Melanocortin receptors - identification and characterization by melanotropic peptide agonists and antagonists

Foundational review by the Mac E. Hadley and Victor J. Hruby group at the University of Arizona — an obligatory historical reference on melanocortin receptors (MCRs). Hadley and Hruby authored the structural modifications that led to NDP-α-MSH ([Nle⁴,D-Phe⁷]α-MSH), the super-potent enzymatically stable analog that served as the basis for development of afamelanotide, melanotan I and II.

This review consolidated the knowledge accumulated in the 1980s-1990s on five subtypes of melanocortin receptors (MC1R, MC2R, MC3R, MC4R, MC5R), their tissue distributions and physiological functions: MC1R in melanocytes (pigmentation) and immune cells; MC2R in adrenal cortex (ACTH); MC3R/MC4R in CNS (appetite, energy balance, sexuality); MC5R in exocrine glands. α-MSH was characterized as a pan-melanocortin agonist with variable affinities for the five subtypes.

The work discusses in depth the structure-activity of synthetic α-MSH analogs developed by the group: D-amino acid substitutions (NDP-MSH), cyclization for restricted conformations, C-terminal fragments (Ac-DPhe-Arg-DTrp-NH₂), and subtype-selective analogs. These compounds were critical tools for pharmacological characterization of MCRs after their cloning in 1992-1993. The authors also anticipate therapeutic applications — appetite (obesity), inflammation, photoprotective pigmentation — that materialized into clinical drugs decades later (setmelanotide, afamelanotide).

This review is an obligatory reference for any work on α-MSH and the melanocortin system. It establishes the scientific basis for the current use of α-MSH and its analogs in research and clinic, and contextualizes the subsequent development of setmelanotide (FDA 2020) for monogenic obesity and afamelanotide (FDA 2019) for erythropoietic protoporphyria — two modern therapeutic indications based on the knowledge consolidated here.