MT-1 (Melanotan I)

MT-1 (Melanotan I, Afamelanotide) is a synthetic 13 amino acid linear analogue of alpha-MSH incorporating Nle4 (norleucine replacing oxidation-prone Met4) and D-Phe7 (replacing L-Phe7 to enhance receptor affinity and protease resistance). MT-1 is the most MC1R-selective compound in the synthetic melanocortin research toolkit and is identical to Afamelanotide — an FDA-approved and EMA-approved pharmaceutical for erythropoietic protoporphyria (EPP), providing an unusually extensive published clinical pharmacology dataset for a research tool compound.

MC1R (melanocortin-1 receptor) is the primary therapeutic and research target of MT-1. In melanocytes, MC1R activation by alpha-MSH or MT-1 drives the Gs/cAMP/PKA cascade. PKA phosphorylates CREB at Ser133, activating MITF (Microphthalmia-associated transcription factor) transcription. MITF drives expression of melanogenic enzymes: tyrosinase (rate-limiting, converts tyrosine to DOPA and DOPA to dopaquinone), TRP-1 (DHICA oxidase), and TRP-2 (dopachrome tautomerase). The downstream product is eumelanin — the brown/black melanin polymer synthesised in melanosomes, packaged, and transferred to surrounding keratinocytes via exocytosis and dendritic transfer. Eumelanin provides photoprotection by absorbing UV radiation and quenching reactive oxygen species generated by UV-DNA interactions.

The clinical application of MT-1 as Afamelanotide in EPP provides strong translational grounding for laboratory MC1R research. EPP results from ferrochelatase mutations impairing haem synthesis, causing protoporphyrin IX accumulation that produces severe phototoxicity — even brief sun exposure causes burning pain. Afamelanotide's MC1R-driven eumelanin induction provides photoprotection against protoporphyrin-photosensitised tissue damage. Published Phase 3 trial data (Langendonk et al., NEJM 2015) characterises: subcutaneous implant pharmacokinetics (sustained release over weeks), peak melanogenic effect at 7-10 days, MC1R selectivity over MC3R and MC4R in vivo, and safety profile across multiple years of use.

MC1R's immunological biology extends beyond melanocyte pigmentation. MC1R is expressed on macrophages, dendritic cells, NK cells, and T lymphocytes — immune cells with no pigmentation function. In these cells, MC1R/Gs/cAMP/PKA signalling suppresses NFkB-driven inflammatory gene transcription, reducing TNF-alpha, IL-6, IL-12, and IL-23 production in response to LPS or other stimuli. This MC1R-mediated immunomodulation represents an endogenous anti-inflammatory system that connects UV-induced alpha-MSH production in keratinocytes to regulation of skin immune homeostasis — and that MT-1 research can examine in monocyte, macrophage, and dendritic cell models.

Human MC1R polymorphisms (RHC variants reducing MC1R signalling efficiency) are associated with red hair, fair skin, poor tanning ability, and increased melanoma risk — establishing MC1R as a tumour suppressor-like receptor in melanocyte biology. MT-1 research in primary melanocyte cultures from donors with different MC1R genotypes allows pharmacological characterisation of variant receptor responsiveness and provides mechanistic insight into the clinical correlation between MC1R variants and melanoma susceptibility.

MW: 1646.87 g/mol. CAS: 75921-69-6. Molecular formula: C78H111N21O19. Reconstitute in bacteriostatic water at 1mg/mL. Store lyophilised at -20°C. For laboratory and analytical research purposes only.

Melanogenesis assay protocol for MT-1 research: seed human primary melanocytes or MNT-1 melanoma cells at 50,000 cells/well in 6-well plates. Treat with MT-1 (0.1nM-100nM) or vehicle for 72-96 hours. Measure melanin content by dissolving cells in 1M NaOH at 80°C for 1 hour, then read absorbance at 405nm against a synthetic melanin standard curve. Measure tyrosinase activity by DOPA oxidation assay (cell lysate + L-DOPA substrate, absorbance at 475nm). Confirm MC1R-dependence using the MC1R antagonist agouti signalling protein (ASIP) at 1ug/mL pre-treatment. For MC1R immunofluorescence: use anti-MC1R primary antibody, paraformaldehyde-fixed non-permeabilised cells to detect surface MC1R only. MW: 1646.87 g/mol. CAS: 75921-69-6. Reconstitute in bacteriostatic water at 1mg/mL. Store lyophilised at -20°C. For laboratory and analytical research purposes only.