一系列新型阿托品类似物的构效关系。1. N，N'-二取代的6,7-二氮杂双环[3.2.2]壬烷衍生物。

Structure-activity relationship in a new series of atropine analogues. 1. N,N'-Disubstituted 6,7-diazabicyclo[3.2.2]nonane derivatives.

作者信息

Cherkez S, Yellin H, Kashman Y, Yaavetz B, Sokolovsky M

出版信息

J Med Chem. 1979 Jan;22(1):18-21. doi: 10.1021/jm00187a004.

Abstract

The synthesis of a new series of N,N'-disubstituted 6,7-diazabicyclo[3.2.2]nonane derivatives is described. The antimuscarinic potency of these drugs was evaluated in the guinea pig ileum and compared to that of atropine sulfate. All the drugs tested competitively inhibited the acetylcholine-induced contractions. Kd values were calculated and, in several cases, compared to those obtained by direct binding to the muscarinic receptor from mouse brain. The order of potencies followed that which is known for various tropine and pseudotropine esters; that is, the 3alpha configuration is more potent than the 3beta configuration, and the quaternary analogues are more potent than the tertiary ones. The antimuscarinic activity of the drugs is dicussed in terms of their acetylcholine-like molecular arrangement that gives rise to a characteristic interaction pharmacophore.

摘要

描述了一系列新的N，N'-二取代6,7-二氮杂双环[3.2.2]壬烷衍生物的合成。在豚鼠回肠中评估了这些药物的抗毒蕈碱效力，并与硫酸阿托品进行了比较。所有测试的药物均竞争性抑制乙酰胆碱诱导的收缩。计算了Kd值，并在几种情况下与通过直接与小鼠脑毒蕈碱受体结合获得的值进行了比较。效力顺序与各种托品和假托品酯的已知顺序一致；即，3α构型比3β构型更有效，季铵类似物比叔铵类似物更有效。根据其产生特征性相互作用药效团的乙酰胆碱样分子排列讨论了药物的抗毒蕈碱活性。