MSG606 TFA

MSG606 TFA is the trifluoroacetate salt form of MSG606 (CAS No.: 1416983-77-1). MSG606 is a thioether-cyclized modified peptide compound with the amino acid sequence Cyclo [(CH₂)₃CO-Gly-His-D-Phe-Arg-D-Trp-Cys (S-)]-Asp-Arg-Phe-Gly-NH₂, and is a highly selective melanocortin 1 receptor (MC1R) antagonist. It has a binding IC₅₀ of 17 nM for human MC1R, with more than 70-fold selectivity over MC3R (IC₅₀ 3900 nM) and MC5R (IC₅₀ 1300 nM), and shows no obvious binding to MC4R at a concentration of 10⁻⁵ M; functionally, it has no intrinsic agonist activity at MC1R, does not induce cAMP production in cells stably transfected with human MC1R at 10⁻⁵ M, and has cAMP induction EC₅₀ values of 103 nM for MC3R and 1300 nM for MC5R.

This compound participates in two core pathways by antagonizing MC1R: one is the sex-specific regulatory pathway of morphine-induced hyperalgesia, and the other is the α-MSH-mediated MC1R/PKA/CREB/MITF melanogenesis pathway; blocking the latter can downregulate tyrosinase transcription and inhibit melanin synthesis. In cellular experiments, MSG606 is commonly used in HEK293 cells stably transfected with human melanocortin receptors to determine receptor binding affinity and cAMP functional activity, and it can also be used as an MC1R-specific tool inhibitor to validate the mechanism of melanogenesis signaling pathways in an α-MSH-induced PIG1 melanocyte model.

Animal experiments can be used for the treatment of disease models, such as a mouse model of hyperalgesia induced by continuous morphine infusion, with intracerebroventricular administration at a dose of 7.5 μg / mouse (5 μL volume), and intrathecal administration is also effective; in female mice infused with high-dose morphine at 40 mg/kg per day, MSG606 specifically reverses hyperalgesia, increasing pain latency by approximately 60%, with no significant effect in male mice; in a hyperalgesia model induced by low-dose morphine at 1.6 mg/kg per day, MSG606 has no reversal effect; after acute subcutaneous progesterone pretreatment in ovariectomized female mice, the hyperalgesia-reversing effect of MSG606 is significantly enhanced, showing sex-difference characteristics regulated by ovarian hormones.

References:

[1] Juni A, Cai M, Stankova M, Waxman AR, Arout C, Klein G, Dahan A, Hruby VJ, Mogil JS, Kest B. Sex-specific mediation of opioid-induced hyperalgesia by the melanocortin-1 receptor. Anesthesiology. 2010 Jan;112(1):181-8. doi: 10.1097/ALN.0b013e3181c53849. PMID: 19996949; PMCID: PMC4642894.

[2] Arout CA, Caldwell M, Rossi G, Kest B. Spinal and supraspinal N-methyl-D-aspartate and melanocortin-1 receptors contribute to a qualitative sex difference in morphine-induced hyperalgesia. Physiol Behav. 2015 Aug 1;147:364-72. doi: 10.1016/j.physbeh.2015.05.006. Epub 2015 May 14. PMID: 25982086.

[3] Li J, Jiang S, Huang C, Yang X. Atraric Acid Ameliorates Hyperpigmentation through the Downregulation of the PKA/CREB/MITF Signaling Pathway. Int J Mol Sci. 2022 Dec 15;23(24):15952. doi: 10.3390/ijms232415952. PMID: 36555593; PMCID: PMC9788525.