Nilsson B M, Vargas H M, Hacksell U
Department of Organic Pharmaceutical Chemistry, University of Uppsala, Sweden.
J Med Chem. 1992 Jul 24;35(15):2787-98. doi: 10.1021/jm00093a011.
A series of amide, urea, and carbamate analogues of the muscarinic (M1) ganglionic stimulant [4-[[N-(3-chlorophenyl)carbamoyl]oxy]-2-butynyl]trimethylammonium chloride (McN-A-343; 1) was prepared. The C1-methyl-substituted carbamates 8-11 were resolved into the enantiomers. In order to investigate the ganglionic stimulant activity and affinity of the new compounds we studied their ability to increase mean arterial blood pressure (MAP) in the pithed rat and their ability to displace the M1 receptor selective antagonist [3H]pirenzepine from rabbit sympathetic ganglia. The quaternary ammonium derivatives of 1, but not their corresponding tertiary amines, displayed ganglionic stimulant properties. The urea derivative 14 and the acetamide derivative 18 were almost equipotent to 1 as ganglionic agonists. In addition, 14 and 18 showed only 2- to 3-fold less affinity to ganglionic muscarinic receptors than 1. Introduction of a methyl group in the 1 position of the butynyl chain of 1 and its 4-chlorophenyl analogue increased ganglionic stimulant potency. The resulting (+/-)-9 and (+/-)-11 were the most potent analogues in this study. They were found to be partial agonists and showed 5- and 16-fold higher potency than 1, respectively, in increasing the MAP. They also displayed 6- and 18-fold higher affinity than 1 for ganglionic M1 receptors. The (S)-enantiomers of 9 and 11 were 1.5- and 4.9-fold more potent, respectively, than their antipodes as ganglionic muscarinic stimulants. The C1-methyl-substituted urea and acetamide derivatives (15 and 19) were 1.5- and 3-fold less potent than 1 and displayed several-fold lower affinity for ganglionic M1 receptors. The new quaternary analogues retained the selectivity for ganglionic muscarinic receptors since they produced weak partial agonist effects on the guinea pig ileum and showed several-fold lower nicotinic activity than 1 in the frog rectus abdominis assay.
制备了一系列毒蕈碱（M1）神经节兴奋剂[4-[[N-（3-氯苯基）氨基甲酰基]氧基]-2-丁炔基]三甲基氯化铵（McN-A-343；1）的酰胺、脲和氨基甲酸酯类似物。将C1-甲基取代的氨基甲酸酯8-11拆分为对映体。为了研究新化合物的神经节兴奋活性和亲和力，我们研究了它们在去脑大鼠中升高平均动脉血压（MAP）的能力以及它们从兔交感神经节中置换M1受体选择性拮抗剂[3H]哌仑西平的能力。1的季铵衍生物，而不是其相应的叔胺，表现出神经节兴奋特性。脲衍生物14和乙酰胺衍生物18作为神经节激动剂几乎与1等效。此外，14和18对神经节毒蕈碱受体的亲和力仅比1低2至3倍。在1及其4-氯苯基类似物的丁炔链的1位引入甲基增加了神经节兴奋效力。所得的（±）-9和（±）-11是本研究中最有效的类似物。发现它们是部分激动剂，在升高MAP方面分别比1高5倍和16倍。它们对神经节M1受体的亲和力也比1高6倍和18倍。9和11的（S）-对映体作为神经节毒蕈碱兴奋剂分别比其对映体强1.5倍和4.9倍。C1-甲基取代的脲和乙酰胺衍生物（15和19）的效力比1低1.5倍和3倍，并且对神经节M1受体的亲和力低几倍。新的季铵类似物保留了对神经节毒蕈碱受体的选择性，因为它们对豚鼠回肠产生微弱的部分激动剂作用，并且在蛙腹直肌试验中显示出比1低几倍的烟碱活性。
