The melanocortin receptors as targets for general obesity: contextualizing clinical failures and analyzing future perspectives

The melanocortin system is a genetically conserved and clinically validated target for the treatment of obesity. Hundreds of studies establish the role of the melanocortin receptors, particularly the melanocortin-4 receptor, in food intake, weight control, and energy expenditure. Over the last several decades, the pharmaceutical industry pursued melanocortin-4 receptor-selective agonists for the treatment of general obesity. Many candidates failed to demonstrate meaningful weight loss in the clinic due to potency, selectivity or side effect profiles, leading pharmaceutical companies to dismiss the use of melanocortin compounds for treating general obesity. Recent advancements in the field demonstrate the importance of modulating both melanocortin-3 and -4 receptors for optimal weight loss and offer solutions to mitigate undesired side effects associated with melanocortin agonism. Considering these discoveries, it is imperative to review past clinical attempts and compare them with programs currently in development. A thorough understanding of the shortcomings of past clinical programs will enable the development of novel melanocortin therapeutics for the treatment of general obesity.