Melanocortin-4 receptor antagonists as potential therapeutics in the treatment of cachexia.

The melanocortin-4 (MC4) receptor subtype plays a pivotal role in body weight regulation. Knock-out or mutation of MC4 receptors in animals or humans leads to severe obesity and acute or sub-acute antagonism of central MC4 receptors produces an increase in food intake and a decrease in metabolism. Knock-out or antagonism of MC4 receptors in animal models of cachexia leads to a protection from anorexia and the loss of both lean and fat body mass, suggesting that an MC4 antagonist may be beneficial in wasting diseases, which are poorly treated by available therapies. Considerable progress has been made in the discovery of non-peptide antagonists with high affinity and selectivity for MC4 receptors. Optimization of these compounds has produced molecules that are active upon systemic administration and are effective in protecting against cachectic symptoms in animal models of tumor-induced wasting. Further development of such compounds is greatly anticipated as a potential means to combat the cachexia that results from chronic diseases such as cancer, AIDS, renal failure, liver failure, congestive heart failure and lung disease.