Physicochemical and pharmacological studies of some 8-substituted decahydroisoquinolines
Several compounds of a diastereoisomeric series of 8-substituted 2-methyldecahydroisoquinolines have been found to be equipotent or more potent than quinidine in prolonging the refractory period of isolated guinea pig atria. The effects of selected compounds on the intracellularly recorded transmemb...
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Veröffentlicht in: | Journal of medicinal chemistry 1976-03, Vol.19 (3), p.385-391 |
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container_title | Journal of medicinal chemistry |
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creator | Mathison, Ian W. Morgan, Phillip H. Wojciechowski, Norbert J. Bandura, Jack P. Wennemark, James R. |
description | Several compounds of a diastereoisomeric series of 8-substituted 2-methyldecahydroisoquinolines have been found to be equipotent or more potent than quinidine in prolonging the refractory period of isolated guinea pig atria. The effects of selected compounds on the intracellularly recorded transmembrane action potential of isolated canine Purkinje fibers indicated a mechanism of action similar to quinidine in causing a large decrease in the rising velocity of rapid depolarization. Acid dissociation constants and percentage buccal membrane absorption have been determined, in an attempt to correlate these physiochemical properties and the stereochemistry of the derivatives with the observed antiarrhythmic potency. Compounds with high lipophilicity and the trans ring-juncture stereochemistry generally appear to possess superior potency. |
doi_str_mv | 10.1021/jm00225a009 |
format | Article |
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The effects of selected compounds on the intracellularly recorded transmembrane action potential of isolated canine Purkinje fibers indicated a mechanism of action similar to quinidine in causing a large decrease in the rising velocity of rapid depolarization. Acid dissociation constants and percentage buccal membrane absorption have been determined, in an attempt to correlate these physiochemical properties and the stereochemistry of the derivatives with the observed antiarrhythmic potency. Compounds with high lipophilicity and the trans ring-juncture stereochemistry generally appear to possess superior potency.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm00225a009</identifier><identifier>PMID: 1255662</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Absorption ; Action Potentials - drug effects ; Animals ; Cell Membrane - metabolism ; Chemical Phenomena ; Chemistry, Physical ; Dogs ; Electric Stimulation ; Guinea Pigs ; Heart Atria - drug effects ; Heart Rate - drug effects ; Humans ; In Vitro Techniques ; Isoquinolines - metabolism ; Isoquinolines - pharmacology ; Kinetics ; Membrane Potentials - drug effects ; Purkinje Fibers - drug effects ; Purkinje Fibers - physiology ; Refractory Period, Electrophysiological - drug effects ; Stereoisomerism ; Structure-Activity Relationship</subject><ispartof>Journal of medicinal chemistry, 1976-03, Vol.19 (3), p.385-391</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a354t-3350781f73cbcb5119a616bf4d1bed0f3f629d93cd51b668a5b9b3bb8c1164603</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/jm00225a009$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm00225a009$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,2752,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/1255662$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Mathison, Ian W.</creatorcontrib><creatorcontrib>Morgan, Phillip H.</creatorcontrib><creatorcontrib>Wojciechowski, Norbert J.</creatorcontrib><creatorcontrib>Bandura, Jack P.</creatorcontrib><creatorcontrib>Wennemark, James R.</creatorcontrib><title>Physicochemical and pharmacological studies of some 8-substituted decahydroisoquinolines</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Several compounds of a diastereoisomeric series of 8-substituted 2-methyldecahydroisoquinolines have been found to be equipotent or more potent than quinidine in prolonging the refractory period of isolated guinea pig atria. The effects of selected compounds on the intracellularly recorded transmembrane action potential of isolated canine Purkinje fibers indicated a mechanism of action similar to quinidine in causing a large decrease in the rising velocity of rapid depolarization. Acid dissociation constants and percentage buccal membrane absorption have been determined, in an attempt to correlate these physiochemical properties and the stereochemistry of the derivatives with the observed antiarrhythmic potency. Compounds with high lipophilicity and the trans ring-juncture stereochemistry generally appear to possess superior potency.