Melanin-concentrating hormone receptor antagonists as potential antiobesity agents

Melanin-concentrating hormone (MCH) has been regarded as an appetite-stimulating peptide since the mid 1990s. The recent discovery of two receptors for this orexigenic peptide has prompted efforts to block the effects of MCH through the development of receptor antagonists. Pharmacological evidence supports the use of melanin-concentrating hormone receptor 1 (MCH1R)as an important receptor for mediating the effects of MCH on appetite and body weight. The cloning of the MCH1R has enabled high-throughput screening to identify ligands for this receptor. Subsequent medicinal chemistry efforts have lead to the disclosure of several structurally diverse MCH1R antagonists. Many of these molecules appear drug-like and two have shown impressive effects on reduction of feeding and/or body weight in animal models of obesity. The reports of such drug-like molecules, coupled with the strong evidence for MCH1R as an important regulator of body weight, suggest that inhibitors of MCH1R may soon be investigated as therapeutics for obesity in clinical trials.