Peptoid NPhe in AGRP-Based c[Pro-Arg-Phe-Phe-Xxx-Ala-Phe-DPro] Scaffolds Maintain Mouse MC4R Antagonist Potency.

The melanocortin receptors are involved in numerous physiological functions and are regulated by agonists derived from the proopiomelanocortin gene transcript and two endogenous antagonists, agouti and agouti-related protein (AGRP). The key binding and functional determinant of AGRP, an MC3R and MC4R antagonist, is an Arg-Phe-Phe tripeptide sequence located on an exposed hexapeptide (Arg-Phe-Phe-Asn-Ala-Phe) loop. It has previously been observed that cyclizing this sequence through a DPro-Pro motif (c[Pro-Arg-Phe-Phe-Asn-Ala-Phe-DPro]) resulted in a macrocyclic scaffold with MC4R antagonist activity, with increased MC4R potency when a diaminopropionic acid (Dap) residue is substituted at position 5. In this report, a series of 11 single-peptoid substitutions were performed in the AGRP-derived macrocycles. While most peptoid substitutions decreased MC4R antagonist potency, it was observed that NPhe (compounds and ) or NDab (diaminobutyric acid, compound ) maintained MC4R antagonist potency. The NPhe substitutions also resulted in MC5R antagonist and inverse agonist activity equipotent to the parent scaffolds. These data may be used in the design of future MC4R and MC5R antagonist leads and probes that possess increased metabolic stability due to the presence of peptoid residues.