Indole amide derivatives: synthesis, structure-activity relationships and molecular modelling studies of a new series of histamine H-1-receptor antagonists

A number of indole amide derivatives bearing a basic side chain, in which t he indole ring replaces the isoster benzimidazole nucleus typical of some w ell-known antihistamines, were prepared and tested for their H-1-antihistam inic activity. The 1-benzyl-3-indolecarboxamides 32-42 showed antihistamini c (H-1) activity (pA(2) 6-8); the 3-indolylglyoxylylamides 7-16 and the 2-i ndolecarboxamides 48-56 showed little or no activity. Insertion of the basi c side chain of the active 3-indolecarboxamide derivatives into a piperazin e ring (compounds 57-59) led to a dramatic loss of activity. All the active compounds proved to be competitive antagonists, since the values of the re gression slope were not statistically different from 1. The most active com pounds, 32, 33, 38-41, were also tested both in vitro for their anticholine rgic activity and in vivo for their ability to antagonize histamine-induced cutaneous vascular permeability in rats. The biological results and the st ructure-activity relationships of the novel compounds are discussed in the light of molecular modelling studies, taking the molecule of astemizole as a model, and referring to proposed H-1-receptor pharmacophore models. (C) E lsevier, Paris.