HOMOLOGS OF HISTAMINE AS HISTAMINE H-3 RECEPTOR ANTAGONISTS - A NEW POTENT AND SELECTIVE H-3 ANTAGONIST, 4(5)-(5-AMINOPENTYL)-1H-IMIDAZOLE

The influence of alkyl chain length variation on the histamine H-3 receptor activity of histamine homologs 1 was investigated. A series of 4(5)-(omega-aminoalkyl)-1H-imidazoles 1 was prepared with an alkyl chain length varying from one methylene group to 10 methylene groups. Besides the H-3 activity, the affinities of these compounds for the H-1 and H-2 receptors were determined. The ethylene chain of histamine is optimal for agonistic activity on all three histamine receptor subtypes. For the H-3 receptor, elongation of the alkyl chain from three methylene groups on leads to compounds with antagonistic properties. 4(5)-(5-Aminopentyl)-1H-imidazole (impentamine, 1e) is the most potent and selective H-3 antagonist from this series of 4(5)-(omega-aminoalkyl)-1H-imidazoles 1, with a pA(2) value of 8.4 (on guinea pig jejunum). A specific antagonistic binding site for this compound is proposed.