Melanotan 1

Melanotan I—also designated afamelanotide, NDP-α-MSH, or [Nle4,D-Phe7]-α-MSH—is a potent linear synthetic analog of α-melanocyte-stimulating hormone (α-MSH) with two amino acid modifications relative to the native 13-residue peptide: norleucine (Nle) replaces methionine at position 4, and D-phenylalanine (D-Phe) replaces L-phenylalanine at position 7. These substitutions increase receptor binding affinity approximately 1000-fold over native α-MSH and confer resistance to endoprotease cleavage, substantially extending the biological half-life. Melanotan I is distinguished from Melanotan II—a cyclic heptapeptide analog—by its linear structure and its notably higher selectivity for MC1R relative to MC3R, MC4R, and MC5R. This selectivity profile makes Melanotan I the primary research tool for studying MC1R-specific pharmacology in melanogenesis, photoprotection, and anti-inflammatory signaling without the sexual arousal or appetite effects mediated by MC3R/MC4R agonism in Melanotan II. Afamelanotide (the INN designation for the same molecule) received European Medicines Agency approval in 2014 as Scenesse for erythropoietic protoporphyria (EPP), a rare photodermatosis, generating controlled clinical trial data that few research peptides in this class have matched. This 10 mg vial format is a high-dose configuration suited for multi-experiment protocols. Peptides.SO aggregates 96 supplier listings from 65 distinct vendors for Melanotan I 10mg. Offered strictly for laboratory and preclinical investigation under Research Use Only (RUO) conditions.

Mechanism of Action:

Melanotan I binds MC1R, the primary receptor on cutaneous melanocytes, with sub-nanomolar affinity (Ki ~0.1 nM in competitive binding assays against radiolabeled NDP-α-MSH). MC1R is a class A Gs-coupled GPCR; agonist binding activates adenylyl cyclase, raises intracellular cAMP, activates protein kinase A, and phosphorylates the transcription factor MITF (microphthalmia-associated transcription factor). MITF upregulates transcription of the enzymes and transport proteins of the melanogenesis pathway: tyrosinase (TYR), tyrosinase-related proteins 1 and 2 (TYRP1, TYRP2/DCT), and the melanosome membrane protein Pmel17. The net effect is a shift in melanocyte pigment production toward eumelanin (brown-black) and away from pheomelanin (red-yellow), increasing the UV-absorbing capacity of skin and reducing UV-induced DNA damage in keratinocytes through bystander melanin deposition. Beyond melanogenesis, MC1R activation on melanocytes and macrophages triggers anti-inflammatory signaling via NF-κB suppression and IL-10 induction, a mechanism implicated in photoprotection independent of pigmentation. The lack of significant MC4R activity in Melanotan I—in contrast to Melanotan II—means it does not substantially engage the hypothalamic circuits governing sexual arousal or appetite, making it a cleaner tool for isolating MC1R biology.

Key Research Studies:

Dorr RT et al. (1994) published the foundational clinical pharmacology study of NDP-α-MSH (Melanotan I) in 28 healthy volunteers receiving subcutaneous injections of 0.16 mg/kg over 10 consecutive days. Measured increases in skin pigmentation (reflectometry) and urinary 6-sulphatoxymelatonin were dose-dependent; the predominant adverse effects were transient nausea and facial flushing. No serious adverse events were observed. This paper established the compound's human safety and photoprotection potential and led to the EPP development program. (PMID 8188636)

Harms JH et al. (2009) conducted a double-blind, placebo-controlled trial of afamelanotide 20 mg subcutaneous implant in 20 EPP patients, demonstrating that treated patients had significantly longer pain-free exposure to sunlight and reduced photosensitivity episodes versus placebo, confirming the photoprotection hypothesis in a clinical setting. (PMID 19706797)

Langan EA et al. (2010) reviewed the mechanistic evidence connecting MC1R-mediated melanogenesis with nuclear repair pathways, noting that Melanotan I–stimulated melanocytes show upregulation of nucleotide excision repair (NER) enzymes following UV exposure, suggesting the peptide's photoprotective effects extend beyond pigment density to direct DNA damage repair enhancement. (PMID 20620421)

Böhm M et al. (2005) demonstrated in vitro that α-MSH analogs including NDP-α-MSH activated MC1R on human dermal macrophages and mast cells, suppressing LPS-stimulated TNF-α production and NF-κB nuclear translocation, establishing a direct anti-inflammatory mechanism for MC1R agonism in skin-resident immune cells. (PMID 16081829)

Research Applications:

