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Novel alkoxy-oxazolyl-tetrahydropyridine muscarinic cholinergic receptor antagonists
The purpose of the present studies was to compare a novel series of alkoxy-oxazolyl-tetrahydropyridines (A-OXTPs) as muscarinic receptor antagonists. The affinity of these compounds for muscarinic receptors was determined by inhibition of [3H]pirenzepine to M1 receptors in hippocampus, [3H]QNB to M2...
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Published in: | Psychopharmacology 1995-01, Vol.117 (2), p.208-215 |
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creator | Shannon, H E Bymaster, F P Hendrix, J C Quimby, S J Mitch, C H |
description | The purpose of the present studies was to compare a novel series of alkoxy-oxazolyl-tetrahydropyridines (A-OXTPs) as muscarinic receptor antagonists. The affinity of these compounds for muscarinic receptors was determined by inhibition of [3H]pirenzepine to M1 receptors in hippocampus, [3H]QNB to M2 receptors in brainstem, and [3H]oxotremorine-M to high affinity muscarinic agonist binding sites in cortex. All of the compounds had higher affinity for [3H]pirenzepine than for [3H]QNB or [3H]oxotremorine-M labeled receptors, consistent with an interpretation that they are relatively selective M1 receptor antagonists, although none were as selective as pirenzepine. In addition, dose-response curves were determined for antagonism of oxotremorine-induced salivation (mediated by M3 receptors) and tremor (mediated by non-M1 receptors) in mice. In general, the A-OXTPs were equipotent and equieffective in antagonizing both salivation and tremor, although there were modest differences for some compounds. Dose-response curves also were determined on behavior maintained under a spatial-alternation schedule of food presentation in rats as a measure of effects on working memory. The A-OXTPs produced dose-related decreases in percent correct responding at doses three- to ten-fold lower than those which decreased rates of responding. However, only one compound, MB-OXTP, produced effects on percent correct responding consistent with a selective effect on memory as opposed to non-memory variables. The present results provide evidence that these alkoxy-oxazolyl-tetrahydropyridines are a novel series of modestly M1-selective muscarinic receptor antagonists, and that one member of the series, MB-OXTP, appears to be more selective in its effects on memory than previously studies muscarinic antagonists. |
doi_str_mv | 10.1007/BF02245189 |
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The affinity of these compounds for muscarinic receptors was determined by inhibition of [3H]pirenzepine to M1 receptors in hippocampus, [3H]QNB to M2 receptors in brainstem, and [3H]oxotremorine-M to high affinity muscarinic agonist binding sites in cortex. All of the compounds had higher affinity for [3H]pirenzepine than for [3H]QNB or [3H]oxotremorine-M labeled receptors, consistent with an interpretation that they are relatively selective M1 receptor antagonists, although none were as selective as pirenzepine. In addition, dose-response curves were determined for antagonism of oxotremorine-induced salivation (mediated by M3 receptors) and tremor (mediated by non-M1 receptors) in mice. In general, the A-OXTPs were equipotent and equieffective in antagonizing both salivation and tremor, although there were modest differences for some compounds. 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The present results provide evidence that these alkoxy-oxazolyl-tetrahydropyridines are a novel series of modestly M1-selective muscarinic receptor antagonists, and that one member of the series, MB-OXTP, appears to be more selective in its effects on memory than previously studies muscarinic antagonists.