Urea and 2-imidazolidone derivatives of the muscarinic agents oxotremorine and N-methyl-N-(1-methyl-4-pyrrolidino-2-butynyl)acetamide.
Some urea and 2-imidazolidone analogues of the muscarinic agents oxotremorine (1) and N-methyl-N-(1-methyl-4-pyrrolidino-2-butynyl)acetamide [10; BM-5] have been synthesized and assayed for muscarinic and antimuscarinic activity on the isolated guinea pig ileum. The new compounds (15-24) were found to be muscarinic agonists, partial agonists, or antagonists. The compounds were also tested for in vitro receptor binding to homogenates of the rat cerebral cortex using the muscarinic antagonist [3H]-3-quinuclidinyl benzilate ([3H]QNB) as the ligand. They were found to be less potent than 1 in this assay. On the guinea pig ileum, the N-3-methyl substituted imidazolidone analogue 20 was the most potent agonist of the new compounds studied; 20 was 5-fold more potent in inducing contractions of the ileum and had 4-fold higher affinity for ileal muscarinic receptors than the 3-methyl substituted 2-pyrrolidone 6. However, the N-3-unsubstituted urea and imidazolidone derivatives 15 and 19 were several-fold less potent than the parent acetamide N-methyl-N-(4-pyrrolidino-2-butynyl)acetamide [9; UH-5] and 1, respectively. The urea analogue (16) of the partial muscarinic agonist 10 was devoid of intrinsic activity and displayed 3-fold lower affinity than 10 for ileal muscarinic receptors.
Nilsson
B M
BM
Department of Organic Pharmaceutical Chemistry, University of Uppsala, Sweden.
Vargas
H M
HM
Hacksell
U
U
D000818:Animals; D002540:Cerebral Cortex / Q000378:metabolism; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D007093:Imidazoles / Q000737:chemistry*; D015394:Molecular Structure; D018727:Muscarinic Antagonists; D009119:Muscle Contraction / Q000187:drug effects; D010095:Oxotremorine / Q000031:analogs & derivatives*; D010277:Parasympathomimetics / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D011759:Pyrrolidines / Q000737:chemistry*; D011813:Quinuclidinyl Benzilate / Q000378:metabolism; D051381:Rats; D011976:Receptors, Muscarinic / Q000378:metabolism; D013329:Structure-Activity Relationship; D014508:Urea / Q000737:chemistry*
D007093:Imidazoles; D018727:Muscarinic Antagonists; D010277:Parasympathomimetics; D011759:Pyrrolidines; D011976:Receptors, Muscarinic; D010095:Oxotremorine; D011813:Quinuclidinyl Benzilate; C038672:N-methyl-N-(1-methyl-4-pyrrolidino-2-butynyl)acetamide; D014508:Urea