Acylhydrazones as M1/M3 selective muscarinic agonists

To improve receptor binding affinity and to investigate functional selectivity of 2,8-dimethyl-1-oxa-8-azaspiro[4.5]decan-3-one acetylhydrazone 2 at muscarinic receptor subtypes, a series of acylhydrazones A was synthesized. The SAR indicates that the binding affinity in the pirenzepine assay (M1) correlates well with lipophilicity. Intrinsic activity (30% of carbachol response) of agonists at M1 remains unchanged. Compounds with n = 0 and 6, where X = NHCO(CH2)nMe, did not inhibit cAMP formation in rat heart membrane (M2). Most of the compounds are more efficacious at the M3 receptor than at M1. The results suggest that the M1 and M3 receptors can better tolerate bulky and long chained substituents than the M2 receptor.