Abstract

Mu opioid receptor (MOR) agonism induces palatable food consumption principally through the modulation of rewarding properties of food. GSK1521498, (N-{[3,5-difluoro-3'-(1H-1,2,4-triazol-3-yl)-4-biphenylyl]methyl}-2,3-dihydro-1H-inden-2-amine phosphate (1:1), is a novel opioid receptor inverse agonist that, based on in vitro affinity assays, is greater than 10-fold or 50-fold selective for human or rat MOR, respectively, compared with kappa opioid receptors (KOR) and delta opioid receptors (DOR). Similarly, preferential MOR occupancy versus KOR and DOR was observed by autoradiography in brain slices from Long Evans rats dosed orally with the drug. GSK1521498 suppressed nocturnal food consumption of standard or palatable chow in lean and diet-induced obese (DIO) Long Evans rats. Both the dose-response relationship and time course of efficacy in lean rats fed palatable chow correlated with mu receptor occupancy and the plasma concentration profile of the drug. Chronic oral administration of GSK1521498 induced body weight loss in DIO rats which was comprised of fat mass reduction. The reduction in body weight was equivalent to the cumulative reduction in food consumption, thus, the effect of GSK1521498 on body weight is related to inhibition of food consumption. GSK1521498 suppressed the preference for sucrose-containing solutions in lean rats. In operant response models also using lean rats, GSK1521498 reduced the reinforcement efficacy of palatable food reward and enhanced satiety. In conclusion, GSK1521498 is a potent, MOR-selective inverse agonist that modulates hedonic aspects of ingestion and, therefore, could represent a pharmacological treatment for obesity and binge-eating disorders.