Lipp R, Arrang J M, Garbarg M, Luger P, Schwartz J C, Schunack W
Institute of Pharmacy, Freie Universität Berlin, Germany.
J Med Chem. 1992 Nov 13;35(23):4434-41. doi: 10.1021/jm00101a021.
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.
根据所选的合成途径，神经递质组胺的结构变异导致了α,β-二甲基组胺的混合物以及相应的纯光学异构体。其中一种异构体，即(αR,βS)-α,β-二甲基组胺，被证明是一种具有卓越受体选择性的高效H3受体激动剂。该化合物的绝对构型通过其氢溴酸盐的X射线结构分析，利用溴的反常散射得以确定。在用(R)-2-甲氧基-2-苯基乙酰氯对胺进行酰化后，通过1HNMR研究检查了赤藓糖型α,β-二甲基组胺两种对映体的光学纯度。正如预期的那样，H3受体对标题化合物与其αS,βR构型的对映体有非常明显的区分。后者的激动效力比(αR,βS)-α,β-二甲基组胺的效力低2个数量级。
