Calcium Entry Blockers and Activators: Conformational and Structural Determinants of Dihydropyrimidine Calcium Channel Modulators
Dihydropyrimidines 4, 6, and 15, uniquely designed to unambiguously establish structural and conformational determinants for DHP receptor occupation and for modulation of calcium channel function, were prepared and examined for calcium channel modulation. Our results confirm and firmly establish a p...
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| Veröffentlicht in: | Journal of medicinal chemistry 1995-01, Vol.38 (1), p.119-129 |
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| container_title | Journal of medicinal chemistry |
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| creator | Rovnyak, George C Kimball, S. David Beyer, Barbara Cucinotta, Gabriella DiMarco, John D Gougoutas, Jack Hedberg, Anders Malley, Mary McCarthy, James P |
| description | Dihydropyrimidines 4, 6, and 15, uniquely designed to unambiguously establish structural and conformational determinants for DHP receptor occupation and for modulation of calcium channel function, were prepared and examined for calcium channel modulation. Our results confirm and firmly establish a preference for syn-orientation of an unsymmetrically substituted aryl moiety at the DHP receptor (15d vs 15e). We propose a normal vs capsized DHP boat model to explain structural and conformational requirements for modulation of calcium channel function that requires an obligatory left-hand side alkoxy cis-carbonyl interaction for maximal DHP receptor affinity, the effect of channel function being determined by orientation of the 4-aryl group. Enantiomers having an up-oriented pseudoaxial aryl group (normal DHP boat) will elicit calcium antagonist activity, whereas enantiomers having a down-oriented pseudoaxial aryl group (capsized DHP boat) will elicit calcium agonist activity. Single enantiomers of macrocyclic lactone 15b demonstrate opposite channel activity. Antagonist activity resides in enantiomer 15b-A (S-configuration, left-hand side alkoxy cis-carbonyl with up-oriented pseudoaxial aryl group and normal DHP boat), whereas agonist activity resides in enantiomer 15b-B (R-configuration, left-hand side alkoxy cis-carbonyl with down-oriented pseudoaxial aryl group and capsized DHP boat). Moreover, this model is consistent with and provides a rational explanation of previous literature in this area, most notably the observation of chiral inversion and potency diminution upon replacement of ester by hydrogen in the Bay K 8644 series. |
| doi_str_mv | 10.1021/jm00001a017 |
| format | Article |
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David ; Beyer, Barbara ; Cucinotta, Gabriella ; DiMarco, John D ; Gougoutas, Jack ; Hedberg, Anders ; Malley, Mary ; McCarthy, James P</creator><creatorcontrib>Rovnyak, George C ; Kimball, S. David ; Beyer, Barbara ; Cucinotta, Gabriella ; DiMarco, John D ; Gougoutas, Jack ; Hedberg, Anders ; Malley, Mary ; McCarthy, James P</creatorcontrib><description>Dihydropyrimidines 4, 6, and 15, uniquely designed to unambiguously establish structural and conformational determinants for DHP receptor occupation and for modulation of calcium channel function, were prepared and examined for calcium channel modulation. Our results confirm and firmly establish a preference for syn-orientation of an unsymmetrically substituted aryl moiety at the DHP receptor (15d vs 15e). We propose a normal vs capsized DHP boat model to explain structural and conformational requirements for modulation of calcium channel function that requires an obligatory left-hand side alkoxy cis-carbonyl interaction for maximal DHP receptor affinity, the effect of channel function being determined by orientation of the 4-aryl group. Enantiomers having an up-oriented pseudoaxial aryl group (normal DHP boat) will elicit calcium antagonist activity, whereas enantiomers having a down-oriented pseudoaxial aryl group (capsized DHP boat) will elicit calcium agonist activity. Single enantiomers