Ligands for Melanocortin Receptors: Beyond Melanocyte-Stimulating Hormones and Adrenocorticotropin.

This review paper traces more than a century of melanocortin research, from the initial discovery of melanocortins in 1916 to contemporary therapeutic applications. It describes the five known melanocortin receptors (MC1R–MC5R), with particular attention to the two neural receptors—MC3R and MC4R—which are predominantly expressed in the central nervous system and play key roles in regulating energy homeostasis. The authors systematically categorize ligands for these receptors into three groups: classical ligands (endogenous melanocyte-stimulating hormones and agouti-related peptide), nonclassical ligands (lipocalin 2, β-defensins, small molecules, and pharmacoperones), and clinically approved or repurposed agents (ACTH, setmelanotide, bremelanotide, and certain repurposed drugs). The review highlights how early medicinal chemistry efforts modifying endogenous peptides yielded potent and selective tool compounds, and how targeting neural MCRs has emerged as a viable strategy for metabolic conditions such as obesity and cachexia. Limitations inherent to this paper include its review design—it synthesizes existing literature rather than generating new experimental data—and therefore cannot independently establish clinical efficacy or safety for any specific ligand.

Why this grade: This is a narrative review synthesizing over a century of melanocortin receptor ligand research; it generates no original experimental data and does not constitute a primary clinical or preclinical study.