Synthesis, Absolute-Configuration, Stereoselectivity, And Receptor Selectivity Of (Alpha-R,Beta-S)-Alpha,Beta-Dimethylhistamine, A Novel Highly Potent Histamine H-3 Receptor Agonist

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 (alphaR,betaS)-alpha,beta-dimethylhistamine, proved to be a highly potent H-3 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 H-1 NMR investigations after acylation of the amines with (R)-2-methoxy-2-phenylacetyl chloride. As expected H-3 receptors distinguish in a very strong way between the title compound and its alphaS,betaR-configured enantiomer. The agonistic potency of the latter is 2 orders of magnitude lower than the potency of (alphaR,betaS)-alpha,beta-dimethylhistamine.