A number of S-methylsulfonium analogues of the conformationally restricted muscarinic agonists of the 3-alk-oxy-4,5,6,7-tetrahydroisoxazolo[4,5-c]pyridine (O-alkyl-THPO) type have been synthesized. The effects on muscarinic receptors of these 3-alkoxy-5-methyl-6,7-dihydro-4H-thiopyrano[3,4-d]isoxazol-5 -ium (O-alkyl-S-methyl-DHTO) analogues (7a-d) were assessed in receptor-binding experiments with tritiated oxotremorine M, pirenzepine, and quinuclidinyl benzilate as ligands and were supported by studies on the isolated guinea pig ileum. The degree of muscarinic agonist activity of the compounds (M-agonist index) and their selectivity for M-1 or M-2 muscarinic receptor subtypes (M-2/M-1 index) were estimated on the basis of receptor-binding studies. The in vitro pharmacological profiles of the compounds were compared with those of arecoline and its sulfonium and 3-methoxyisoxazole isosteres, sulfoarecoline and O,5-dimethyl-THPO, respectively. While O-methyl-DHTO (5a) and N-methyl-DHTO (6a) were inactive, all of the sulfonium analogues 7a-d were muscarinic agonists with the exception of O-ethyl-S-methyl-DHTO (7b), which showed a muscarinic antagonist profile.