PHARMACOLOGICAL CHARACTERIZATION OF GT-2016, A NON-THIOUREA-CONTAINING HISTAMINE H3 RECEPTOR ANTAGONIST - IN-VITRO AND IN-VIVO STUDIES

GT-2016, a non-thiourea-containing imidazole, has been developed as a histamine H-3 antagonist. In vitro and in vivo studies in rats were co nducted to characterize receptor selectivity and autoreceptor function ality for GT-2016. GT-2016 demonstrated high affinity (43.8 +/- 3.0 nM ) and selectivity for the histamine H-3 receptor in vitro. In vivo, GT -2016 (3, 10 and 30 mg/kg i.p. and p.o.) was shown to cross the blood- brain barrier and dose-dependently bind to cortical histamine H-3 rece ptors. GT-2016 induced dose-dependent increases in histamine turnover at concentrations that exhibited significant histamine H-3, receptor o ccupancy. Also, in vivo microdialysis experiments were conducted in aw ake, freely moving rats treated with GT-2016. GT-2016 (10 and 30 mg/kg i.p.) increased histamine release by similar to 75% above baseline wi thin 1 hr, and elevated histamine release was observed for up to 2.5 h r after the higher dose. In contrast, GT-2016 was devoid of activity o n histamine methyltransferase in vitro at concentrations up to 3 mu M. Taken together, the results show that GT-2016 crosses the blood-brain barrier, binds to H-3 receptors and increases the release of histamin e in the cerebral cortex, consistent with blockade of presynaptic H-3 autoreceptors. In summary, these findings allowed us to identify and c haracterize the in vitro and in vivo biochemical properties of a novel H-3 receptor antagonist, GT-2016.