Phenothiazine drug metabolites: dopamine D2 receptor, alpha 1- and alpha 2-adrenoceptor binding
The in vitro binding affinities of levomepromazine, chlorpromazine, fluphenazine, perphenazine and methoxypromazine and their main metabolites to dopamine D2 receptors, alpha 1- and alpha 2-adrenoceptors in rat brain, were examined using [3H]spiperone, [3H]WB 4101 and [3H]yohimbine binding. All comp...
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Veröffentlicht in: | European journal of pharmacology 1986-06, Vol.125 (3), p.373-381 |
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container_title | European journal of pharmacology |
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creator | Hals, P A Hall, H Dahl, S G |
description | The in vitro binding affinities of levomepromazine, chlorpromazine, fluphenazine, perphenazine and methoxypromazine and their main metabolites to dopamine D2 receptors, alpha 1- and alpha 2-adrenoceptors in rat brain, were examined using [3H]spiperone, [3H]WB 4101 and [3H]yohimbine binding. All compounds had 10-500 times lower affinities to alpha 2-adrenoceptors than to dopamine D2 receptors and alpha 1-adrenoceptors. Ring-hydroxylated and N-demethylated metabolites had relative potencies for dopamine D2 receptor and alpha 1-adrenoceptor binding ranging from 20 to 70%, compared to that of the parent drugs. The ring sulphoxides of levomepromazine, chlorpromazine and perphenazine, except dextro levomepromazine sulphoxide, were virtually inactive in all binding systems. The results indicate that the metabolites having the highest binding affinities for dopamine D2 receptor and alpha 1-adrenoceptor binding may contribute significantly to the therapeutic effect and side-effects of the drugs, and should be measured together with the parent drugs in blood level-effect studies. |
doi_str_mv | 10.1016/0014-2999(86)90793-4 |
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All compounds had 10-500 times lower affinities to alpha 2-adrenoceptors than to dopamine D2 receptors and alpha 1-adrenoceptors. Ring-hydroxylated and N-demethylated metabolites had relative potencies for dopamine D2 receptor and alpha 1-adrenoceptor binding ranging from 20 to 70%, compared to that of the parent drugs. The ring sulphoxides of levomepromazine, chlorpromazine and perphenazine, except dextro levomepromazine sulphoxide, were virtually inactive in all binding systems. The results indicate that the metabolites having the highest binding affinities for dopamine D2 receptor and alpha 1-adrenoceptor binding may contribute significantly to the therapeutic effect and side-effects of the drugs, and should be measured together with the parent drugs in blood level-effect studies.</description><identifier>ISSN: 0014-2999</identifier><identifier>DOI: 10.1016/0014-2999(86)90793-4</identifier><identifier>PMID: 2874041</identifier><language>eng</language><publisher>Netherlands</publisher><subject>Animals ; Antipsychotic Agents - metabolism ; Biotransformation ; Brain - metabolism ; In Vitro Techniques ; Kinetics ; Male ; Methotrimeprazine - metabolism ; Methotrimeprazine - pharmacology ; Rats ; Rats, Inbred Strains ; Receptors, Adrenergic, alpha - metabolism ; Receptors, Dopamine - metabolism ; Receptors, Dopamine D2</subject><ispartof>European journal of pharmacology, 1986-06, Vol.125 (3), p.373-381</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/2874041$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hals, P A</creatorcontrib><creatorcontrib>Hall, H</creatorcontrib><creatorcontrib>Dahl, S G</creatorcontrib><title>Phenothiazine drug metabolites: dopamine D2 receptor, alpha 1- and alpha 2-adrenoceptor binding</title><title>European journal of pharmacology</title><addtitle>Eur J Pharmacol</addtitle><description>The in vitro binding affinities of levomepromazine, chlorpromazine, fluphenazine, perphenazine and methoxypromazine and their main metabolites to dopamine D2 receptors, alpha 1- and alpha 2-adrenoceptors in rat brain, were examined using [3H]spiperone, [3H]WB 4101 and [3H]yohimbine binding. All compounds had 10-500 times lower affinities to alpha 2-adrenoceptors than to dopamine D2 receptors and alpha 1-adrenoceptors. Ring-hydroxylated and N-demethylated metabolites had relative potencies for dopamine D2 receptor and alpha 1-adrenoceptor binding ranging from 20 to 70%, compared to that of the parent drugs. The ring sulphoxides of levomepromazine, chlorpromazine and perphenazine, except dextro levomepromazine sulphoxide, were virtually inactive in all binding systems. The results indicate that the metabolites having the highest binding affinities for dopamine D2 receptor and alpha 1-adrenoceptor binding may contribute significantly to the therapeutic effect and side-effects of the drugs, and should be measured together with the parent drugs in blood level-effect studies.