A Further Search for Selective Antagonists at M2-muscarinic Receptors

In an attempt to obtain more selective antagonists acting at muscarinic M2-receptors, analogues of 4-diphenylacetoxy-N-methylpiperidine methobromide (4-DAMP methobromide) have been synthesized. These were tested, along with silabenzhexol, procyclidine, sila-procyclidine and AFDX-116, in dose-ratio experiments with guinea-pig isolated atria at 30 degrees C and ileum at 30 degrees C and 37 degrees C. The agonist was carbachol and the selectivity was assessed from the difference between log K for receptors in ileum and log K for receptors in atria. The selectivity was not related to the affinity and some weakly active compounds retained appreciable selectivity but no compound had greater selectivity than 4-DAMP methobromide or pentamethylene bis-(4-diphenylacetoxy-N-methylpiperidinium) bromide. Structure-activity relations are discussed. There seem to be steric limits to affinity but there are no obvious indications of the structural features associated with selectivity. It is suggested that more selective drugs may be obtained by introducing groups which may reduce affinity.