title: Characterization of the striatal M2 muscarinic receptor mediating inhibition of cyclic AMP using selective antagonists: a comparison with the brainstem M2 receptor.
abstract: Pharmacological profiles of the striatal and brainstem M2 receptors were developed with a group of selective muscarinic antagonists. The striatal M2 muscarinic receptor was identified by its inhibition of [3H]cyclic AMP levels, whereas the brainstem M2 receptor was characterized using competition with [3H]quinuclidinyl benzilate binding. The potency of pirenzepine does not differentiate clearly between the striatal M2 receptor (Ki approximately 300 nM) and the brainstem M2 receptor (Ki = 219 nM) or peripheral M2 receptors. In the present study, we used 4-diphenylacetoxy-N-methylpiperidine methbromide, hexahydrosiladifenidol, AF-DX 116 and methoctramine to characterize the striatal and brainstem M2 receptors in more pharmacological detail. For comparison, the potencies of these antagonists were also measured at cortical M2 receptors (using competition with [3H]pirenzepine binding). The potencies of 4-diphenylacetoxy-N-methylpiperidine methbromide (KB = 0.19 nM) and hexahydrosiladifenidol (KB = 14 nM) in blocking the striatal M2 receptor suggested similarity to those M2 receptors localized in certain smooth muscles or in glands. However, AF-DX 116 (KB = 155 nM) and methoctramine (KB = 47 nM) were considerably more potent in blocking the striatal M2 receptor than as reported in functional studies in smooth muscle or glands. Thus, the profile of the striatal M2 receptor obtained with these antagonists did not match in all respects with either glandular (probable M4 gene product) or cardiac (probable M2 gene product) muscarinic receptors. In contrast, our data with the brainstem M2 receptor was highly correlated (r = 0.93) with literature data regarding the cardiac muscarinic system.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department 47W, Abbott Laboratories, Abbott Park, Illinois.
authors.forename: M
authors.initials: M
authors.lastname: McKinney
authors.forename: D
authors.initials: D
authors.lastname: Anderson
authors.forename: C
authors.initials: C
authors.lastname: Forray
authors.forename: E E
authors.initials: EE
authors.lastname: el-Fakahany
mesh_terms: D000818:Animals; D001933:Brain Stem / Q000187:drug effects*; D003342:Corpus Striatum / Q000187:drug effects*; D000242:Cyclic AMP / Q000037:antagonists & inhibitors*; D003959:Diamines / Q000494:pharmacology; D010276:Parasympatholytics / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology; D010890:Pirenzepine / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D011976:Receptors, Muscarinic / Q000187:drug effects* / Q000378:metabolism
chemical_list: D003959:Diamines; D010276:Parasympatholytics; D010880:Piperidines; D011976:Receptors, Muscarinic; D010890:Pirenzepine; C042375:4-diphenylacetoxy-1,1-dimethylpiperidinium; D000242:Cyclic AMP; C046773:hexahydrosiladifenidol; C054938:methoctramine; C048593:otenzepad