Ringdahl_1988_J.Med.Chem_31_164

Dimethylsulfonium (6a and 6b) and thiolanium analogues (7a and 7b) of oxotremorine were synthesized and found to be potent muscarinic agents in vivo and vitro. Compound 6a exceeded oxotremorine in potency. Their affinities for muscarinic receptors in the guinea pig ileum and urinary bladder, estimated pharmacologically, were higher than those of the corresponding trimethylammonium (8a and 8b) and N-methylpyrrolidinium compounds (9a and 9b). However, the new compounds had lower intrinsic efficacies than their quaternary ammonium analogues. The compounds also had high affinity for central muscarinic receptors as measured by displacement of specifically bound (-)-[3H]-N-methylscopolamine from homogenates of the rat cerebral cortex. Half-maximal occupation of cortical muscarinic receptors by 6a, 6b, 7a, and 7b was achieved at concentrations of 0.8, 5.4, 0.3, and 3.3 microM, respectively. The competition curves of 6a, 6b, and 7a were adequately described by a two-site binding equation. The ratio of low- and high-affinity dissociation constants agreed with relative efficacy estimated on the ileum. The thiolanium salt 7a was a fairly potent nicotinic agent on the frog rectus abdominis.