1026412-65-6Relevant articles and documents
Histaprodifens: Synthesis, pharmacological in vitro evaluation, and molecular modeling of a new class of highly active and selective histamine H1-receptor agonists
Elz, Sigurd,Kramer, Kai,Pertz, Heinz H.,Detert, Heiner,Ter Laak, Anton M.,Kühne, Ronald,Schunack, Walter
, p. 1071 - 1084 (2000)
A new class of histamine analogues characterized by a 3,3-diphenylpropyl substituent at the 2-position of the imidazole nucleus has been prepared outgoing from 4,4-diphenylbutyronitrile (4b) via cyclization of the corresponding 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 compounds displayed partial agonism on contractile H1 receptors of the guinea-pig ileum and endothelium-denuded aorta, respectively, except 10 (histaprodifen; 2-[2-(3,3-diphenylpropyl)1H-imidazol-4-yl]ethanamine) which was a full agonist in the ileum assay. While 10 was equipotent with histamine (1), methylhistaprodifen (13) and dimethylhistaprodifen (14) exceeded the functional potency of 1 by a factor of 3-5 (13) and 2-3 (14). Compounds 10 and 13-17 relaxed precontracted rat aortic rings (intact endothelium) with relative potencies of 3.3- up to 28-fold (compared with 1), displaying partial agonism as well. Agonist effects were sensitive to blockade by the selective H1-receptor antagonist mepyramine (pA2 ? 9 (guinea-pig) and pA2 ? 8 (rat aorta)). The affinity of 10 and 13-17 for guinea-pig H1 receptors increased 20- to 100-fold compared with 1. Two lower homologues of 10 were weak partial H1-receptor agonists while two higher homologues of 10 were silent antagonists endowed with micromolar affinity for rat and guinea-pig H1 receptors. In functional selectivity experiments, 10, 13, and 14 did not stimulate H2, H3, and several other neurotransmitter receptors. They displayed only low to moderate affinity for these sites (pA2 1 receptor were studied using molecular dynamics simulations. Remarkable differences were found between the binding modes of 10, 13, and 14 and that of 1. The imidazole ring of 10, 13, and 14 was placed 'upside down' compared with 1, making the interaction of the N(π)-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(α)-atom which was positioned more between TM III and TM VI. This orientation can explain both the increased relative potency and the maximum effect of 10, 13, and 14 compared with 1. Compound 13 (methylhistaprodifen; N(α)-methyl-2-[2-(3,3-diphenylpropyl)-1H-imidazol-4- yl]ethanamine) is the most potent histamine H1-receptor agonist reported so far in the literature and may become a valuable tool for the study of physiological and pathophysiological H1-receptor-mediated effects.
