Nilsson B M, Vargas H M, Ringdahl B, Hacksell U
Department of Organic Pharmaceutical Chemistry, Uppsala Biomedical Center, University of Uppsala, Sweden.
J Med Chem. 1992 Jan 24;35(2):285-94. doi: 10.1021/jm00080a013.
A series of phenyl-substituted analogues of the muscarinic agent oxotremorine (1) have been prepared. The new compounds (3b-11b and 9c) were assayed for antimuscarinic activity on the isolated guinea pig ileum and in intact mice. They were also evaluated for ability to inhibit the binding of the muscarinic antagonist (-)-[3H]-N-methylscopolamine to homogenates of the rat cerebral cortex. The phenyl-substituted derivatives were devoid of intrinsic muscarinic activity. Instead, they behaved as competitive muscarinic antagonists in these assays with similar or lower affinity for muscarinic receptors than the corresponding methyl-substituted analogues. The succinimide (8b) and the pyrrolidone (3b) derivatives of 1 substituted with a phenyl group at position 1 of the butynyl chain showed the highest antimuscarinic potency with dissociation constants (KD) of 0.10 and 0.20 microM, respectively, in the ileum assay. The phenyl-substituted analogues showed an approximately 10-fold lower in vivo antimuscarinic potency than their corresponding methyl-substituted positional isomers. A correlation was observed between in vitro and in vivo potency within subsets consisting of methyl- and phenyl-substituted derivatives.
已制备了一系列毒蕈碱剂氧化震颤素（1）的苯基取代类似物。对新化合物（3b - 11b和9c）在离体豚鼠回肠和完整小鼠体内进行了抗毒蕈碱活性测定。还评估了它们抑制毒蕈碱拮抗剂（-）-[3H]-N-甲基东莨菪碱与大鼠大脑皮层匀浆结合的能力。苯基取代衍生物没有内在的毒蕈碱活性。相反，在这些测定中它们表现为竞争性毒蕈碱拮抗剂，对毒蕈碱受体的亲和力与相应的甲基取代类似物相似或更低。在丁炔链1位被苯基取代的1的琥珀酰亚胺（8b）和吡咯烷酮（3b）衍生物在回肠测定中显示出最高的抗毒蕈碱效力，解离常数（KD）分别为0.10和0.20微摩尔。苯基取代类似物在体内的抗毒蕈碱效力比其相应的甲基取代位置异构体低约10倍。在由甲基和苯基取代衍生物组成的亚组中，观察到体外和体内效力之间的相关性。
