Target Background

The melanocortin receptors (MCRs) are a family of five G protein-coupled receptors (MC1R–MC5R) that mediate the effects of melanocortin peptides derived from proopiomelanocortin (POMC), including adrenocorticotropic hormone (ACTH) and α-, β-, and γ-melanocyte-stimulating hormones (MSH). Each subtype exhibits distinct tissue distribution and physiological function, spanning pigmentation, steroidogenesis, energy balance, and immune regulation.

Upon ligand binding, MCRs primarily couple to Gs proteins, stimulating adenylate cyclase, increasing intracellular cAMP, and activating downstream protein kinase A (PKA) and Epac signaling pathways. MC1R, expressed in melanocytes, regulates skin and hair pigmentation and photoprotection. MC2R, the ACTH receptor in the adrenal cortex, is essential for glucocorticoid synthesis. MC3R and MC4R, found in the hypothalamus and other CNS regions, play central roles in appetite regulation, satiety, and energy expenditure, with MC4R mutations strongly associated with monogenic obesity. MC5R, broadly expressed in exocrine glands and immune cells, modulates sebaceous gland activity and inflammatory responses.

Pharmacologically, MCRs are important therapeutic targets across multiple fields. MC1R agonists are being explored for dermatological and anti-inflammatory indications, while MC4R agonists have gained approval for treating rare genetic obesity syndromes. Broader efforts aim to develop subtype-selective ligands and multi-receptor agonists to address complex metabolic and inflammatory diseases. With their diverse physiological roles, MCRs remain at the forefront of GPCR-based drug discovery.