Detailed pharmacological characterization of GT-2331 for the rat histamine H3 receptor

Histamine H3 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 H3 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 [35S]GTPγS binding at the recombinant rat histamine H3 receptor. In contrast, in vivo, GT-2331 had no effect on brain histamine turnover while the histamine H3 receptor agonist R-α-methylhistamine significantly decreased histamine turnover. Furthermore, GT-2331 completely blocked R-α-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 H3 receptor ligands need to be carefully evaluated in various paradigms.