High antagonist potency of GT-2227 and GT-2331, new histamine H3 receptor antagonists, in two functional models.
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 H3 receptor antagonists. The functional activity of these ligands on the histamine H3 receptor-mediated inhibition of neurogenic contraction of the guinea-pig jejunum and histamine H3 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)-alpha-methylhistamine on the contraction induced by electrical field stimulation in the guinea-pig jejunum with pA2 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 ((1R,2R)-trans-2-(1H-imidazol-4-yl)cyclopropylamine), a histamine H3 receptor agonist. The current results demonstrate the antagonist activity for both GT-2227 and GT-2331 in two functional assays for histamine H3 receptors.
Gliatech, Cleveland, OH 44122, USA.
C E
CE
Tedford
M
M
Hoffmann
N
N
Seyedi
R
R
Maruyama
R
R
Levi
S L
SL
Yates
S M
SM
Ali
J G
JG
Phillips
D000818:Animals; D004558:Electric Stimulation; D006168:Guinea Pigs; D017442:Histamine Agonists / Q000494:pharmacology; D006633:Histamine Antagonists / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D007583:Jejunum / Q000187:drug effects / Q000502:physiology; D008297:Male; D008761:Methylhistamines / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D009206:Myocardium / Q000378:metabolism / Q000648:ultrastructure; D009638:Norepinephrine / Q000378:metabolism; D018100:Receptors, Histamine H3 / Q000187:drug effects*; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
C114969:4-(2-(5,5-dimethylhex-1-ynyl)cyclopropyl)imidazole; C114968:4-(6-cyclohexylhex-3-enyl)imidazole; D017442:Histamine Agonists; D006633:Histamine Antagonists; D007093:Imidazoles; D008761:Methylhistamines; D018100:Receptors, Histamine H3; C069357:alpha-methylhistamine; D009638:Norepinephrine