Characterization of the binding site of the histamine H3 receptor.: 1.: Various approaches to the synthesis of 2-(1H-imidazol-4-yl)cyclopropylamine and histaminergic activity of (1R,2R)- and (1S,2S)-2-(1H-imidazol-4-yl)cyclopropylamine

Various approaches to the synthesis of all four stereoisomers of 2-(1-H-imidazol-4-yl) cyclopropylamine (cyclopropylhistamine) are described. The rapid and convenient synthesis and resolution of trans-cyclopropylhistamine is reported. The absolute configuration of its enantiomers was determined by single-crystal X-ray crystallographic analysis. The distinct transcyclopropylhistamine enantiomers were tested for their activity and affinity on the histamine H-3 receptor. (1S,2S)-Cyclopropylhistamine (VUF 5297) acts as an agonist both on the rat cortex (pD(2) = 7.1; alpha = 0.75) and on guinea pig jejunum (pD(2) = 6.6; alpha = 0.75). Its enantiomer, (1R,2R)-cyclopropylhistamine (VUF 5296), is about 1 order of magnitude less active. Both enantiomers show we ak activity on H-1 and H-2 receptors. All synthetic attempts to cis-cyclopropylhistamine were unsuccessful. Nevertheless, the results of this study provide an ideal template for molecular modeling studies of histamine H-3 receptor ligands.