Characterization of the striatal M2 muscarinic receptor mediating inhibition of cyclic AMP using selective antagonists: A comparison with the brainstem M2 receptor

M. McKinney, D. Anderson, C. Forray, E. E. El-Fakahany

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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 (K(i) ~ 300 nM) and the brainstem M2 receptor (K(i) = 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 (K(B) = 0.19 nM) and hexahydrosiladifenidol (K(B) = 14 nM) in blocking the striatal M2 receptor suggested similarity to those M2 receptors localized in certain smooth mucles or in glands. However, AF-DX 116 (K(B) = 155 nM) and methoctramine (K(B) = 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. The profile of the striatal M2 receptor (with the exception of pirenzepine) appears remarkably similar to that we obtained for the cortical M1 receptor using competition with 6 nM [3H]pirenzepine (r = 0.995), a feature suggesting involvement of the M3 or M4 gene products rather than the M2 gene product. Inasmuch as the M3 gene product, which predominates in striatum, has been shown to couple efficiently to cyclic AMP inhibition, we suggest that the unique profile we obtained with antagonists in the blockade of carbachol-mediated [3H]cyclic AMP inhibition in striatum reflects the pharmacological equivalent of a neurally expressed M3 gene product. Furthermore, because anatomical data indicate the expression of M2 mRNA in pons-medulla, we suggest that our antagonist profile of the brainstem muscarinic receptor is the pharmacological equivalent of a neurally located, cardiac-type M2 receptor.

Original languageEnglish (US)
Pages (from-to)565-572
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume250
Issue number2
StatePublished - 1989

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