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Analysis of Three-dimensional Structure of Antagonist-Binding Site of GABA Receptors

GABA受体拮抗剂结合位点三维结构分析

基本信息

批准号：
10660112
负责人：
OZOE Yoshihisa
金额：
$ 0.9万
依托单位：
Shimane University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1998
资助国家：
日本
起止时间：
1998 至 2000
项目状态：
已结题

项目摘要

To obtain information on the three-dimensional structure of noncompetitive antagonist-binding site of the γ-aminobutyric acid (GABA) receptor, molecular probes were synthesized and examined for their abilities to bind to the site and structure-activity relationships.1. Analysis with probe 1, picrodendrinsPicrodendrins, plant-derived terpenoids, act as GABA antagonists. Some of the compounds showed binding activity toward both rat and housefly receptors, while other compounds exhibited selectivity for housefly receptors. Our three-dimensional binding site model, consisting of four subsites, proved to successfully explain the manifestation of picrodendrins' activity and selectivity.2. Analysis with probe 2, bicyclophosphorothionatesBicyclophosphorothionates, bearing appropriate 3- and 4-substituents, exhibited selectivity for housefly GABA receptors, suggesting structural differences between rat and housefly GABA receptors. Three-dimensional quantitative structure-activity relationship analysis of these compounds led to defining the region of putative subsites B and C in housefly receptors.3. Analysis with probe 3, acyclic esters and ethersMost compounds of this group displayed antagonist activity for rat GABA receptors, while they had only low potency for housefly receptors. These compounds are supposed to interact with three of four subsites, and so an interaction with the other subsite (i.e., B) could be of importance for antagonists to exhibit selectivity.

为了获得γ-氨基丁酸（GABA）受体非竞争性拮抗剂结合位点的三维结构信息，我们合成了分子探针，并检测了它们与该位点的结合能力和构效关系。探针1的分析sprodendrins是一种植物源萜类化合物，具有GABA拮抗剂的作用。部分化合物对大鼠和家蝇受体均有结合活性，其余化合物对家蝇受体有选择性。我们的三维结合位点模型由四个亚位点组成，成功地解释了巨齿树突蛋白活性和选择性的表现。用探针2分析，双环硫代膦酸盐，含有适当的3-和4-取代基，对家蝇GABA受体表现出选择性，表明大鼠和家蝇GABA受体的结构差异。通过对这些化合物的三维定量构效关系分析，确定了家蝇受体中假定的亚位B和C的区域。探针3、无环酯和醚分析该组化合物大部分对大鼠GABA受体具有拮抗活性，而对家蝇受体的拮抗活性较低。这些化合物应该与四个亚位点中的三个相互作用，因此与另一个亚位点（即B）的相互作用对于拮抗剂表现出选择性可能很重要。