Design and Synthesis of a Novel Tetrapeptide with Improved Selectivity Towards the hMC1R

The melanocortin system plays vital roles with regard to maintaining homeostasis. The endogenous melanotropin peptides (α-, β-, γ-melanocyte stimulating hormones (MSH) are derived from the proopiomelanocortin (POMC) preprohormone gene. These melanotropin peptides all contain the same core pharmacophore amino acid sequence: His-Phe-Arg-Trp [1,2]. This sequence is important for binding to the five human melanocortin receptors (MC1R, MC2R, MC3R, MC4R, and MC5R). Binding of the endogenous melanotropin peptides to these melanocortin receptors results in several responses depending on which receptor is activated. Such responses involve feeding behavior, learning behavior, pain modulation, pigmentation, and sexual function. The primary native ligand for all five of the melanocortin receptors is α-MSH. Unfortunately, α-MSH along with the other endogenous melanotropin peptides do not possess high selectivity for any of the melanocortin receptors as well as are biologically unstable. Thus, the quest to discover potent, biologically stable, and highly selective peptides began.