Synthesis, absolute configuration, stereoselectivity, and receptor selectivity of (alpha R, beta S)-alpha,beta-dimethylhistamine, a novel high potent histamine H3 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 (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.
D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D006168:Guinea Pigs; D006632:Histamine / Q000031:analogs & derivatives*; D017442:Histamine Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006636:Histamine Release / Q000187:drug effects; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011968:Receptors, Histamine / Q000187:drug effects*; D018100:Receptors, Histamine H3; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D017442:Histamine Agonists; D011968:Receptors, Histamine; D018100:Receptors, Histamine H3; D006632:Histamine