Urea and 2-Imidazolidone Derivatives of the Muscarinic Agents Oxotremorine and N-Methyl-N-(1-methyl-4-pyrrolidino-2-butynyl)acetamide

Article abstract of DOI:10.1021/jm00095a025

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 for 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.