Extensive studies in rodents with
melanin-concentrating hormone (MCH) have demonstrated that the
neuropeptide hormone is a potent orexigen. Acutely, MCH causes an increase in food intake, while chronically it leads to increased
weight gain, primarily as an increase in fat mass. Multiple knockout mice models have confirmed the importance of MCH in modulating energy homeostasis. Animals lacking MCH, MCH-containing neurons, or the
MCH receptor all are resistant to diet-induced
obesity. These genetic and pharmacologic studies have prompted a large effort to identify potent and selective
MCH receptor antagonists, initially as tool compounds to probe pharmacology in models of
obesity, with an ultimate goal to identify novel
anti-obesity drugs. In animal models, MCH antagonists have consistently shown efficacy in reducing food intake acutely and inhibiting
body-weight gain when given chronically. Five compounds have proceeded into clinical testing. Although they were reported as well-tolerated, none has advanced to long-term efficacy and safety studies.