title: Detailed pharmacological characterization of GT-2331 for the rat histamine H3 receptor.
abstract: 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.
authors.affiliation: Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., Tsukuba, Ibaraki 300-2611, Japan.
authors.forename: Sayaka
authors.initials: S
authors.lastname: Ito
authors.forename: Ryo
authors.initials: R
authors.lastname: Yoshimoto
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Miyamoto
authors.forename: Yuko
authors.initials: Y
authors.lastname: Mitobe
authors.forename: Takao
authors.initials: T
authors.lastname: Nakamura
authors.forename: Akane
authors.initials: A
authors.lastname: Ishihara
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: MacNeil
authors.forename: Akio
authors.initials: A
authors.lastname: Kanatani
authors.forename: Shigeru
authors.initials: S
authors.lastname: Tokita
mesh_terms: 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*
chemical_list: 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