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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
Ist Teil von
Journal of medicinal chemistry, 1999-04, Vol.42 (7), p.1115-1122
Ort / Verlag
Washington, DC: American Chemical Society
Erscheinungsjahr
1999
Quelle
MEDLINE
Beschreibungen/Notizen
Various approaches to the synthesis of all four stereoisomers of 2-(1H-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 trans-cyclopropylhistamine enantiomers were tested for their activity and affinity on the histamine H3 receptor. (1S,2S)-Cyclopropylhistamine (VUF 5297) acts as an agonist both on the rat cortex (pD 2 = 7.1; α = 0.75) and on guinea pig jejunum (pD 2 = 6.6; α = 0.75). Its enantiomer, (1R,2R)-cyclopropylhistamine (VUF 5296), is about 1 order of magnitude less active. Both enantiomers show weak activity on H1 and H2 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 H3 receptor ligands.