GSK1059865 is a highly selective orexin-1 receptor antagonist that significantly reduces voluntary ethanol intake in ethanol-dependent mice following chronic intermittent ethanol exposure, producing dose-dependent suppression of alcohol consumption without affecting sucrose intake, while exhibiting minimal effects in non-dependent controls except at high doses, thereby highlighting its utility for investigating orexin signaling in alcohol dependence and addictive behaviors.

In receptor assays, GSK1059865 acted as an Orexin-1 (OX1) receptor antagonist with a pKB of 8.77. At low concentrations (0.3-10 nM), it functioned as an insurmountable antagonist suppressing the maximal Orexin-A response, whereas at higher concentrations (0.1-3.3 μM), it exhibited a surmountable profile characterized by a parallel rightward shift of the EC50 [1].

In ethanol-dependent mice (CIE model), GSK1059865 reduced ethanol consumption in a dose-dependent manner. In control mice (air-exposed), consumption was only affected at the highest dose tested. The compound showed no effect on sucrose intake. In rat fMRI studies, intraperitoneal administration of GSK1059865 inhibited the relative cerebral blood volume (rCBV) response induced by Yohimbine in specific brain regions. Pretreatment with the compound was associated with a baseline mean arterial blood pressure higher than that of the control group [1][3].

DMSO: 160 mg/mL (366.7 mM), Sonication is recommended.