</description><identifier>ISSN: 0033-3158</identifier><identifier>EISSN: 1432-2072</identifier><identifier>DOI: 10.1007/BF02245189</identifier><identifier>PMID: 7753969</identifier><language>eng</language><publisher>Germany</publisher><subject>Animals ; Behavior, Animal - drug effects ; Body Temperature - drug effects ; Conditioning, Operant - drug effects ; Dose-Response Relationship, Drug ; Hippocampus - drug effects ; Hippocampus - metabolism ; In Vitro Techniques ; Male ; Membranes - drug effects ; Membranes - metabolism ; Mice ; Mice, Inbred Strains ; Muscarinic Antagonists ; Oxazoles - pharmacology ; Pyridines - pharmacology ; Rats ; Rats, Inbred F344 ; Rats, Sprague-Dawley ; Reinforcement Schedule ; Salivation - drug effects ; Tremor - chemically induced</subject><ispartof>Psychopharmacology, 1995-01, Vol.117 (2), p.208-215</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c282t-490c5ec325af7f8a1f462e0cf20db73dde3186f7f8b80df59e822b0c7d5d3d8a3</citedby><cites>FETCH-LOGICAL-c282t-490c5ec325af7f8a1f462e0cf20db73dde3186f7f8b80df59e822b0c7d5d3d8a3</cites></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/7753969$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Shannon, H E</creatorcontrib><creatorcontrib>Bymaster, F P</creatorcontrib><creatorcontrib>Hendrix, J C</creatorcontrib><creatorcontrib>Quimby, S J</creatorcontrib><creatorcontrib>Mitch, C H</creatorcontrib><title>Novel alkoxy-oxazolyl-tetrahydropyridine muscarinic cholinergic receptor antagonists</title><title>Psychopharmacology</title><addtitle>Psychopharmacology (Berl)</addtitle><description>The purpose of the present studies was to compare a novel series of alkoxy-oxazolyl-tetrahydropyridines (A-OXTPs) as muscarinic receptor antagonists. 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The present results provide evidence that these alkoxy-oxazolyl-tetrahydropyridines are a novel series of modestly M1-selective muscarinic receptor antagonists, and that one member of the series, MB-OXTP, appears to be more selective in its effects on memory than previously studies muscarinic antagonists.</description><subject>Animals</subject><subject>Behavior, Animal - drug effects</subject><subject>Body Temperature - drug effects</subject><subject>Conditioning, Operant - drug effects</subject><subject>Dose-Response Relationship, Drug</subject><subject>Hippocampus - drug effects</subject><subject>Hippocampus - metabolism</subject><subject>In Vitro Techniques</subject><subject>Male</subject><subject>Membranes - drug effects</subject><subject>Membranes - metabolism</subject><subject>Mice</subject><subject>Mice, Inbred Strains</subject><subject>Muscarinic Antagonists</subject><subject>Oxazoles - pharmacology</subject><subject>Pyridines - pharmacology</subject><subject>Rats</subject><subject>Rats, Inbred F344</subject><subject>Rats, Sprague-Dawley</subject><subject>Reinforcement Schedule</subject><subject>Salivation - drug effects</subject><subject>Tremor - chemically induced</subject><issn>0033-3158</issn><issn>1432-2072</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>1995</creationdate><recordtype>article</recordtype><recordid>eNpFkD1PwzAQhi0EKqGwsCNlRjKc7Th2RqgoIFWwlDly_NEG0jiyU9Tw60nVCm55T3eP3uFB6JrAHQEQ949zoDTjRBYnKCEZo5iCoKcoAWAMM8LlObqI8RPGyWQ2QRMhOCvyIkHLN_9tm1Q1X343YL9TP74ZGtzbPqj1YILvhlCburXpZhu1CnVb61SvfTOewmrcg9W2631IVdurlW_r2MdLdOZUE-3VMafoY_60nL3gxfvz6-xhgTWVtMdZAZpbzShXTjipiMtyakE7CqYSzBjLiMz3r0qCcbywktIKtDDcMCMVm6LbQ68OPsZgXdmFeqPCUBIo92bKfzMjfHOAu221seYPPapgvxdHYOw</recordid><startdate>199501</startdate><enddate>199501</enddate><creator>Shannon, H E</creator><creator>Bymaster, F P</creator><creator>Hendrix, J C</creator><creator>Quimby, S J</creator><creator>Mitch, C H</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope></search><sort><creationdate>199501</creationdate><title>Novel alkoxy-oxazolyl-tetrahydropyridine muscarinic cholinergic receptor antagonists</title><author>Shannon, H E ; Bymaster, F P ; Hendrix, J C ; Quimby, S J ; Mitch, C H</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c282t-490c5ec325af7f8a1f462e0cf20db73dde3186f7f8b80df59e822b0c7d5d3d8a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>1995</creationdate><topic>Animals</topic><topic>Behavior, Animal - drug effects</topic><topic>Body Temperature - drug effects</topic><topic>Conditioning, Operant - drug effects</topic><topic>Dose-Response