Australian Journal of Chemistry

The melanocortin system is essential for survival, with the melanocortin-3 and -4 receptors (hMC3R and hMC4R) regulating energy homeostasis and metabolism, and the melanocortin-1 receptor (hMC1R) controlling pigmentation and skin cancer prevention. However, achieving subtype selectivity among these receptors remains challenging due to their high sequence similarity. Here, we first systematically examined the impact of the α-MSH C-terminal tripeptide –Lys-Pro-Val (–KPV) on melanotropin conformation and receptor selectivity. Incorporation of –KPV enhanced binding affinity toward hMCRs and modulated receptor preference. We identified a selective hMC3R antagonist, peptide 5 ([CO(CH₂)₂CO-DNal(2′)-Arg-Trp-Lys]-Gly-Lys-Pro-Val-NH₂) and a selective hMC3R agonist, peptide 20 (H-DNal(2′)-c[Asp-Pro-DPhe-Arg-Trp-Lys]-Ala-Gly-Pro-Val-NH₂). Additionally, several hMC1R-selective agonists (peptides 9–11 and 13–18) were discovered. These findings reveal the pivotal role of the –KPV motif in modulating melanotropin selectivity and provide a framework for developing receptor subtype-selective melanocortin ligands.