Histaprodifens: Synthesis, pharmacological in vitro evaluation, and molecular modeling of a new class of highly active and selective histamine H-1-receptor agonists

A new class of histamine analogues characterized by a 3,3-diphenylpropyl su bstituent at the 2-position of the imidazole nucleus has been prepared outg oing from 4,4-diphenylbutyronitrile (4b) via cyclization of the correspondi ng methyl imidate 5b with 2-oxo-4-phthalimido-1-butyl acetate or 2-oxo-1,4- butandiol in liquid ammonia, followed by standard reactions. The title comp ounds displayed partial agonism on contractile H-1 receptors of the guinea- pig ileum and endothelium-denuded aorta, respectively, except 10 (histaprod ifen; 2-[2-(3,3-diphenglpropyl)-1H-imidazol-4-yl]ethanamine) which was a fu ll agonist in the ileum ass ay. While 10 was equipotent with histamine (1), methylhistaprodifen (13) and dimethylhistaprodifen (14) exceeded the funct ional potency of 1 by a factor of 3-5 (13) and 2-3 (14). Compounds 10 and 1 3-17 relaxed precontracted rat aortic rings (intact endothelium) with relat ive potencies of 3.3- up to 28-fold (compared with 1), displaying partial a gonism as well. Agonist effects were sensitive to blockade by the selective Hi-receptor antagonist mepyramine (pA(2) approximate to 9 (guineapig) and pA(2) approximate to 8 (rat aorta)). The affinity of 10 and 13-17 for guine a-pig H-1 receptors increased 20- to 100-fold compared with 1. Two lower ho mologues of 10 were weak partial H-1-receptor agonists while two higher hom ologues of 10 were silent antagonists endowed with micromolar affinity for rat and guinea-pig H-1 receptors. In functional selectivity experiments, 10 , 13, and 14 did not stimulate H-2, H-3, and several other neurotransmitter receptors. They displayed only low to moderate affinity for these sites (p A(2) < 6). For a better understanding of structure-activity relationships, the interaction of 1 and 10, 13 and 14 within the transmembrane (TM) domain s of the human histamine H-1 receptor were studied using molecular dynamics simulations. Remarkable differences were found between the binding modes o f 10, 13, and 14 and that of 1. The imidazole ring of 10, 13, and 14 was pl aced 'upside down' compared with 1, making the interaction of the N-pi-atom with Tyr431 possible. This new orientation was mainly caused by the space filling substitution at the 2-position of the imidazole ring and influenced the location of the protonated N-alpha-atom which was positioned more betw een TM III and TM VI. This orientation can explain both the increased relat ive potency and the maximum effect of 10, 13, and 14 compared with 1. Compo und 13 (methylhistaprodifen; N-alpha-methyl-2-[2-(3,3-diphenylpropyl)-1H-im idazol-4-yl]ethanamide) is the most potent histamine H-1-receptor agonist r eported so far in the literature and may become a valuable tool for the stu dy of physiological and pathophysiological H-1-receptor-mediated effects.