Nilsson B M, Vargas H M, Hacksell U
Department of Organic Pharmaceutical Chemistry, University of Uppsala, Sweden.
J Med Chem. 1992 Aug 21;35(17):3270-9. 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 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.
已合成了毒蕈碱剂氧化震颤素（1）和N-甲基-N-（1-甲基-4-吡咯烷基-2-丁炔基）乙酰胺[10；BM-5]的一些尿素和2-咪唑啉酮类似物，并在离体豚鼠回肠上测定了它们的毒蕈碱和抗毒蕈碱活性。发现新化合物（15 - 24）为毒蕈碱激动剂、部分激动剂或拮抗剂。还使用毒蕈碱拮抗剂[3H]-3-喹核醇基苯甲酸酯（[3H]QNB）作为配体，对这些化合物进行了与大鼠大脑皮层匀浆的体外受体结合测试。在该测试中发现它们的效力比1低。在豚鼠回肠上，N-3-甲基取代的咪唑啉酮类似物20是所研究新化合物中最有效的激动剂；在诱导回肠收缩方面，20的效力比3-甲基取代的2-吡咯烷酮6高5倍，对回肠毒蕈碱受体的亲和力高4倍。然而，N-3-未取代的尿素和咪唑啉酮衍生物15和19的效力分别比母体乙酰胺N-甲基-N-（4-吡咯烷基-2-丁炔基）乙酰胺[9；UH-5]和1低几倍。部分毒蕈碱激动剂10的尿素类似物（16）没有内在活性，对回肠毒蕈碱受体的亲和力比10低3倍。
