Sub-Nanomolar hMC1R Agonists by End-Capping of the Melanocortin Tetrapeptide His- -Phe-Arg-Trp-NH2

Twenty three derivatives of the core fragment His6- -Phe7-Arg8-Trp9-NH2 end-capped with carboxylic and sulfonic acids were synthesized and evaluated at human melanocortin receptors (hMC1, hMC3, and hMC4Rs). The SAR within this series allowed us to map the hMCRs near the His6 binding site and design a superpotent MC1R agonist, LK-184, Ph(CH2)3CO-His- -Phe-Arg-Trp-NH2 (19) with EC50 0.01 nM (5 nM at MC3 and MC4Rs).