4-DAMP相关化合物的合成、毒蕈碱阻断活性及分子模拟研究

Synthesis, muscarinic blocking activity and molecular modeling studies of 4-DAMP-related compounds.

作者信息

Recanatini M, Tumiatti V, Budriesi R, Chiarini A, Sabatino P, Bolognesi M L, Melchiorre C

机构信息

Department of Pharmaceutical Sciences, University of Bologna, Italy.

出版信息

Bioorg Med Chem. 1995 Mar;3(3):267-77. doi: 10.1016/0968-0896(95)00021-8.

DOI:10.1016/0968-0896(95)00021-8

PMID:7606388

Abstract

A number of compounds structurally related to 4-DAMP (1) were synthesized and a single crystal X-ray structural study on a representative member of this series was carried out. All the compounds were tested for the antagonist activity in isolated guinea pig atria (M2 muscarinic receptors) and ileum (M3 muscarinic receptors). Affinity values (pA2) for the muscarinic receptor subtypes ranged from 5.39 to 9.71 (M2) and from 5.68 to 9.92 (M3), depending on different structural features of the compounds. A molecular modeling study was performed, with the aim of rationalizing the affinity data for both M2 and M3 muscarinic receptor subtypes. The presence in the series of two highly active, structurally constrained derivatives allowed us to define two different pharmacophoric frames on which all the compounds could be fitted in a satisfactory manner.

摘要

合成了许多与4-DAMP（1）结构相关的化合物，并对该系列的一个代表性成员进行了单晶X射线结构研究。所有化合物都在离体豚鼠心房（M2毒蕈碱受体）和回肠（M3毒蕈碱受体）中进行了拮抗剂活性测试。毒蕈碱受体亚型的亲和力值（pA2）范围为5.39至9.71（M2）和5.68至9.92（M3），这取决于化合物的不同结构特征。进行了分子建模研究，目的是使M2和M3毒蕈碱受体亚型的亲和力数据合理化。该系列中存在两种高活性、结构受限的衍生物，这使我们能够定义两种不同的药效基团框架，所有化合物都可以以令人满意的方式适配于其上。