PHENYL-SUBSTITUTED ANALOGS OF OXOTREMORINE AS MUSCARINIC ANTAGONISTS
PHENYL-SUBSTITUTED ANALOGS OF OXOTREMORINE AS MUSCARINIC ANTAGONISTS
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DOI：
10.1021/jm00080a013
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发表时间：
1992-01-24
影响因子：
7.3
通讯作者：
HACKSELL, U
中科院分区：
文献类型：
--
作者：
NILSSON, BM;VARGAS, HM;HACKSELL, U
已制备了一系列毒蕈碱剂oxotremorine（1）的苯基取代类似物。 测定了新化合物（3b-11b和9 c）在离体豚鼠回肠和完整小鼠中的抗毒蕈碱活性。 还评价了它们抑制毒蕈碱拮抗剂（-）-[H-3]-N-甲基东莨菪碱与大鼠大脑皮层匀浆结合的能力。 苯基取代的衍生物缺乏固有的毒蕈碱活性。 相反，它们在这些测定中表现为竞争性毒蕈碱拮抗剂，与相应的甲基取代的类似物相比，对毒蕈碱受体具有相似或更低的亲和力。 在回肠试验中，丁炔基链的1位被苯基取代的1的琥珀酰亚胺（8b）和吡咯烷酮（3b）衍生物显示出最高的抗毒蕈碱效力，解离常数（K（D））分别为0.10和0.20 μ M。 苯基取代的类似物显示出比其相应的甲基取代的位置异构体低约10倍的体内抗毒蕈碱效力。 在由甲基和苯基取代的衍生物组成的子集内，观察到体外和体内效价之间的相关性。
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 (-)-[H-3]-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 (K(D)) of 0.10 and 0.20-mu-M, 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.