Synthesis and pharmacology of the putative novel muscarinic agonist (S)-4-F-MePyMcN [(S)-4-(pyrrolidino)-1-methyl-2-butynyl-N-(4-fluorophenyl) carbamate oxalate]

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• 作者：Athmani ; Saleh ; Bradley ; Karen N. ; Harvey ; Alan L. ; Kornisiuk ; Edgar ; Jerusalinsky ; Diana
• 关键词：muscarinic receptors ; selective agonists ; ligand binding ; McN-A-343 ; N-methylscopolamine
• 刊名：European Journal of Medicinal Chemistry
• 出版年：1998
• 出版时间：December, 1998
• 年：1998
• 卷：33
• 期：1
• 页码：935-941
• 全文大小：403 K

文摘

(S)-4-F-MePyMcN [(S)-4-(pyrrolidino)-1-methyl-2-butynyl-N-(4-fluorophenyl) carbamate oxalate] has been suggested to be a selective agonist at the M₁ subtype of muscarinic receptor [Lambrecht G. et al., Life Sci. 56 (1995) 815-822]. We synthesized the compound and tested its selectivity for different muscarinic receptors with binding experiments using rat cerebral cortex synaptosomal membranes and cloned human m1 to m5 receptors and by functional experiments on rabbit vas deferens preparations. There was little difference in affinity for the compound at the different cloned muscarinic receptors (IC₅₀s for displacement of ³H-N-methylscopolamine were 0.7-1.0 μM). On rabbit vas deferens preparations, (S)-4-F-MePyMcN did reduce twitch responses to electrical stimulation like the known M₁ agonist McN-A-343, but unlike McN-A-343 the compound reduced postsynaptic sensitivity to noradrenaline, ATP and KCl. Because of these additional actions, (S)-4-F-MePyMcN may not be suitable as a tool to study M₁ muscarinic receptors selectively.