Resolved pyrrolidine, piperidine, and perhydroazepine analogues of the muscarinic agent N-methyl-N-(1-methyl-4-pyrrolidino-2-butynyl)acetamide.
A series of conformationally restricted analogues of the partial muscarinic agonist N-methyl-N-(1-methyl-4-pyrrolidino-2-butynyl)acetamide (BM 5; 1) was synthesized. Three of the racemic derivatives were resolved into the enantiomers. The compounds were investigated for muscarinic and antimuscarinic activity in the isolated guinea pig ileum. They were found to be fairly potent muscarinic antagonists or weak partial agonists. The new compounds were either equally or less potent than 1 in inhibiting (-)-[3H]-N-methylscopolamine binding in homogenates of the rat cerebral cortex. Thus, structural modifications to 1 in which the amide moiety and the methyl group in the butynyl chain have been joined to form a six- or seven-membered ring preserve affinity but abolish efficacy. The R enantiomers were found to have 14-79 times higher affinity to ileal muscarinic receptors than the respective antipodes. The enantiomeric affinity ratios were nearly identical in both preparations studied. As suggested by molecular mechanics calculations, the difference in affinity between the five-membered and the six- and seven-membered ring analogues may be rationalized in conformational terms.
Lundkvist
J R
JR
Department of Organic Pharmaceutical Chemistry, Uppsala University, Sweden.
Vargas
H M
HM
Caldirola
P
P
Ringdahl
B
B
Hacksell
U
U
D000818:Animals; D001381:Azepines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D001667:Binding, Competitive; D002540:Cerebral Cortex / Q000378:metabolism; D055598:Chemical Phenomena; D002621:Chemistry; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008968:Molecular Conformation; D015394:Molecular Structure; D009119:Muscle Contraction / Q000187:drug effects; D019832:N-Methylscopolamine; D010277:Parasympathomimetics / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D010880:Piperidines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D011759:Pyrrolidines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011976:Receptors, Muscarinic / Q000378:metabolism; D012602:Scopolamine Derivatives / Q000378:metabolism; D013237:Stereoisomerism
D001381:Azepines; D010277:Parasympathomimetics; D010880:Piperidines; D011759:Pyrrolidines; D011976:Receptors, Muscarinic; D012602:Scopolamine Derivatives; C038672:N-methyl-N-(1-methyl-4-pyrrolidino-2-butynyl)acetamide; C048618:hexahydroazepine; D019832:N-Methylscopolamine