Synthesis and receptor affinities of some conformationally restricted analogs of the dopamine D1 selective ligand (5R)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepin-7-ol
The synthesis of a structurally novel series of 6,6a,7,8,9,13b-hexahydro-5H-benzo[d]naphtho[2,1-b]azepines (2), conformationally restricted analogues of the dopamine D1 antagonist (5R)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepin -7-ol (SCH 23390, 1c), is described. Affinity for D1...
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| Veröffentlicht in: | Journal of medicinal chemistry 1989-08, Vol.32 (8), p.1913-1921 |
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| container_end_page | 1921 |
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| container_issue | 8 |
| container_start_page | 1913 |
| container_title | Journal of medicinal chemistry |
| container_volume | 32 |
| creator | Berger, Joel G Chang, Wei K Clader, John W Hou, Donald Chipkin, Richard E McPhail, Andrew T |
| description | The synthesis of a structurally novel series of 6,6a,7,8,9,13b-hexahydro-5H-benzo[d]naphtho[2,1-b]azepines (2), conformationally restricted analogues of the dopamine D1 antagonist (5R)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepin -7-ol (SCH 23390, 1c), is described. Affinity for D1 receptors was determined by competition for rat striatal binding sites labeled by [3H]SCH 23390; affinity for D2 receptors was similarly determined by competition experiments using [3H]spiperone. Compounds in this series having the B/C-trans ring junction (2b and related analogues), where the D ring is unequivocally fixed in an equatorial orientation, possess considerably more D1 receptor affinity and selectivity vs the D2 receptor than the conformationally mobile cis stereoisomers (2a), thus leading to the conclusion that axial substituents at the 4- or 5-positions of the benzazepine nucleus are detrimental to D1 receptor affinity. Resolution and X-ray analysis demonstrated that D1 receptor affinity was preferentially associated with the (-)-6aS,13bR enantiomer of 2b. |
| doi_str_mv | 10.1021/jm00128a038 |
| format | Article |
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Affinity for D1 receptors was determined by competition for rat striatal binding sites labeled by [3H]SCH 23390; affinity for D2 receptors was similarly determined by competition experiments using [3H]spiperone. Compounds in this series having the B/C-trans ring junction (2b and related analogues), where the D ring is unequivocally fixed in an equatorial orientation, possess considerably more D1 receptor affinity and selectivity vs the D2 receptor than the conformationally mobile cis stereoisomers (2a), thus leading to the conclusion that axial substituents at the 4- or 5-positions of the benzazepine nucleus are detrimental to D1 receptor affinity. Resolution and X-ray analysis demonstrated that D1 receptor affinity was preferentially associated with the (-)-6aS,13bR enantiomer of 2b.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm00128a038</identifier><identifier>PMID: 2666667</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Animals ; Benzazepines - chemical synthesis ; Benzazepines - metabolism ; Benzazepines - pharmacology ; Binding, Competitive ; Chemical Phenomena ; Chemistry ; Dopamine Antagonists ; Exact sciences and technology ; Heterocyclic compounds ; Heterocyclic compounds with only one n hetero atom and condensed derivatives ; In Vitro Techniques ; Male ; Models, Molecular ; Molecular Conformation ; Organic chemistry ; Preparations and properties ; Rats ; Rats, Inbred Strains ; Receptors, Dopamine - drug effects ; Receptors, Dopamine - metabolism ; Stereoisomerism ; Structure-Activity Relationship</subject><ispartof>Journal of medicinal chemistry, 1989-08, Vol.32 (8), p.1913-1921</ispartof><rights>1991 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a316t-dae9f39731102ad697cc152a0852fb55eba5885f1242b19074b845782f13757f3</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm00128a038$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm00128a038$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>315,782,786,2769,27085,27933,27934,56747,56797</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=19476947$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/2666667$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Berger, Joel