High antagonist potency of GT 2227 and GT-2331, new histamine H3 receptor antagonists, in two functional models.

Abstract GT-2227 (4-(6-cyclohexylhex- cis -3-enyl)imidazole) and GT-2331 ((1 R ,2 R )-4-(2-(5,5-dimethylhex-1-ynyl)cyclopropyl)imidazole) were developed as new potent histamine H 3 receptor antagonists. The functional activity of these ligands on the histamine H 3 receptor-mediated inhibition of neurogenic contraction of the guinea-pig jejunum and histamine H 3 receptor-mediated inhibition of norepinephrine release from guinea-pig heart synaptosomes were investigated. GT-2227 and GT-2331 both antagonized the inhibitory effects of ( R )-α-methylhistamine on the contraction induced by electrical field stimulation in the guinea-pig jejunum with p A 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 release in cardiac synaptosomes by GT-2203 ((1 R ,2 R )- trans -2-(1 H -imidazol-4-yl)cyclopropylamine), a histamine H 3 receptor agonist. The current results demonstrate the antagonist activity for both GT-2227 and GT-2331 in two functional assays for histamine H 3 receptors.