Melanocortin tetrapeptides modified at the N-terminus, His, Phe, Arg, and Trp positions

The endogenous melanocortin agonists all contain the conserved His-Phe-Arg-Trp sequence proposed to be important for melanocortin receptor selectivity and stimulation. We have generated peptide libraries consisting of over 100 peptides modified at the N-terminus and at each of the four amino acid positions. These peptides were characterized at the mouse melanocortin MC1, MC3, MC4, and MC5 receptors for agonist or antagonist functional activity. The results from these studies include the identification of a nM MC4 versus MC3 receptor selective (>4700-fold) agonist (JRH 420-12), a nM MC4 receptor agonist that is a nM MC3 receptor antagonist (JRH 322-18), a nM MC5 receptor selective (>100-fold) agonist versus the MC1, MC3, and MC4 receptors (FFM 1-60), and side-chain substitutions that may be utilized for non-peptide design considerations.