a-MSH TFA

α‑Melanocyte-stimulating hormone (α‑MSH, CAS No.: 171869-93-5) is a 13-mer peptide (Ac‑Ser‑Tyr‑Ser‑Met‑Glu‑His‑Phe‑Arg‑Trp‑Gly‑Lys‑Pro‑Val‑NH₂) generated by cleavage of proopiomelanocortin (POMC). It acts as an endogenous agonist of the melanocortin receptors MC1R–MC5R, with the highest affinity for MC1R, at nanomolar or even subnanomolar levels. By activating the MC1R Gαs‑AC‑cAMP pathway, α‑MSH promotes melanin synthesis in melanocytes and skin pigmentation, accompanied by rapid endocytosis of the receptor‑ligand complex; in the hypothalamus, it acts on MC3R and MC4R to participate in the regulation of energy homeostasis, suppressing food intake, increasing energy expenditure, and regulating blood pressure and heart rate through the sympathetic nervous system; in addition, it has anti-inflammatory and cytoprotective effects in multiple organs. Based on its high affinity for MC1R, engineered analogs (such as Ac‑[Nle⁴,D‑Phe⁷]‑α‑MSH) have a binding IC₅₀ of approximately 0.21 nM for MC1R and are widely used as MC1R-targeting molecules.

At the cellular level, mouse melanoma cells such as B16/F1 and B16/F10, as well as human-derived melanoma cells, are commonly used in receptor binding, internalization, and melanogenesis assays. α‑MSH and its analogs can generally activate the MC1R‑cAMP pathway and induce melanin synthesis at nanomolar concentrations. An RGD-conjugated α‑MSH analog reduced the clonogenicity of B16 cells by approximately 65% after treatment at 100 nM for 3 hours, reflecting both receptor-targeting and tumor-suppressive potential. In vitro studies have also shown that α‑MSH, at appropriate concentrations, can inhibit the release of pro-inflammatory factors, alleviate oxidative damage, and exert protective effects on hepatocytes and other tissue cells.

In animal experiments, α‑MSH significantly alleviated hepatic necrosis and reduced plasma ALT/AST in an acetaminophen-induced acute liver injury model in male CBA mice (2.5 mg/kg, intraperitoneal injection), indicating its anti-inflammatory and organ-protective effects; this effect was completely blocked by its antisense pentapeptide LVKAT (0.8 mg/kg, co-injected equimolarly with α‑MSH), supporting an α‑MSH-dependent mechanism. In mouse models such as B16 melanoma, various radiolabeled cyclic α‑MSH analogs (such as ⁹⁹ᵐTc- and ¹¹¹In-labeled analogs) can efficiently accumulate in tumors with high MC1R expression, with tumor uptake reaching approximately 4%–17% ID/g; after further labeling with therapeutic radionuclides such as ¹⁸⁸Re, ¹⁷⁷Lu, and ²¹²Pb, they can inhibit tumor growth and prolong survival in a dose-dependent manner, forming a typical class of MC1R-targeted radiotherapeutic probes.

At the clinical level, natural α‑MSH and structurally optimized analogs have been used in humans to induce tanning, improve sexual function, and for other purposes. Low-dose administration is generally well tolerated, with no significant systemic toxicity observed. Epidemiological studies show that in non-diabetic overweight/obese individuals with hypertension, plasma α‑MSH levels are not significantly correlated with body weight or the degree of blood pressure elevation, whereas neuropeptide Y is positively correlated with obesity and hypertension, suggesting that peripheral α‑MSH levels are not a major driver in human metabolic syndrome. Clinical studies of α‑MSH analogs as radioactive imaging agents or therapeutic probes remain at an early stage. Preliminary data suggest that ¹¹¹In-labeled bivalent α‑MSH analogs can achieve a sensitivity of approximately 89% in melanoma imaging, demonstrating favorable potential for MC1R-targeted diagnosis and therapy.

References:

[1] Quinn T, Zhang X, Miao Y. Targeted melanoma imaging and therapy with radiolabeled alpha-melanocyte stimulating hormone peptide analogues. G Ital Dermatol Venereol. 2010 Apr;145(2):245-58. PMID: 20467398; PMCID: PMC2999912.

[2] Baltazi M, Katsiki N, Savopoulos C, Iliadis F, Koliakos G, Hatzitolios AI. Plasma neuropeptide Y (NPY) and alpha-melanocyte stimulating hormone (a-MSH) levels in patients with or without hypertension and/or obesity: a pilot study. Am J Cardiovasc Dis. 2011;1(1):48-59. Epub 2011 May 20. PMID: 22254185; PMCID: PMC3253505.

[3] Houra K, Turčić P, Gabričević M, Weitner T, Konjevoda P, Stambuk N. Interaction of α-melanocortin and its pentapeptide antisense LVKAT: effects on hepatoprotection in male CBA mice. Molecules. 2011 Aug 26;16(9):7331-43. doi: 10.3390/molecules16097331. PMID: 21873934; PMCID: PMC6264190.