become an even greater priority with the cloning of five DA receptor subtypes. The use of agonist affinity at recombinant receptors selectively expressed in clonal cells as the dependent variable in QSAR presents a unique opportunity for accuracy and precision in measurement of biological values. Bound conformations of 11 agonists (for which both affinity data at the recombinant D1A DA receptor and stereochemical configurations were available) were determined by alignment with a template compound, SKF38393, which shows high affinity and selectivity for D1A receptors and is fairly rigid in structure. These aligned structures suggested a 3-point pharmacophore map (one cationic nitrogen and two electronegative centers) of the D1A DA receptor. This map shows both similarities and differences when compared with a previously reported D2 DA receptor pharmacophore map based on biological data from rat brain and with a recently published map of the native D1 DA receptor using several semirigid compounds. Log(1/K d) values at recombinant D1A DA receptors were used as the target property for a CoMFA (comparative molecular field analysis) of the 11 aligned structures. The resulting CoMFA model yielded a cross-validated r 2 (q 2) value of 0.829 and a simple r 2 = 0.96. In contrast, when a CoMFA model was developed for 10 of these compounds using striatal D1 K d values, the q 2 value was reduced to 0.178. These results are consistent with the idea that drug affinity data obtained from clonal cells expressing recombinant receptors may be superior to that obtained using heterogeneous mixtures of native receptors prepared from brain membranes. The predictive utility of the CoMFA model was evaluated using several high-affinity dopamine agonists and m- and p-tyramine, two compounds with a single hydroxyl group on the aromatic ring. Predictions were fairly accurate for all compounds but the two tyramines.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>8632409</pmid><doi>10.1021/jm950447w</doi><tpages>10</tpages></addata></record> |
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subjects | Animals Cell Line Cercopithecus aethiops Computer Graphics Dopamine - analogs & derivatives Dopamine - chemistry Dopamine - metabolism Dopamine Agonists - chemistry Dopamine Agonists - metabolism Glioma Humans Kinetics Models, Molecular Receptors, Dopamine D1 - metabolism Recombinant Proteins - metabolism Structure-Activity Relationship Tumor Cells, Cultured |
title | Comparative Molecular Field Analysis-Based Prediction of Drug Affinities at Recombinant D1A Dopamine Receptors |
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