Mutational analysis of the histamine H1-receptor binding pocket of histaprodifens
Mutational analysis of the histamine H1-receptor binding pocket of histaprodifens
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DOI：
10.1016/j.ejphar.2004.01.028
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发表时间：
2004-03-08
影响因子：
5
通讯作者：
Leurs, R
中科院分区：
文献类型：
--
作者：
Bruysters, M;Pertz, HH;Leurs, R
Histaprodifens是一类新的组胺H-1受体激动剂。这些配体可以被认为是杂合分子，由在咪唑环的两个位置通过丙基链连接到两个苯环的组胺部分组成，这是几种H-1受体拮抗剂的特征之一。为了描述各种histaprodifen样配体的结合位点，我们产生了突变组胺H-1受体，其中各种氨基酸，参与组胺或H-1受体拮抗剂的结合，被丙氨酸取代。野生型和突变型H-1受体在非洲绿色猴肾细胞（COS-7）中瞬时表达，并通过[H-3]美吡拉敏放射性配体结合研究和核因子kappaB（NF-kappaB）报告基因测定来评估其与组胺和各种组胺药的相互作用。我们的数据表明，在组胺H-1受体结合口袋，histaprodifens相互作用与激动剂和拮抗剂结合位点，导致高亲和力组胺H-1受体激动剂。(C)2004 Elsevier B. V.保留所有权利。
Histaprodifens constitute a new class of histamine H-1-receptor agonists. These ligands can be regarded as hybrid molecules, consisting of a histamine moiety linked at the two-position of the imidazole ring by a propyl chain to two phenyl rings, one of the characteristic features of several H-1-receptor antagonists. To delineate the binding site of various histaprodifen-like ligands, we generated mutant histamine H-1 receptors, in which various amino acids, involved in the binding of either histamine or H-1-receptor antagonists, were replaced by alanine. Wild-type and mutant H-1 receptors were transiently expressed in African green monkey kidney cells (COS-7) and evaluated for their interaction with histamine and various histaprodifens by [H-3]mepyramine radioligand-binding studies and by nuclear factor kappaB (NF-kappaB) reporter-gene assays. Our data show that, within the histamine H-1-receptor binding pocket, histaprodifens interact with both agonist and antagonist binding sites, resulting in high affinity histamine H-1-receptor agonists. (C) 2004 Elsevier B.V. All rights reserved.