G</creatorcontrib><creatorcontrib>Chang, Wei K</creatorcontrib><creatorcontrib>Clader, John W</creatorcontrib><creatorcontrib>Hou, Donald</creatorcontrib><creatorcontrib>Chipkin, Richard E</creatorcontrib><creatorcontrib>McPhail, Andrew T</creatorcontrib><title>Synthesis and receptor affinities of some conformationally restricted analogs of the dopamine D1 selective ligand (5R)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepin-7-ol</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>The synthesis of a structurally novel series of 6,6a,7,8,9,13b-hexahydro-5H-benzo[d]naphtho[2,1-b]azepines (2), conformationally restricted analogues of the dopamine D1 antagonist (5R)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepin -7-ol (SCH 23390, 1c), is described. Affinity for D1 receptors was determined by competition for rat striatal binding sites labeled by [3H]SCH 23390; affinity for D2 receptors was similarly determined by competition experiments using [3H]spiperone. Compounds in this series having the B/C-trans ring junction (2b and related analogues), where the D ring is unequivocally fixed in an equatorial orientation, possess considerably more D1 receptor affinity and selectivity vs the D2 receptor than the conformationally mobile cis stereoisomers (2a), thus leading to the conclusion that axial substituents at the 4- or 5-positions of the benzazepine nucleus are detrimental to D1 receptor affinity. Resolution and X-ray analysis demonstrated that D1 receptor affinity was preferentially associated with the (-)-6aS,13bR enantiomer of 2b.</description><subject>Animals</subject><subject>Benzazepines - chemical synthesis</subject><subject>Benzazepines - metabolism</subject><subject>Benzazepines - pharmacology</subject><subject>Binding, Competitive</subject><subject>Chemical Phenomena</subject><subject>Chemistry</subject><subject>Dopamine Antagonists</subject><subject>Exact sciences and technology</subject><subject>Heterocyclic compounds</subject><subject>Heterocyclic compounds with only one n hetero atom and condensed derivatives</subject><subject>In Vitro Techniques</subject><subject>Male</subject><subject>Models, Molecular</subject><subject>Molecular Conformation</subject><subject>Organic chemistry</subject><subject>Preparations and properties</subject><subject>Rats</subject><subject>Rats, Inbred Strains</subject><subject>Receptors, Dopamine - drug effects</subject><subject>Receptors, Dopamine - metabolism</subject><subject>Stereoisomerism</subject><subject>Structure-Activity Relationship</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1989</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkUuPFCEUhStGM_aMrlyb1EZHY6M8iqJqacbHOOnEx7TRXYWiLtO0FJRAG3v-mf9O2u6MLiQhkHs-DnBPUTwg-DnBlLxYjxgT2kjMmlvFjHCKUdXg6nYxw5hSRGvK7hbHMa4xxoxQdlQc0Xo3xKz4dbl1aQXRxFK6oQygYEo-lFJr40wyEEuvy-hHKJV32odRJuOdtHab4ZiCUQmGfFZaf_WHzW7l4Cc5GgflK1JGsKCS-QGlNVe7O57wT09Rg9TK-uARnbN5NecoQQpytR1yiaER0mprEUfTClzekPNc7MFdy2uYjEMCeXuvuKOljXD_sJ4Un9-8Xp6do8X7t-_OXi6QZKROaJDQatYKRnKv5FC3QqncIokbTnXPOfSSNw3XhFa0Jy0WVd9UXDRUEya40OykeLz3nYL_vslf7kYTFVgrHfhN7ERLSNXWTQaf7UEVfIwBdDcFM8qw7QjudkF1_wSV6YcH200_wnDDHpLJ-qODLqOSVgfplIl_LdtK1HlmDu05ExP8vNFl-NZlF8G75YfLrvpy8XXxccm7i8yf7nmpYrf2m5CTi_994W854baR</recordid><startdate>19890801</startdate><enddate>19890801</enddate><creator>Berger, Joel G</creator><creator>Chang, Wei K</creator><creator>Clader, John W</creator><creator>Hou, Donald</creator><creator>Chipkin, Richard E</creator><creator>McPhail, Andrew T</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><scope>7X8</scope></search><sort><creationdate>19890801</creationdate><title>Synthesis and receptor affinities of some conformationally restricted analogs of the dopamine D1 selective ligand (5R)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepin-7-ol</title><author>Berger, Joel G ; Chang, Wei K ; Clader, John W ; Hou, Donald ; Chipkin, Richard E ; McPhail, Andrew T</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a316t-dae9f39731102ad697cc152a0852fb55eba5885f1242b19074b845782f13757f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1989</creationdate><topic>Animals</topic><topic>Benzazepines - chemical synthesis</topic><topic>Benzazepines - metabolism</topic><topic>Benzazepines - pharmacology</topic><topic>Binding, Competitive</topic><topic>Chemical Phenomena</topic><topic>Chemistry</topic><topic>Dopamine Antagonists</topic><topic>Exact sciences and technology</topic><topic>Heterocyclic compounds</topic><topic>Heterocyclic compounds with only one n hetero atom and condensed derivatives</topic><topic>In Vitro Techniques</topic><topic>Male</topic><topic>Models, Molecular</topic><topic>Molecular Conformation</topic><topic>Organic chemistry</topic><topic>Preparations and properties</topic><topic>Rats</topic><topic>Rats, Inbred Strains</topic><topic>Receptors, Dopamine - drug effects</topic><topic>Receptors, Dopamine - metabolism</topic><topic>Stereoisomerism</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Berger, Joel G</creatorcontrib><creatorcontrib>Chang, Wei K</creatorcontrib><creatorcontrib>Clader, John W</creatorcontrib><creatorcontrib>Hou, Donald</creatorcontrib><creatorcontrib>Chipkin, Richard E</creatorcontrib><creatorcontrib>McPhail, Andrew T</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><collection>MEDLINE - Academic</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Berger, Joel G</au><au>Chang, Wei K</au><au>Clader, John W</au><au>Hou, Donald</au><au>Chipkin, Richard E</au><au>McPhail, Andrew T</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis and receptor affinities of some conformationally restricted analogs of the dopamine D1 selective ligand (5R)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepin-7-ol</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>1989-08-01</date><risdate>1989</risdate><volume>32</volume><issue>8</issue><spage>1913</spage><epage>1921</epage><pages>1913-1921</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>The synthesis of a structurally novel series of 6,6a,7,8,9,13b-hexahydro-5H-benzo[d]naphtho[2,1-b]azepines (2), conformationally restricted analogues of the dopamine D1 antagonist (5R)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepin -7-ol (SCH 23390, 1c), is described. Affinity for D1 receptors was determined by competition for rat striatal binding sites labeled by [3H]SCH 23390; affinity for D2 receptors was similarly determined by competition experiments using [3H]spiperone. Compounds in this series having the B/C-trans ring junction (2b and related analogues), where the D ring is unequivocally fixed in an equatorial orientation, possess considerably more D1 receptor affinity and selectivity vs the D2 receptor than the conformationally mobile cis stereoisomers (2a), thus leading to the conclusion that axial substituents at the 4- or 5-positions of the benzazepine nucleus are detrimental to D1 receptor affinity. Resolution and X-ray analysis demonstrated that D1 receptor affinity was preferentially associated with the (-)-6aS,13bR enantiomer of 2b.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>2666667</pmid><doi>10.1021/jm00128a038</doi><tpages>9</tpages></addata></record> |
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| ispartof | Journal of medicinal chemistry, 1989-08, Vol.32 (8), p.1913-1921 |
| issn | 0022-2623 1520-4804 |
| language | eng |
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| source | MEDLINE; ACS Publications |
| subjects | Animals Benzazepines - chemical synthesis Benzazepines - metabolism Benzazepines - pharmacology Binding, Competitive Chemical Phenomena Chemistry Dopamine Antagonists Exact sciences and technology Heterocyclic compounds Heterocyclic compounds with only one n hetero atom and condensed derivatives In Vitro Techniques Male Models, Molecular Molecular Conformation Organic chemistry Preparations and properties Rats Rats, Inbred Strains Receptors, Dopamine - drug effects Receptors, Dopamine - metabolism Stereoisomerism Structure-Activity Relationship |
| title | Synthesis and receptor affinities of some conformationally restricted analogs of the dopamine D1 selective ligand (5R)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepin-7-ol |
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