</description><subject>Absorption</subject><subject>Action Potentials - drug effects</subject><subject>Animals</subject><subject>Cell Membrane - metabolism</subject><subject>Chemical Phenomena</subject><subject>Chemistry, Physical</subject><subject>Dogs</subject><subject>Electric Stimulation</subject><subject>Guinea Pigs</subject><subject>Heart Atria - drug effects</subject><subject>Heart Rate - drug effects</subject><subject>Humans</subject><subject>In Vitro Techniques</subject><subject>Isoquinolines - metabolism</subject><subject>Isoquinolines - pharmacology</subject><subject>Kinetics</subject><subject>Membrane Potentials - drug effects</subject><subject>Purkinje Fibers - drug effects</subject><subject>Purkinje Fibers - physiology</subject><subject>Refractory Period, Electrophysiological - drug effects</subject><subject>Stereoisomerism</subject><subject>Structure-Activity Relationship</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1976</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkEtLxDAUhYMoOj5WroWudCHVPJq0XYpvUBxwBHchrzoZ22bMbcH591Yr6sLVhXM-zoUPoX2CTwim5HTRYEwpVxiXa2hCOMVpVuBsHU0-85QKyrbQNsACY8wIZZtok1DOhaAT9Dydr8CbYOau8UbViWptspyr2CgT6vDylUHXW-8gCVUCoXFJkUKvofNd3zmbWGfUfGVj8BDeet-G2rcOdtFGpWpwe993Bz1dXc7Ob9K7h-vb87O7VDGedSljHOcFqXJmtNGckFIJInSVWaKdxRWrBC1tyYzlRAtRKK5LzbQuDCEiE5jtoMNxdxmH7w462Xgwrq5V60IPsmAsEznNBvB4BE0MANFVchl9o-JKEiw_Pco_Hgf64Hu2142zv-wobujTsffQufefWsVXKXKWczmbPsr7gs_u-dWFnA780cgrA3IR-tgOUv79_AENqopf</recordid><startdate>19760301</startdate><enddate>19760301</enddate><creator>Mathison, Ian W.</creator><creator>Morgan, Phillip H.</creator><creator>Wojciechowski, Norbert J.</creator><creator>Bandura, Jack P.</creator><creator>Wennemark, James R.</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>19760301</creationdate><title>Physicochemical and pharmacological studies of some 8-substituted decahydroisoquinolines</title><author>Mathison, Ian W. ; Morgan, Phillip H. ; Wojciechowski, Norbert J. ; Bandura, Jack P. ; Wennemark, James R.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a354t-3350781f73cbcb5119a616bf4d1bed0f3f629d93cd51b668a5b9b3bb8c1164603</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1976</creationdate><topic>Absorption</topic><topic>Action Potentials - drug effects</topic><topic>Animals</topic><topic>Cell Membrane - metabolism</topic><topic>Chemical Phenomena</topic><topic>Chemistry, Physical</topic><topic>Dogs</topic><topic>Electric Stimulation</topic><topic>Guinea Pigs</topic><topic>Heart Atria - drug effects</topic><topic>Heart Rate - drug effects</topic><topic>Humans</topic><topic>In Vitro Techniques</topic><topic>Isoquinolines - metabolism</topic><topic>Isoquinolines - pharmacology</topic><topic>Kinetics</topic><topic>Membrane Potentials - drug effects</topic><topic>Purkinje Fibers - drug effects</topic><topic>Purkinje Fibers - physiology</topic><topic>Refractory Period, Electrophysiological - drug effects</topic><topic>Stereoisomerism</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Mathison, Ian W.</creatorcontrib><creatorcontrib>Morgan, Phillip H.</creatorcontrib><creatorcontrib>Wojciechowski, Norbert J.</creatorcontrib><creatorcontrib>Bandura, Jack P.</creatorcontrib><creatorcontrib>Wennemark, James R.</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>Mathison, Ian W.</au><au>Morgan, Phillip H.</au><au>Wojciechowski, Norbert J.</au><au>Bandura, Jack P.</au><au>Wennemark, James R.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Physicochemical and pharmacological studies of some 8-substituted decahydroisoquinolines</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>1976-03-01</date><risdate>1976</risdate><volume>19</volume><issue>3</issue><spage>385</spage><epage>391</epage><pages>385-391</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>Several compounds of a diastereoisomeric series of 8-substituted 2-methyldecahydroisoquinolines have been found to be equipotent or more potent than quinidine in prolonging the refractory period of isolated guinea pig atria. The effects of selected compounds on the intracellularly recorded transmembrane action potential of isolated canine Purkinje fibers indicated a mechanism of action similar to quinidine in causing a large decrease in the rising velocity of rapid depolarization. Acid dissociation constants and percentage buccal membrane absorption have been determined, in an attempt to correlate these physiochemical properties and the stereochemistry of the derivatives with the observed antiarrhythmic potency. Compounds with high lipophilicity and the trans ring-juncture stereochemistry generally appear to possess superior potency.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>1255662</pmid><doi>10.1021/jm00225a009</doi><tpages>7</tpages></addata></record> |
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subjects | Absorption Action Potentials - drug effects Animals Cell Membrane - metabolism Chemical Phenomena Chemistry, Physical Dogs Electric Stimulation Guinea Pigs Heart Atria - drug effects Heart Rate - drug effects Humans In Vitro Techniques Isoquinolines - metabolism Isoquinolines - pharmacology Kinetics Membrane Potentials - drug effects Purkinje Fibers - drug effects Purkinje Fibers - physiology Refractory Period, Electrophysiological - drug effects Stereoisomerism Structure-Activity Relationship |
title | Physicochemical and pharmacological studies of some 8-substituted decahydroisoquinolines |
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