Editorial [Hot Topic: Therapeutic Application of Melanocortin-4 Receptor Ligands (Guest Editor: John P. Mayer)]

From the initial discovery of its role in amphibian skin pigmentation to the more recently established involvement in multiple physiological processes such as food intake, energy balance, inflammation, sexual function, depression and anxiety, the history of the melanocortin system represents one of the more important chapters in pituitary endocrinology. Although certain therapeutic applications were foreseeable decades ago, it was only following the cloning, expression and biological characterization of the MC-1 through MC-5 receptor subtypes in the early 1990's that the scientific community began to contemplate the full therapeutic utility of the melanocortin pathway. While each of the five receptor subtypes represents a potential drug target, the MC-4 receptor (MC-4R) subtype has received by far the greatest share of interest and visibility. In this issue of Current Topics in Medicinal Chemistry we have focused on four MC-4R related therapeutic indications which have received considerable recognition. 1) Extensive preclinical and clinical evidence suggests that the MC-4R subtype is intimately involved in the control of food intake and energy expenditure. Numerous animal studies with either melanocortin ligands or transgenic rodents have implicated the involvement of this receptor in food intake and body weight regulation. The correlation of mutations in the human MC-4R with obesity has reinforced these preclinical findings and suggested that stand alone or adjunctive administration of a MC-4R agonist may be beneficial in antiobesity therapy. Progress in this area is summarized by Paul Emmerson and co-workers from Eli Lilly and Co. 2) Based on the above preclinical and clinical validation, an equally convincing argument can also be made for the use of MC-4R antagonists for the treatment of conditions characterized by caloric deficit such as cachexia and anorexia resulting from cancer or AIDS. In these scenarios, the down regulation of MC-4R signaling could offer an important treatment option. This therapeutic approach has been validated in a number of animal models of tumor-induced wasting. The rationale and progress in this area is reviewed by Alan Foster and Chen Chen from Neurocrine Biosciences. 3) Treatment of male and female sexual dysfunction represents another potential therapeutic indication for MC-4R agonists. Stimulation of penile erection has been demonstrated with selective MC-4R agonists in a number of rodent models. More importantly, a statistically significant erectile response has been shown clinically upon intranasal or subcutaneous administration of bremelanotide, PT-141, a nonselective melanocortin agonist. Additionally, these agents may also be useful in the treatment of female sexual arousal disorder. These indications are updated by Annette Shadiack and co-workers from Palatin Technologies. 4) The potential utility of MC-4R antagonists in the treatment of CNS disorders is highlighted through application to anxiety and depression. The key observation that melanocortin agonists produce stress-induced grooming behavior in rodents which is reversible through administration of a selective antagonist prompted exploration of this pathway for the treatment of anxiety and depression. This novel therapeutic concept is reviewed by Shigeyuki Chaki and Taketoshi Okubo from the Taisho Pharmaceutical Company.