Dimethylsulfonium and thiolanium analogues of the muscarinic agent oxotremorine.
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.
Ringdahl
B
B
Department of Pharmacology, School of Medicine, University of California, Los Angeles 90024-1735.
D000818:Animals; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D009119:Muscle Contraction / Q000187:drug effects; D009861:Onium Compounds / Q000138:chemical synthesis*; D010095:Oxotremorine / Q000031:analogs & derivatives*; D010277:Parasympathomimetics / Q000138:chemical synthesis* / Q000494:pharmacology; D011760:Pyrrolidinones / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D013452:Sulfonium Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D001743:Urinary Bladder / Q000187:drug effects / Q000502:physiology
D007202:Indicators and Reagents; D009861:Onium Compounds; D010277:Parasympathomimetics; D011760:Pyrrolidinones; D013438:Sulfhydryl Compounds; D013452:Sulfonium Compounds; D010095:Oxotremorine