- MC1R pharmacology: receptor binding, selectivity screening versus MC3R/MC4R/MC5R panels - Melanogenesis pathway: tyrosinase induction, MITF regulation, eumelanin/pheomelanin ratio studies - UV-DNA damage protection models: keratinocyte photodamage assays with melanocyte co-cultures - Nucleotide excision repair induction: NER pathway upregulation in primary melanocyte cultures - Anti-inflammatory signaling: NF-κB suppression in macrophage and mast cell models - Photodermatosis preclinical models: EPP-analog porphyrin accumulation assays - Comparative melanocortin pharmacology: Melanotan I vs. Melanotan II vs. α-MSH selectivity - Depigmentation disease research: vitiligo melanocyte rescue protocols

Typical Research Concentrations:

In vitro MC1R binding assays use 0.01 nM to 100 nM Melanotan I for competition binding curves against [125I]-NDP-α-MSH. Melanogenesis functional assays in B16-F10 melanoma cells use 1–100 nM concentrations and typically measure intracellular cAMP accumulation, MITF protein levels, or tyrosinase activity at 48–72 hours. Anti-inflammatory assays in THP-1 macrophages use 10–100 nM concentrations. The 10 mg vial supports extensive multi-experiment protocols at these concentrations.

Safety Profile from Published Research:

Afamelanotide (identical compound to Melanotan I) was evaluated in Phase 3 clinical trials by CLINUVEL Pharmaceuticals encompassing hundreds of EPP patients. The most common adverse events were nausea (predominantly mild to moderate, transient), flushing, and injection-site reactions from the subcutaneous implant delivery system. Importantly, the clinical data did not reveal evidence of melanoma induction or promotion with the approved dosing schedule (20 mg implant every 60 days), and post-market pharmacovigilance data gathered since 2014 in the EU has not reversed this safety conclusion. In high-dose rodent toxicology studies (100× human equivalent doses for 90 days), hyperpigmentation of melanin-containing tissues was the most prominent finding; no carcinogenicity signals were detected. The compound does not penetrate the blood-brain barrier substantially at research-relevant doses and does not produce CNS effects observed with MC4R-active analogs.

For Research Use Only (RUO). Not for human or veterinary use, diagnosis, treatment, cure, or prevention of any disease. This product is intended for in vitro and preclinical laboratory use only.

Melanotan I vs. Melanotan II: Research Distinctions:

Melanotan I and Melanotan II are frequently conflated in lay usage, but they are structurally and pharmacologically distinct research tools with non-overlapping optimal use cases:

- Structure: Melanotan I is a linear 13-residue analog of α-MSH; Melanotan II is a cyclic 7-residue peptide (ring formed by a Cys5-Asp10 lactam bridge) derived from α-MSH fragment 4-10. - Receptor selectivity: Melanotan I shows high MC1R selectivity with reduced MC4R activity relative to native α-MSH; Melanotan II engages MC1R, MC3R, MC4R, and MC5R with broader selectivity. - Physiological effects: Melanotan I's MC1R selectivity means it produces strong melanogenesis effects with minimal CNS activity (no sexual arousal, no appetite changes); Melanotan II's MC4R activity makes it a tool for studying sexual arousal, appetite, and hypothalamic circuits. - Regulatory status: Afamelanotide (Melanotan I) is EMA-approved for EPP; Melanotan II has no approved medical use. - Research application mapping: Use Melanotan I when the experimental question is pure MC1R biology (melanogenesis, photoprotection, MC1R-mediated anti-inflammation); use Melanotan II when the research requires MC3R/MC4R engagement in addition to or instead of MC1R.

For receptor selectivity screening experiments (e.g., building selectivity profiles for novel melanocortin analogs), both compounds should be run in parallel as reference standards along with α-MSH and cyclic-7 (MT-II) at each receptor subtype in competitive binding assays.

Market Context and Product Availability:

The 10 mg vial format for Melanotan I is the high-dose standard for multi-experiment laboratory protocols. Peptides.SO aggregates 96 listings from 65 vendors. Pricing ranges from $30–$100 per 10 mg vial; at $4–$10 per milligram this is one of the more economical melanocortin analogs relative to its characterization depth. Suppliers should provide HPLC (≥98%) and MS certificates confirming MW 1646.9 Da for the correct linear tridecapeptide structure; cyclic impurities (ring closure artifacts) have distinct MS fragmentation and different receptor selectivity profiles. Storage: lyophilized at -20°C indefinitely; reconstituted in bacteriostatic water at 1 mg/mL, stable 4 weeks at 4°C.