The melanocortin system is implicated in multiple physiological pathways including pigmentation, inflammation, erectile function, feeding behavior, energy homeostasis, weight homeostasis, and exocrine gland function, just to list a few. The endogenous agonists for the melanocortin receptors include the gene transcripts derived from the proopiomelanocortin gene and include the core tetrapeptide His-Phe-Arg-Trp sequence postulated to be important for melanocortin receptor selectivity and stimulation. Posttranslational processing of the proopiomelanocortin derived agonists results in the N-terminal acetylation and C-terminal amidation of α-melanocyte stimulation hormone (α-MSH). In this study we generated 25 N-terminally "capped" tetrapeptides containing the core sequence X-His-D-Phe-Arg-Trp-NH2 and pharmacologically characterized them at the mouse melanocortin MC1 receptor, melanocortin MC3 receptor, melanocortin MC4 receptor, and melanocortin MC5 receptor. The N-terminal "capping" groups consisted of linear, cyclic, or aromatic moieties and all resulted in full agonist activity at the melanocortin receptors examined in this study. Increasing aliphatic chain length increased potency of the tetrapeptide derivatives, with the addition of octanoyl capping group resulting in 70- to 110-fold increased tetrapeptide potency at the melanocortin MC1 receptor (EC50=0.4 nM), melanocortin MC3 receptor (EC50=4.0 nM), and melanocortin MC4 receptor (EC50=0.4 nM) while only enhancing potency at the melanocortin MC5 receptor (EC50=0.8 nM) by 8-fold, compared to the tetrapeptide His-D-Phe-Arg-Trp-NH2. This octanoyl derivative surprisingly resulted in a 14-fold greater potency than α-MSH (EC50=5.4 nM) at the mouse melanocortin MC4 receptor implicated in feeding behavior and obesity. The 3,3,3-triphenylpropionyl derivative resulted in greater than 14 μM agonist potencies at the melanocortin MC1 receptor, melanocortin MC3 receptor, and melanocortin MC4 receptor and possessed a 140 nM agonist EC50 value at the melanocortin MC5 receptor. This 3,3,3-triphenylpropionyl-His-D-Phe-Arg-Trp-NH2 peptide is a 100-fold selective agonist for the melanocortin MC5 receptor, versus the other melanocortin receptors studied herein, and is the first melanocortin MC5 receptor selective tetrapeptide derivative reported to date with nanomolar potency.
Bibliographical noteFunding Information:
This work has been supported by NIH Grant RO1-DK57080. Carrie Haskell-Luevano is a recipient of a Burroughs Wellcome fund Career Award in the Biomedical Sciences. We would like to give special thanks to Dr. Arthur S. Edison and Mr. James R. Rocca at the University of Florida McKnight Brain Institute for their extensive technical assistance in the acquisition and analysis of NMR data.
- G-protein-coupled receptor
- Melanocortin receptor