of macrocyclic lactone 15b demonstrate opposite channel activity. Antagonist activity resides in enantiomer 15b-A (S-configuration, left-hand side alkoxy cis-carbonyl with up-oriented pseudoaxial aryl group and normal DHP boat), whereas agonist activity resides in enantiomer 15b-B (R-configuration, left-hand side alkoxy cis-carbonyl with down-oriented pseudoaxial aryl group and capsized DHP boat). Moreover, this model is consistent with and provides a rational explanation of previous literature in this area, most notably the observation of chiral inversion and potency diminution upon replacement of ester by hydrogen in the Bay K 8644 series.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm00001a017</identifier><identifier>PMID: 7837222</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Animals ; Biological and medical sciences ; Calcium Channel Agonists - chemical synthesis ; Calcium Channel Agonists - chemistry ; Calcium Channel Agonists - pharmacology ; Calcium Channel Blockers - chemical synthesis ; Calcium Channel Blockers - chemistry ; Calcium Channel Blockers - pharmacology ; Cardiovascular system ; Dihydropyridines - chemical synthesis ; Dihydropyridines - chemistry ; Dihydropyridines - pharmacology ; Esters - chemical synthesis ; Esters - chemistry ; Esters - pharmacology ; In Vitro Techniques ; Male ; Medical sciences ; Models, Molecular ; Molecular Conformation ; Pharmacology. Drug treatments ; Rabbits ; Stereoisomerism ; Structure-Activity Relationship ; Vasodilator agents. Cerebral vasodilators</subject><ispartof>Journal of medicinal chemistry, 1995-01, Vol.38 (1), p.119-129</ispartof><rights>1995 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a449t-7e740b3b388f1416194862436248ca4ef1eab34588a25eb4b683500b94c9d0bb3</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/jm00001a017$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm00001a017$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,2752,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=3394018$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/7837222$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Rovnyak, George C</creatorcontrib><creatorcontrib>Kimball, S. David</creatorcontrib><creatorcontrib>Beyer, Barbara</creatorcontrib><creatorcontrib>Cucinotta, Gabriella</creatorcontrib><creatorcontrib>DiMarco, John D</creatorcontrib><creatorcontrib>Gougoutas, Jack</creatorcontrib><creatorcontrib>Hedberg, Anders</creatorcontrib><creatorcontrib>Malley, Mary</creatorcontrib><creatorcontrib>McCarthy, James P</creatorcontrib><title>Calcium Entry Blockers and Activators: Conformational and Structural Determinants of Dihydropyrimidine Calcium Channel Modulators</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Dihydropyrimidines 4, 6, and 15, uniquely designed to unambiguously establish structural and conformational determinants for DHP receptor occupation and for modulation of calcium channel function, were prepared and examined for calcium channel modulation. Our results confirm and firmly establish a preference for syn-orientation of an unsymmetrically substituted aryl moiety at the DHP receptor (15d vs 15e). We propose a normal vs capsized DHP boat model to explain structural and conformational requirements for modulation of calcium channel function that requires an obligatory left-hand side alkoxy cis-carbonyl interaction for maximal DHP receptor affinity, the effect of channel function being determined by orientation of the 4-aryl group. Enantiomers having an up-oriented pseudoaxial aryl group (normal DHP boat) will elicit calcium antagonist activity, whereas enantiomers having a down-oriented pseudoaxial aryl group (capsized DHP boat) will elicit calcium agonist activity. Single enantiomers of macrocyclic lactone 15b demonstrate opposite channel activity. Antagonist activity resides in enantiomer 15b-A (S-configuration, left-hand side alkoxy cis-carbonyl with up-oriented pseudoaxial aryl group and normal DHP boat), whereas agonist activity resides in enantiomer 15b-B (R-configuration, left-hand side alkoxy cis-carbonyl with down-oriented pseudoaxial aryl group and capsized DHP boat). Moreover, this model is consistent with and provides a rational explanation of previous literature in this area, most notably the observation of chiral inversion and potency diminution upon replacement of ester by hydrogen in the Bay K 8644 series.