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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / drug effects
  • Brain / metabolism
  • Guinea Pigs
  • Histamine / analogs & derivatives*
  • Histamine Agonists / chemical synthesis*
  • Histamine Agonists / chemistry
  • Histamine Agonists / pharmacology
  • Histamine Release / drug effects
  • Male
  • Muscle, Smooth / drug effects
  • Muscle, Smooth / metabolism
  • Rats
  • Rats, Wistar
  • Receptors, Histamine / drug effects*
  • Receptors, Histamine H3
  • Stereoisomerism
  • Structure-Activity Relationship


  • Histamine Agonists
  • Receptors, Histamine
  • Receptors, Histamine H3
  • Histamine