</description><subject>Animals</subject><subject>Antipsychotic Agents - metabolism</subject><subject>Biotransformation</subject><subject>Brain - metabolism</subject><subject>In Vitro Techniques</subject><subject>Kinetics</subject><subject>Male</subject><subject>Methotrimeprazine - metabolism</subject><subject>Methotrimeprazine - pharmacology</subject><subject>Rats</subject><subject>Rats, Inbred Strains</subject><subject>Receptors, Adrenergic, alpha - metabolism</subject><subject>Receptors, Dopamine - metabolism</subject><subject>Receptors, Dopamine D2</subject><issn>0014-2999</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1986</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9kMtKAzEUhrNQaq2-gUJWomA090nclXqFgi50PeQ2bWRuJjMLfXorHVwd_vN_fBwOAGcE3xBM5C3GhCOqtb5U8krjQjPED8D8f30EjnP-xBgLTcUMzKgqOOZkDsq3bWi7YRvNT2wD9GncwCYMxnZ1HEK-g77rTfNX3VOYggv90KVraOp-ayBB0LR-ChQZn3auPQJtbH1sNyfgsDJ1DqfTXICPx4f31TNavz69rJZr1BOmBuSxo1pUnCjpNWay2h1HlMCecEttkNxyRyvBpS2ow5JKHgrLONXMKSckZQtwsff2qfsaQx7KJmYX6tq0oRtzWUjNlRBiB55P4Gib4Ms-xcak73L6CPsFQudgGw</recordid><startdate>19860624</startdate><enddate>19860624</enddate><creator>Hals, P A</creator><creator>Hall, H</creator><creator>Dahl, S G</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope></search><sort><creationdate>19860624</creationdate><title>Phenothiazine drug metabolites: dopamine D2 receptor, alpha 1- and alpha 2-adrenoceptor binding</title><author>Hals, P A ; Hall, H ; Dahl, S G</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-p138t-d0c295f4186d9036f0411850d14b2be64b4c2f546b72c06264e7b34293c8c5623</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1986</creationdate><topic>Animals</topic><topic>Antipsychotic Agents - metabolism</topic><topic>Biotransformation</topic><topic>Brain - metabolism</topic><topic>In Vitro Techniques</topic><topic>Kinetics</topic><topic>Male</topic><topic>Methotrimeprazine - metabolism</topic><topic>Methotrimeprazine - pharmacology</topic><topic>Rats</topic><topic>Rats, Inbred Strains</topic><topic>Receptors, Adrenergic, alpha - metabolism</topic><topic>Receptors, Dopamine - metabolism</topic><topic>Receptors, Dopamine D2</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hals, P A</creatorcontrib><creatorcontrib>Hall, H</creatorcontrib><creatorcontrib>Dahl, S G</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>MEDLINE - Academic</collection><jtitle>European journal of pharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hals, P A</au><au>Hall, H</au><au>Dahl, S G</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Phenothiazine drug metabolites: dopamine D2 receptor, alpha 1- and alpha 2-adrenoceptor binding</atitle><jtitle>European journal of pharmacology</jtitle><addtitle>Eur J Pharmacol</addtitle><date>1986-06-24</date><risdate>1986</risdate><volume>125</volume><issue>3</issue><spage>373</spage><epage>381</epage><pages>373-381</pages><issn>0014-2999</issn><abstract>The in vitro binding affinities of levomepromazine, chlorpromazine, fluphenazine, perphenazine and methoxypromazine and their main metabolites to dopamine D2 receptors, alpha 1- and alpha 2-adrenoceptors in rat brain, were examined using [3H]spiperone, [3H]WB 4101 and [3H]yohimbine binding. All compounds had 10-500 times lower affinities to alpha 2-adrenoceptors than to dopamine D2 receptors and alpha 1-adrenoceptors. Ring-hydroxylated and N-demethylated metabolites had relative potencies for dopamine D2 receptor and alpha 1-adrenoceptor binding ranging from 20 to 70%, compared to that of the parent drugs. The ring sulphoxides of levomepromazine, chlorpromazine and perphenazine, except dextro levomepromazine sulphoxide, were virtually inactive in all binding systems. The results indicate that the metabolites having the highest binding affinities for dopamine D2 receptor and alpha 1-adrenoceptor binding may contribute significantly to the therapeutic effect and side-effects of the drugs, and should be measured together with the parent drugs in blood level-effect studies.</abstract><cop>Netherlands</cop><pmid>2874041</pmid><doi>10.1016/0014-2999(86)90793-4</doi><tpages>9</tpages></addata></record> |
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subjects | Animals Antipsychotic Agents - metabolism Biotransformation Brain - metabolism In Vitro Techniques Kinetics Male Methotrimeprazine - metabolism Methotrimeprazine - pharmacology Rats Rats, Inbred Strains Receptors, Adrenergic, alpha - metabolism Receptors, Dopamine - metabolism Receptors, Dopamine D2 |
title | Phenothiazine drug metabolites: dopamine D2 receptor, alpha 1- and alpha 2-adrenoceptor binding |
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