GSK1059865 is a potent antagonist of the orexin 1 receptor.

GSK1059865 (0.3?nM-10?nM) produces non-surmountable antagonism with a dose-dependent rightward shift of the OXA EC50 and a concomitant decrease of the agonist maximal response.?The calculated pKB value is 8.77±0.12 for GSK1059865.?GSK1059865 (0.1-3.3?μM) produces a classical surmountable profile with parallel rightward shift of the OXA EC50 without depression of the agonist maximal response.?Intraperitoneal administration of GSK1059865 produces a region-dependent inhibition of yohimbine-induced relative cerebral blood volume response.?The administration of GSK1059865 per se produces a weak relative cerebral blood volume increase in several brain regions.?GSK1059865-pretreated animals exhibit slightly higher baseline mean arterial blood pressure values than controls.Treatment with GSK1059865 significantly decreases ethanol drinking in a dose-dependent manner in CIE-exposed mice.?In contrast GSK1059865 decreases drinking in air-exposed mice only at the highest dose used.?There is no effect of GSK1059865 on sucrose intake.