Preclinical Evaluation of Melanin-Concentrating Hormone Receptor 1 Antagonism for the Treatment of Obesity and Depression

• DOI: 10.1124/jpet.108.143362
• Publication Date: 2009-01-31T02:53:34Z
• Authors: Donald R. Gehlert; Kurt Rasmussen; Janice Shaw; Xia Li; Paul Ardayfio; Libbey Craft; Tamer Coskun; Hong Y. Zhang; Yanyun Chen; Jeffrey M. Witkin
• Keywords: Melanin-concentrating hormone; Depression

The mammalian neuropeptide, melanin-concentrating hormone, interacts with two G protein-coupled receptors, hormone receptor (MCHR) 1 and MCHR2; however, only MCHR1 is expressed in rats mice. In the present study, we evaluated antagonism preclinical models believed to be predictive of antiobesity antidepressant activity. Central activity selective antagonist, GW803430 [6-(4-chloro-phenyl)-3-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-3H-thieno[3,2-d]pyrimidin-4-one], was using ex vivo binding autoradiography. Effective doses (1 3 mg/kg p.o.) were correlated a 14-day study diet-induced obese rats. subsequently for antidepressant-like effects mice Acute subchronic administration reduced immobility time mouse forced-swim test at (acute) 10 (chronic) p.o., an effect that absent MCHR1(-/-) Combined subeffective (0.3 imipramine (5 mg/kg) produced robust response. compound also active tail suspension dose p.o. (30 significantly submissive behaviors weeks 2 3, model behavior may predict onset. decreased marble burying 10, 30 assay detects anxiolytic-like effects. Thus, produces compete central vivo. As such, should considered as promising target future drug discovery efforts.