</description><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Calcium Channel Agonists - chemical synthesis</subject><subject>Calcium Channel Agonists - chemistry</subject><subject>Calcium Channel Agonists - pharmacology</subject><subject>Calcium Channel Blockers - chemical synthesis</subject><subject>Calcium Channel Blockers - chemistry</subject><subject>Calcium Channel Blockers - pharmacology</subject><subject>Cardiovascular system</subject><subject>Dihydropyridines - chemical synthesis</subject><subject>Dihydropyridines - chemistry</subject><subject>Dihydropyridines - pharmacology</subject><subject>Esters - chemical synthesis</subject><subject>Esters - chemistry</subject><subject>Esters - pharmacology</subject><subject>In Vitro Techniques</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Models, Molecular</subject><subject>Molecular Conformation</subject><subject>Pharmacology. Drug treatments</subject><subject>Rabbits</subject><subject>Stereoisomerism</subject><subject>Structure-Activity Relationship</subject><subject>Vasodilator agents. Cerebral vasodilators</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1995</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkUtv1DAUhS0EKsPAijWSFwgWKOBXEqe7Ni0P0RGPlg0b68ZxVE8Te7AdxCz557idYcQCS1eWdT6de30uQk8peU0Jo2_WE8mHAqH1PbSgJSOFkETcRwtCGCtYxfhD9CjGdaY4ZfwIHdWS14yxBfrdwqjtPOFzl8IWn45e35gQMbgen-hkf0LyIR7j1rvBhwmS9Q7GO_kyhVmnOeTnmUkmTNaBSxH7AZ_Z620f_GYb7GR76wz-26a9BufMiFe-n8c778fowQBjNE_29xJ9e3t-1b4vLj69-9CeXBQgRJOK2tSCdLzjUg5U0Io2QlZM8FxSgzADNdBxUUoJrDSd6CrJS0K6RuimJ13Hl-jFzncT_I_ZxKQmG7UZR3DGz1HVNeUlzQkt0asdqIOPMZhBbfI3IGwVJeo2cPVP4Jl-tredu8n0B3afcNaf73WIGsYhgNM2HjDOG0GozFixw2xM5tdBhnCjqprXpbr6fKm-su-rj6dfVup2yJc7HnRUaz-HvJX43wH_ACbvpNw</recordid><startdate>19950101</startdate><enddate>19950101</enddate><creator>Rovnyak, George C</creator><creator>Kimball, S. David</creator><creator>Beyer, Barbara</creator><creator>Cucinotta, Gabriella</creator><creator>DiMarco, John D</creator><creator>Gougoutas, Jack</creator><creator>Hedberg, Anders</creator><creator>Malley, Mary</creator><creator>McCarthy, James P</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>19950101</creationdate><title>Calcium Entry Blockers and Activators: Conformational and Structural Determinants of Dihydropyrimidine Calcium Channel Modulators</title><author>Rovnyak, George C ; Kimball, S. David ; Beyer, Barbara ; Cucinotta, Gabriella ; DiMarco, John D ; Gougoutas, Jack ; Hedberg, Anders ; Malley, Mary ; McCarthy, James P</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a449t-7e740b3b388f1416194862436248ca4ef1eab34588a25eb4b683500b94c9d0bb3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1995</creationdate><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Calcium Channel Agonists - chemical synthesis</topic><topic>Calcium Channel Agonists - chemistry</topic><topic>Calcium Channel Agonists - pharmacology</topic><topic>Calcium Channel Blockers - chemical synthesis</topic><topic>Calcium Channel Blockers - chemistry</topic><topic>Calcium Channel Blockers - pharmacology</topic><topic>Cardiovascular system</topic><topic>Dihydropyridines - chemical synthesis</topic><topic>Dihydropyridines - chemistry</topic><topic>Dihydropyridines - pharmacology</topic><topic>Esters - chemical synthesis</topic><topic>Esters - chemistry</topic><topic>Esters - pharmacology</topic><topic>In Vitro Techniques</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Models, Molecular</topic><topic>Molecular Conformation</topic><topic>Pharmacology. Drug treatments</topic><topic>Rabbits</topic><topic>Stereoisomerism</topic><topic>Structure-Activity Relationship</topic><topic>Vasodilator agents. Cerebral