Conformationally restricted analogues of the muscarinic agent N-methyl-N-(1-methyl-4-pyrrolidino-2-butynyl)acetamide.
Conformationally restricted analogues of the selective partial muscarinic agonist N-methyl-N-(1-methyl-4-pyrrolidino-2-butynyl)acetamide (BM 5; 2) were synthesized. The compounds were tested for muscarinic and antimuscarinic activity in the isolated guinea pig ileum and in intact mice. They were found to be moderately potent muscarinic antagonists or weak partial agonists. The new compounds were less potent than 2 in inhibiting (-)-[3H]-N-methylscopolamine binding in the rate cerebral cortex. Thus, structural modifications of 2 in which part of the amide moiety has been connected with the methyl group in the butynyl chain to form a five-membered ring decrease affinity and in most cases abolish efficacy.
Lundkvist
J R
JR
Department of Organic Pharmaceutical Chemistry, Uppsala Biomedical Center, University of Uppsala, Sweden.
Ringdahl
B
B
Hacksell
U
U
D000818:Animals; D001681:Biological Assay; D002540:Cerebral Cortex / Q000378:metabolism; D055598:Chemical Phenomena; D002621:Chemistry; D006168:Guinea Pigs; D007082:Ileum / Q000502:physiology; D051379:Mice; D008968:Molecular Conformation; D009119:Muscle Contraction / Q000187:drug effects; D019832:N-Methylscopolamine; D010095:Oxotremorine / Q000037:antagonists & inhibitors; D010277:Parasympathomimetics; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D011976:Receptors, Muscarinic / Q000378:metabolism; D012602:Scopolamine Derivatives / Q000378:metabolism; D013329:Structure-Activity Relationship; D014202:Tremor / Q000139:chemically induced
D010277:Parasympathomimetics; D011759:Pyrrolidines; D011976:Receptors, Muscarinic; D012602:Scopolamine Derivatives; D010095:Oxotremorine; C038672:N-methyl-N-(1-methyl-4-pyrrolidino-2-butynyl)acetamide; D019832:N-Methylscopolamine