Detailed pharmacological characterization of GT-2331 for the rat histamine H3 receptor.
Histamine H(3) receptor antagonists are potential therapeutic agents for cognitive dysfunction, epilepsy, hypersomnia and obesity. GT-2331 (4-[(R,R)-2-(5,5-dimethyl-1-hexynyl)cyclopropyl]-1H-imidazole) was originally identified as a potent histamine H(3) receptor antagonist. However, recent reports demonstrated a complex pharmacology for GT-2331. To further understand the pharmacological profile of GT-2331, we characterized GT-2331 using various in vitro and in vivo assays. In vitro, GT-2331 behaved as a full agonist on adenylyl cyclase inhibition and as a partial agonist on [(35)S]GTPgammaS binding at the recombinant rat histamine H(3) receptor. In contrast, in vivo, GT-2331 had no effect on brain histamine turnover while the histamine H(3) receptor agonist R-alpha-methylhistamine significantly decreased histamine turnover. Furthermore, GT-2331 completely blocked R-alpha-methylhistamine-induced water intake, suggesting that GT-2331 behaves as a full antagonist. Thus, GT-2331 displayed the spectrum of pharmacological activities from full agonism to full antagonism, these observations suggest that histamine H(3) receptor ligands need to be carefully evaluated in various paradigms.
Ito
Sayaka
S
Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., Tsukuba, Ibaraki 300-2611, Japan.
Yoshimoto
Ryo
R
Miyamoto
Yasuhisa
Y
Mitobe
Yuko
Y
Nakamura
Takao
T
Ishihara
Akane
A
MacNeil
Douglas J
DJ
Kanatani
Akio
A
Tokita
Shigeru
S
D000067956:Adenylyl Cyclase Inhibitors; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002460:Cell Line; D003001:Cloning, Molecular; D004327:Drinking Behavior / Q000187:drug effects; D006632:Histamine / Q000378:metabolism; D017442:Histamine Agonists / Q000494:pharmacology*; D006633:Histamine Antagonists / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D008024:Ligands; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D018100:Receptors, Histamine H3 / Q000235:genetics / Q000378:metabolism*
C114969:4-(2-(5,5-dimethylhex-1-ynyl)cyclopropyl)imidazole; D000067956:Adenylyl Cyclase Inhibitors; D017442:Histamine Agonists; D006633:Histamine Antagonists; D007093:Imidazoles; D008024:Ligands; D018100:Receptors, Histamine H3; D006632:Histamine