MC1R antagonist-MSG 606

Introduction 

MSG 606 (Cyclo-[(CH₂) ₃CO-Gly-His-D-Phe-Arg-D-Trp-Cys(S-)]-Asp-Arg-Phe-Gly-NH₂) is a potent and novel cyclic thioether peptide, and selectively antagonizes the MC1R (melanocyte stimulating hormone receptor) subunit (IC₅₀ = 17 nM). The MC1R is present on the surface of various immune cells, macrophages, fibroblasts, monocytes, mast cells and neutrophils and is a potential target for the development of agents for the treatment of acute and chronic inflammatory diseases, neurodegenerative diseases and systemic host reactions. MSG606 is an analogue of γ-MSH (γ-melanocyte-stimulating hormone: H-Tyr-Val-Met-Gly-His-Phe-Arg-Trp-Asp-Arg-Phe-Gly-OH) by cyclizing γ-MSH using a thioether bridge, and the bridge is incorporated between a cysteine side chain and an N-terminal bromoacyl group.

Biological Activity

MSG 606 is the most selective antagonist for the human MC1R to date. Further pharmacological studies have shown that this peptide can specifically target melanoma cells. The NMR analysis of this peptide in a membrane–like environment reveals a new turn structure, specific to the MC1R antagonist, at the C terminal, wherein the side chain and backbone conformation of D-Trp⁵ and Phe⁹ of the peptide are contributors to the MC1R selectivity. Like the most peptides, γ-MSH susceptible to proteplysis in vivo which potentially decreases it beneficial activities, so the thioether bridge of MSG 606 stabilizes the bioactivity of γ-MSH while maintaining its full bioactivity. And it will boost applications of peptide-based drugs in human medicine.

Function

The MC1R is one of five G-protein coupled receptors of the melanocortin subfamily, MC1R gene plays a major role in regulating of fur color in mammals, and α-MSH (α-Melanocyte-stimulating hormone) and ACTH (adrenocorticotropic hormone) are endogenous nonselective agonists for MC1R. Within the last three decades, accumulating evidences have suggested that melanocortin antagonists are potential analgesics for treatment of chronic pain, and the melanocortin peptides regulate pain through MC1R and MC4R. The MC1R is known to be expressed in the PAG (periaqueductal gray matter) of the brain and this is where it plays a role in pain regulation. Delaney et al reported a reduced inflammatory pain response and an increased tolerance to noxious heat in female mice lacking MC1R. Arout et al demonstrated that selective MC1R antagonists MSG606 reversed systemic morphine infusion-induced hyperalgesia in females not males.

References:

1. Minying Cai, Magda Stankova, Alexander V Mayorov, Dhanasekaran Muthu, Zhehui Yang, Devendra Trivedi, Christopher Cabello, and Victor J. Hruby. An Unusual Conformation of MSH Analogues Leads to a Selective Human Melanocortin 1 Receptor Antagonist for Targeting Melanoma Cells. Biochemistry. 2013, 52 (4), 752-764.

2. Caroline A. Arou, Megan Caldwell, Grace Rossi, Benjamin Kest. Spinal and supraspinal N-methyl-D-aspartate and melanocortin-1 receptors contribute to a qualitative sex difference in morphine-induced hyperalgesia. Physiology & Behavior, 2015, 147, 364-372.

3. Aaron Juni, Minying Cai, Magda Stankova, Amanda R. Waxman, Caroline Arout, Gad Klein, Albert Dahan, Victor J. Hruby, Jeffrey S. Mogil, Benjamin Kest. Sex-specific Mediation of Opioid-induced Hyperalgesia by the Melanocortin-1 Receptor. Anesthesiology, 2010, 112, 181-188.