vasodilators</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Rovnyak, George C</creatorcontrib><creatorcontrib>Kimball, S. David</creatorcontrib><creatorcontrib>Beyer, Barbara</creatorcontrib><creatorcontrib>Cucinotta, Gabriella</creatorcontrib><creatorcontrib>DiMarco, John D</creatorcontrib><creatorcontrib>Gougoutas, Jack</creatorcontrib><creatorcontrib>Hedberg, Anders</creatorcontrib><creatorcontrib>Malley, Mary</creatorcontrib><creatorcontrib>McCarthy, James P</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>Rovnyak, George C</au><au>Kimball, S. David</au><au>Beyer, Barbara</au><au>Cucinotta, Gabriella</au><au>DiMarco, John D</au><au>Gougoutas, Jack</au><au>Hedberg, Anders</au><au>Malley, Mary</au><au>McCarthy, James P</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Calcium Entry Blockers and Activators: Conformational and Structural Determinants of Dihydropyrimidine Calcium Channel Modulators</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>1995-01-01</date><risdate>1995</risdate><volume>38</volume><issue>1</issue><spage>119</spage><epage>129</epage><pages>119-129</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>Dihydropyrimidines 4, 6, and 15, uniquely designed to unambiguously establish structural and conformational determinants for DHP receptor occupation and for modulation of calcium channel function, were prepared and examined for calcium channel modulation. Our results confirm and firmly establish a preference for syn-orientation of an unsymmetrically substituted aryl moiety at the DHP receptor (15d vs 15e). We propose a normal vs capsized DHP boat model to explain structural and conformational requirements for modulation of calcium channel function that requires an obligatory left-hand side alkoxy cis-carbonyl interaction for maximal DHP receptor affinity, the effect of channel function being determined by orientation of the 4-aryl group. Enantiomers having an up-oriented pseudoaxial aryl group (normal DHP boat) will elicit calcium antagonist activity, whereas enantiomers having a down-oriented pseudoaxial aryl group (capsized DHP boat) will elicit calcium agonist activity. Single enantiomers of macrocyclic lactone 15b demonstrate opposite channel activity. Antagonist activity resides in enantiomer 15b-A (S-configuration, left-hand side alkoxy cis-carbonyl with up-oriented pseudoaxial aryl group and normal DHP boat), whereas agonist activity resides in enantiomer 15b-B (R-configuration, left-hand side alkoxy cis-carbonyl with down-oriented pseudoaxial aryl group and capsized DHP boat). Moreover, this model is consistent with and provides a rational explanation of previous literature in this area, most notably the observation of chiral inversion and potency diminution upon replacement of ester by hydrogen in the Bay K 8644 series.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>7837222</pmid><doi>10.1021/jm00001a017</doi><tpages>11</tpages></addata></record> |
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| ispartof | Journal of medicinal chemistry, 1995-01, Vol.38 (1), p.119-129 |
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| subjects | Animals Biological and medical sciences Calcium Channel Agonists - chemical synthesis Calcium Channel Agonists - chemistry Calcium Channel Agonists - pharmacology Calcium Channel Blockers - chemical synthesis Calcium Channel Blockers - chemistry Calcium Channel Blockers - pharmacology Cardiovascular system Dihydropyridines - chemical synthesis Dihydropyridines - chemistry Dihydropyridines - pharmacology Esters - chemical synthesis Esters - chemistry Esters - pharmacology In Vitro Techniques Male Medical sciences Models, Molecular Molecular Conformation Pharmacology. Drug treatments Rabbits Stereoisomerism Structure-Activity Relationship Vasodilator agents. Cerebral vasodilators |
| title | Calcium Entry Blockers and Activators: Conformational and Structural Determinants of Dihydropyrimidine Calcium Channel Modulators |
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