Drug target discovery by pharmacogenetics: mutations in the melanocortin system and eating disorders

The identification of the genetic defect underlying the obese phenotype of the viable yellow mouse, ectopic overexpression of the agouti protein which act, as antagonist at the melanocortin-4 receptor, together with the demon stration that the brain melanocortin system was one major downstream effect or pathway of leptin signaling has put forward melanocortin receptors as dr ug targets for obesity, The lack of compounds acting as melanocortin recept or antagonists was the reason why pharmaco logical studies had not recogniz ed melanocortin receptors as important drug targets earlier. Blockade of br ain melanocortin receptors results in increased food intake and body weight , whereas stimulation of the brain melanocortin system results in decreased food intake and activation of the hypothalamo-pituitary-adrenal axis. Anor exia nervosa is characterized by decreased body weight and food intake acco mpanied by changes in neuroendocrine systems such as strong activation of t he hypothalamo-pituitary-adrenal axis. Since agouti-related protein suppres ses the activity of the melanocortin system, the AgRP gene was investigated as candidate gene in anorexia nervosa. One variant of the AgRP gene was as sociated with anorexia nervosa. thus putting forward melanocortin receptor blockade as putative pharmacotherapy. Investigating variations in candidate genes in disease populations appears to be a fruitful approach towards the identification of drug targets. (C) 2001 Published by Elsevier Science B.V .