JPET #143362 1 Preclinical Evaluation of Melanin-Concentrating Hormone Receptor 1 (MCHR1) Antagonism for the Treatment of Obesity and Depression

The mammalian neuropeptide, melanin-concentrating hormone (MCH) interacts with two G-protein coupled receptors, MCHR1 and MCHR2; however, only MCHR1 is expressed in rats and mice. In the present study, we evaluated MCHR1 antagonism in preclinical models believed to be predictive of anti-obesity and antidepressant activity. Central activity of the selective MCHR1 antagonist, 6-(4-Chloro-phenyl)-3-[3-methoxy4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3H-thieno[3,2-d]pyrimidin-4-one (GW803430), was evaluated using ex vivo binding with autoradiography. Effective doses of GW803430 (1 and 3 mg/kg, p.o.) were correlated with anti-obesity activity in a 14 day study of diet-induced obese rats. Subsequently, GW803430 was evaluated for antidepressant-like effects in mice and rats. Acute and subchronic administration reduced immobility time in the mouse forced-swim test at doses of 3 mg/kg, p.o. (acute) and 3 and 10 mg/kg, p.o. (chronic), an effect that was absent in MCHR1-/mice. Combined subeffective doses of GW803430 (0.3 and 1 mg/kg, p.o.) and imipramine (5 mg/kg) produced a robust antidepressant-like response. The compound was also active in the tail suspension test at a dose of 10 mg/kg, p.o. GW803430 (30 mg/kg, p.o.) significantly reduced submissive behaviors at weeks 2 and 3, a model of submissive behavior that may predict antidepressant onset. GW803430 decreased marble-burying in mice at doses of 3, 10 and 30 mg/kg, p.o., an assay that detects anxiolytic-like effects. Thus, GW803430 produces robust anti-obesity and antidepressant-like effects in rats and mice at doses that compete for central MCHR1 in vivo. As such, MCHR1 should be considered as a promising target for future drug discovery efforts. This article has not been copyedited and formatted. The final version may differ from this version. JPET Fast Forward. Published on January 30, 2009 as DOI: 10.1124/jpet.108.143362 at A PE T Jornals on A uust 0, 2017 jpet.asjournals.org D ow nladed from