GT-2227 (4-(6-cyclohexylhex-cis-3-enyl)imidazole) and GT-2331 ((1R,2R)-4-(2-(5,5-dimethylhex-1-ynyl)cyclopropyl)imidazole) were developed as new potent histamine H3receptor antagonists. The functional activity of these ligands on the histamine H3receptor-mediated inhibition of neurogenic contraction of the guinea-pig jejunum and histamine H3receptor-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 pA2values 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 ((1R,2R)-trans-2-(1H-imidazol-4-yl)cyclopropylamine), a histamine H3receptor agonist. The current results demonstrate the antagonist activity for both GT-2227 and GT-2331 in two functional assays for histamine H3receptors. Copyright (C) 1998 Elsevier Science B.V. All rights reserved.
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