Bruysters Martijn, Pertz Heinz H, Teunissen Aloys, Bakker Remko A, Gillard Michel, Chatelain Pierre, Schunack Walter, Timmerman Henk, Leurs Rob
Leiden Amsterdam Center for Drug Research, Department of Pharmacochemistry, Vrije Universiteit Amsterdam, De Boelelaan 1083, 1081 HV, Amsterdam, The Netherlands.
Eur J Pharmacol. 2004 Mar 8;487(1-3):55-63. doi: 10.1016/j.ejphar.2004.01.028.
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 [(3)H]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.
组胺丙双二苯酯构成了一类新型的组胺H(1)受体激动剂。这些配体可被视为杂合分子，由一个组胺部分通过一条丙基链在咪唑环的2位连接到两个苯环组成，这是几种H(1)受体拮抗剂的特征之一。为了描绘各种组胺丙双二苯酯样配体的结合位点，我们构建了突变型组胺H(1)受体，其中参与组胺或H(1)受体拮抗剂结合的各种氨基酸被丙氨酸取代。野生型和突变型H(1)受体在非洲绿猴肾细胞（COS-7）中瞬时表达，并通过[³H]美吡拉敏放射性配体结合研究和核因子κB（NF-κB）报告基因测定评估它们与组胺和各种组胺丙双二苯酯的相互作用。我们的数据表明，在组胺H(1)受体结合口袋内，组胺丙双二苯酯与激动剂和拮抗剂结合位点都相互作用，从而产生高亲和力的组胺H(1)受体激动剂。
