HIGH ANTAGONIST POTENCY OF GT-2227 AND GT-2331, NEW HISTAMINE H-3 RECEPTOR ANTAGONISTS, IN 2 FUNCTIONAL MODELS

GT-2227 (4-(6-cyclohexylhex-cis-3-enyl)imidazole) and GT-2331 -(2-(5,5 -dimethylhex-1-ynyl)cyclopropyl)imidazole) were developed as new poten t histamine H-3 receptor antagonists. The functional activity of these ligands on the histamine H-3 receptor-mediated inhibition of neurogen ic contraction of the guinea-pig jejunum and histamine H-3 receptor-me diated inhibition of norepinephrine release from guinea-pig heart syna ptosomes were investigated. GT-2227 and GT-2331 both antagonized the i nhibitory effects of (R)-alpha-methylhistamine on the contraction indu ced by electrical field stimulation in the guinea-pig jejunum with pA( 2) values of 7.9 +/- 0.1 and 8.5 +/- 0.03, respectively. In addition, GT-2227 and GT-2331 antagonized the inhibition of norepinephrine relea se in cardiac synaptosomes by GT-2203 ((1R, 2R)-trans-2-(1H-imidazol-4 -yl)cyclopropylamine), a histamine H-3 receptor agonist. The current r esults demonstrate the antagonist activity for both GT-2227 and GT-233 1 in two functional assays for histamine H-3 receptors. (C) 1998 Elsev ier Science B.V. All rights reserved.