Relationship, Drug</topic><topic>Hippocampus - drug effects</topic><topic>Hippocampus - metabolism</topic><topic>In Vitro Techniques</topic><topic>Male</topic><topic>Membranes - drug effects</topic><topic>Membranes - metabolism</topic><topic>Mice</topic><topic>Mice, Inbred Strains</topic><topic>Muscarinic Antagonists</topic><topic>Oxazoles - pharmacology</topic><topic>Pyridines - pharmacology</topic><topic>Rats</topic><topic>Rats, Inbred F344</topic><topic>Rats, Sprague-Dawley</topic><topic>Reinforcement Schedule</topic><topic>Salivation - drug effects</topic><topic>Tremor - chemically induced</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Shannon, H E</creatorcontrib><creatorcontrib>Bymaster, F P</creatorcontrib><creatorcontrib>Hendrix, J C</creatorcontrib><creatorcontrib>Quimby, S J</creatorcontrib><creatorcontrib>Mitch, C H</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><jtitle>Psychopharmacology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Shannon, H E</au><au>Bymaster, F P</au><au>Hendrix, J C</au><au>Quimby, S J</au><au>Mitch, C H</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Novel alkoxy-oxazolyl-tetrahydropyridine muscarinic cholinergic receptor antagonists</atitle><jtitle>Psychopharmacology</jtitle><addtitle>Psychopharmacology (Berl)</addtitle><date>1995-01</date><risdate>1995</risdate><volume>117</volume><issue>2</issue><spage>208</spage><epage>215</epage><pages>208-215</pages><issn>0033-3158</issn><eissn>1432-2072</eissn><abstract>The purpose of the present studies was to compare a novel series of alkoxy-oxazolyl-tetrahydropyridines (A-OXTPs) as muscarinic receptor antagonists. The affinity of these compounds for muscarinic receptors was determined by inhibition of [3H]pirenzepine to M1 receptors in hippocampus, [3H]QNB to M2 receptors in brainstem, and [3H]oxotremorine-M to high affinity muscarinic agonist binding sites in cortex. All of the compounds had higher affinity for [3H]pirenzepine than for [3H]QNB or [3H]oxotremorine-M labeled receptors, consistent with an interpretation that they are relatively selective M1 receptor antagonists, although none were as selective as pirenzepine. In addition, dose-response curves were determined for antagonism of oxotremorine-induced salivation (mediated by M3 receptors) and tremor (mediated by non-M1 receptors) in mice. In general, the A-OXTPs were equipotent and equieffective in antagonizing both salivation and tremor, although there were modest differences for some compounds. Dose-response curves also were determined on behavior maintained under a spatial-alternation schedule of food presentation in rats as a measure of effects on working memory. The A-OXTPs produced dose-related decreases in percent correct responding at doses three- to ten-fold lower than those which decreased rates of responding. However, only one compound, MB-OXTP, produced effects on percent correct responding consistent with a selective effect on memory as opposed to non-memory variables. The present results provide evidence that these alkoxy-oxazolyl-tetrahydropyridines are a novel series of modestly M1-selective muscarinic receptor antagonists, and that one member of the series, MB-OXTP, appears to be more selective in its effects on memory than previously studies muscarinic antagonists.</abstract><cop>Germany</cop><pmid>7753969</pmid><doi>10.1007/BF02245189</doi><tpages>8</tpages></addata></record> |
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subjects | Animals Behavior, Animal - drug effects Body Temperature - drug effects Conditioning, Operant - drug effects Dose-Response Relationship, Drug Hippocampus - drug effects Hippocampus - metabolism In Vitro Techniques Male Membranes - drug effects Membranes - metabolism Mice Mice, Inbred Strains Muscarinic Antagonists Oxazoles - pharmacology Pyridines - pharmacology Rats Rats, Inbred F344 Rats, Sprague-Dawley Reinforcement Schedule Salivation - drug effects Tremor - chemically induced |
title | Novel alkoxy-oxazolyl-tetrahydropyridine muscarinic cholinergic receptor antagonists |
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