Available online 25 March 2022, 101603

Melanocortin (MC) drugs act by binding to five different melanocortin receptors.

Their role in multiple organ systems and GPCR nature makes them very attractive as drug targets.

Several MC drugs have already been approved for treating various conditions.

New MC compounds are under clinical development for the treatment of additional indications.

Deeper understanding of GPCR signalling modulation and structure will help design improved MC drugs.

Melanocortin receptors have emerged as important targets with a very unusual versatility, as their widespread distribution on multiple tissues (e.g. skin, adrenal glands, brain, immune cells, exocrine glands) together with the variety of physiological processes they control (pigmentation, cortisol release, satiety mechanism, inflammation, secretions), place this family of receptors as genuine therapeutic targets for many disorders. This review focuses in the journey of the development of melanocortin receptors as therapeutic targets from the discovery of their existence in the early 1990 s to the approval of the first few drugs of this class. Two major areas of development characterise the current state of melanocortin drug development: their role in obesity, recently culminated with the approval of setmelanotide, and their potential for the treatment of chronic inflammatory and autoimmune diseases like rheumatoid arthritis, multiple sclerosis or fibrosis. The pro-resolving nature of these drugs offers the advantage of acting by mimicking the way our body naturally resolves inflammation, expecting fewer side effects and a more balanced (i.e. non-immunosuppressive) response from them. Here we also review the approaches followed for the design and development of novel compounds, the importance of the GPCR nature of these receptors in the process of drug development, therapeutic value, current challenges and successes, and the potential for the implementation of precision medicine approaches through the incorporation of genetics advances.

adrenocorticotropic hormone

G-protein coupled receptor

melanocyte stimulating hormone

GPCR

Melanocortin

Inflammation

Drug development

© 2022 Published by Elsevier Ltd.