The role of melanin-concentrating hormone (MCH), a cyclic 19-amino-acid neuropeptide, in feeding behaviour has been well established in recent years, leading to interest in the possibility of antagonizing its action as a therapeutic approach to obesity. Now, as Borowsky et al. report in Nature Medicine, antagonists of MCHR1 — one of the two G-protein-coupled receptors (GPCRs) that mediate the effects of MCH — might have promise not only in the management of obesity, but also as a treatment for depression and anxiety.

Screening of a GPCR-biased compound collection led to the identification of SNAP-7941, a nanomolar inhibitor of MCHR1 that has 1,000-fold selectivity over the other receptor for MCH, and also over other GPCRs associated with food intake, such as the receptor for neuropeptide Y. Systemic pre-treatment with SNAP-7941 inhibited the increase in food intake elicited by MCH, supporting a role for MCHR1 in mediating MCH-stimulated food intake.

But would pharmacological blockade of MCHR1 reduce basal body weight, or would compensatory mechanisms come into play? The authors found that acute treatment with SNAP-7941 decreased palatable food intake in rats, and that chronic treatment resulted in a marked, sustained decrease in body weight in rats with diet-induced obesity, providing strong support that MCHR1 is a viable target for the treatment of obesity.

Although MCH has been studied most extensively in relation to food intake and body weight, the distribution of SNAP-7941-binding sites (assessed using [3H]-labelled SNAP-7941) and MCHR1 immunoreactivity (determined previously) in regions of the brain such as the amygdala, nucleus accumbens, dorsal raphe and locus coeruleus, indicated that MCH might be involved in mood regulation and anxiety. To investigate this, Borowsky et al. evaluated SNAP-7941 in three animal models of depression and/or anxiety, and compared the results with those for clinically approved drugs. In the rat forced-swim test, which is an experimental model of depression, the profile of SNAP-7941 was similar to the selective serotonin-reuptake inhibitor fluoxetine, and in the rat social-interaction test, which is a model of anxiety, the profile of SNAP-7941 was indicative of an anxiolytic activity analogous to the prototypical benzodiazepine chlordiazepoxide. Finally, in the guinea-pig maternal-separation vocalization test, which is a model of anxiety and depression, the responses to SNAP-7941 were comparable to those to buspirone. So, although the role of MCH in human psychiatric disorders remains largely unknown, it seems that further assessment of MCHR1 antagonists for the treatment of depression and/or anxiety could be warranted.