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

Abstract

The mammalian neuropeptide, melanin-concentrating hormone, interacts with two G protein-coupled receptors, melanin-concentrating hormone receptor (MCHR) 1 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 antiobesity and antidepressant activity. Central activity of the selective MCHR1 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 evaluated using ex vivo binding with autoradiography. Effective doses of GW803430 (1 and 3 mg/kg p.o.) were correlated with antiobesity activity in a 14-day study of diet-induced obese rats. GW803430 was evaluated subsequently 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 (acute) and 3 and 10 (chronic) mg/kg p.o., 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 antiobesity 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.

Acute escitalopram treatment inhibits REM sleep rebound and activation of MCH-expressing neurons in the lateral hypothalamus after long term selective REM sleep deprivation

“…Anyway, our finding about MCH/Fos reducing the effect of escitalopram raises several intriguing new questions regarding the clinical effects of escitalopram and other SSRI antidepressants. One of these could be that the effect of serotonin on MCHcontaining neurons (van den Pol et al 2004) may be a pivotal component in the antidepressant effect of SSRIs, regarding that selective MCH1-R antagonist agents show antidepressant-like effects (Borowsky et al 2002;Gehlert et al 2009) and MCH administered into the dorsal raphe evokes a depressive-like behavior (Lagos et al 2011b;Torterolo et al 2011). In contrast, the role of REM reduction may be questioned by the fact that there are other effective antidepressants, such as bupropion, with its main effect on the noradrenergic and dopaminergic system without affecting the serotonergic system and not suppressing REMS either in human controls or depressed patients (Wilson and Argyropoulos 2005).…”

Effects of a specific MCHR1 antagonist (GW803430) on energy budget and glucose metabolism in diet‐induced obese mice

“…Previous work has shown GW803040 inhibited MCHR1 binding in different areas of the brain and exhibits substantial occupancy of the MCHR1 at doses of 1 mg kg À1 or greater (23). These authors (23) further evaluated the effects of the same compound at a dose of 10 mg kg À1 in MCHR1 þ/þ and MCHR1 À/À mice, respectively.…”

“…Previous work has shown GW803040 inhibited MCHR1 binding in different areas of the brain and exhibits substantial occupancy of the MCHR1 at doses of 1 mg kg À1 or greater (23). These authors (23) further evaluated the effects of the same compound at a dose of 10 mg kg À1 in MCHR1 þ/þ and MCHR1 À/À mice, respectively. The fact that MCHR1 À/À mice did not show a decrease in body weight, but MCHR1 þ/þ mice did, suggested that GW803040 produced significant reductions in body mass, fatness and food intake via MCHR1 antagonism (23).…”

“…These authors (23) further evaluated the effects of the same compound at a dose of 10 mg kg À1 in MCHR1 þ/þ and MCHR1 À/À mice, respectively. The fact that MCHR1 À/À mice did not show a decrease in body weight, but MCHR1 þ/þ mice did, suggested that GW803040 produced significant reductions in body mass, fatness and food intake via MCHR1 antagonism (23). Our findings are consistent with previous studies reporting reductions in body fat mass following administration of other MCHR1 antagonists (15,21,27,28).…”

“…GW803430 is a potent and selective non-peptide MCHR1 antagonist (22) that has been suggested to have weight-reducing effects (23). To examine exactly how GW803430 affected energy balance and glucose homeostasis, we evaluated energy budgets at early (day 4-6) and late (day 22-24) stages of a 30-day oral treatment, compared to a control group receiving only vehicle.…”