Synthesis, absolute configuration, stereoselectivity, and receptor selectivity of (alpha R, beta S)-alpha,beta-dimethylhistamine, a novel high potent histamine H3 receptor agonist.

Abstract

Depending on the selected synthetic pathway, structural variations of the neurotransmitter histamine led to mixtures of alpha,beta-dimethylhistamines as well as to the corresponding pure optical isomers. One of these isomers, namely (alpha R,beta S)-alpha,beta-dimethylhistamine, proved to be a highly potent H3 receptor agonist with exceptional receptor selectivity. The absolute configuration of the compound was determined by X-ray structure analysis of its dihydrobromide using the anomalous dispersion of bromine. The optical purity of both enantiomers of erythro-alpha,beta-dimethylhistamine was checked by 1HNMR investigations after acylation of the amines with (R)-2-methoxy-2-phenylacetyl chloride. As expected H3 receptors distinguish in a very strong way between the title compound and its alpha S,beta R-configured enantiomer. The agonistic potency of the latter is 2 orders of magnitude lower than the potency of (alpha R,beta S)-alpha,beta-dimethylhistamine.