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

Abstract

( 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 M 1 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 (IC 50s 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 M 1 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 M 1 muscarinic receptors selectively.