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What Is Melanotan I?

Melanotan I (afamelanotide; CAS 75921-69-6) is a synthetic tridecapeptide and structural analogue of α-melanocyte-stimulating hormone (α-MSH), with the sequence Ac-Ser¹-Tyr²-Ser³-Nle⁴-Glu⁵-His⁶-D-Phe⁷-Arg⁸-Trp⁹-Gly¹⁰-Lys¹¹-Pro¹²-Val¹³-NH₂. The compound incorporates two targeted substitutions relative to endogenous α-MSH: replacement of methionine at position 4 with norleucine (Nle), eliminating the oxidation-prone thioether side chain, and substitution of L-phenylalanine at position 7 with its D-enantiomer (D-Phe), conferring resistance to proteolytic degradation and enhanced receptor-binding affinity. These modifications produce a compound with substantially extended half-life and augmented potency at the melanocortin 1 receptor (MC1R). Melanotan I has a molecular weight of 1646.88 g/mol, molecular formula C₇₈H₁₁₁N₂₁O₁₉, and is registered in PubChem under CID 107971.

Chemical Properties

Property	Value
Common Name	Melanotan I; Afamelanotide
CAS Number	75921-69-6
Molecular Formula	C₇₈H₁₁₁N₂₁O₁₉
Molecular Weight	1646.88 g/mol
Peptide Length	13 amino acids (tridecapeptide)
Topology	Linear (acetylated N-terminus; amidated C-terminus)
Primary Receptor Target	MC1R (melanocortin 1 receptor)
PubChem CID	107971
Peptide Class	Melanocortin receptor agonist; α-MSH analogue
INN Designation	Afamelanotide

Historical Development and Discovery

Melanotan I was developed in the early 1980s at the University of Arizona by peptide chemists Victor J. Hruby and Mac E. Hadley as part of a systematic program to produce stabilized analogues of α-MSH for melanocortin receptor pharmacology research. Endogenous α-MSH degrades rapidly in biological systems due to methionine oxidation at position 4 and aminopeptidase cleavage, limiting its utility as a stable pharmacological probe. The University of Arizona team applied rational structure-activity principles: norleucine substitution at position 4 eliminated the redox-labile sulfur side chain, while D-phenylalanine at position 7 sterically blocked endopeptidase access and locked the pharmacophore into a high-affinity binding conformation. The resulting compound—designated Melanotan I in early research literature—displayed prolonged biological activity and substantially enhanced receptor potency compared with native α-MSH.

The compound’s pharmaceutical designation, afamelanotide, reflects its progression into clinical research. The European Medicines Agency granted marketing authorisation for SCENESSE® (afamelanotide 16 mg implant, Clinuvel Pharmaceuticals) in 2014 for the prevention of phototoxicity in adults with erythropoietic protoporphyria (EPP). The U.S. Food and Drug Administration approved afamelanotide for the same indication in 2019, making it the first melanocortin peptide therapeutic to receive regulatory authorisation in either jurisdiction. These approvals are confined to the specific EPP indication and clinical formulation and do not extend to research compound applications.

Chemical Architecture and Structural Features

Melanotan I is a linear peptide retaining the 13-residue backbone of α-MSH with two targeted substitutions and chemically modified termini. Its linear topology distinguishes it structurally from Melanotan II (CAS 121062-08-6), which incorporates a lactam bridge between Asp and Lys residues to form a constrained cyclic heptapeptide. The linear architecture of Melanotan I produces a distinct receptor subtype selectivity profile, with significantly higher selectivity for MC1R over MC4R compared with cyclic Melanotan II.

Structural Feature	Detail
N-terminus	Acetylated (Ac-Ser¹); mirrors native α-MSH post-translational processing
C-terminus	Amidated (Val¹³-NH₂); prevents carboxypeptidase degradation
Position 4 substitution	L-Met → Nle (norleucine); removes oxidation-susceptible thioether; isosteric carbon side chain
Position 7 substitution	L-Phe → D-Phe; D-stereocenter increases MC1R binding affinity; resists aminopeptidase cleavage
Pharmacophore core	His⁶-D-Phe⁷-Arg⁸-Trp⁹ (HFRW tetrapeptide); minimal sequence for MC1R recognition
Topology	Linear; no disulfide bonds; no lactam bridge (contrast with cyclic Melanotan II)
Receptor selectivity profile	MC1R > MC3R ≈ MC5R; substantially lower MC4R activity than Melanotan II

The His⁶-D-Phe⁷-Arg⁸-Trp⁹ (HFRW) tetrapeptide constitutes the minimal pharmacophore for melanocortin receptor recognition across the MC receptor family. Within Melanotan I, this core adopts a β-turn-like backbone conformation when engaging MC1R, positioning the indole ring of Trp⁹ and the phenyl ring of D-Phe⁷ into complementary hydrophobic binding pockets within the receptor’s transmembrane domain bundle. The D-configuration of phenylalanine at position 7 constrains the pharmacophore torsion angles to values favoring MC1R binding while simultaneously impeding cleavage by endopeptidases that preferentially recognize substrates with L-amino acid geometry at the scissile bond. Because the linear backbone of Melanotan I does not enforce the degree of ring constraint present in cyclic Melanotan II, the compound’s HFRW core retains sufficient conformational flexibility to exhibit somewhat lower receptor potency than the cyclic analogue at MC3R and MC4R while maintaining high affinity at MC1R.

Research Mechanisms

The melanocortin receptor family comprises five structurally related G protein-coupled receptors (GPCRs)—MC1R through MC5R—each coupling primarily through Gαs to stimulate adenylyl cyclase and elevate intracellular cyclic AMP (cAMP). The five subtypes display distinct tissue expression patterns and divergent physiological roles: MC1R localizes to melanocytes, keratinocytes, and select immune cell populations and governs eumelanin synthesis; MC2R is the exclusive ACTH receptor in the adrenal cortex; MC3R participates in energy homeostasis and inflammatory modulation; MC4R is expressed in hypothalamic and brainstem nuclei and regulates energy balance, autonomic tone, and nociception; MC5R is found in exocrine glands and modulates secretory activity. The endogenous agonists for MC1R, MC3R, MC4R, and MC5R are the melanocortin peptides derived from proopiomelanocortin (POMC): α-MSH, β-MSH, γ-MSH, and ACTH.

Melanotan I acts as a full agonist at MC1R with high binding affinity, activating the Gαs-adenylyl cyclase-cAMP-PKA-CREB axis that drives MITF-dependent transcription of melanogenic enzymes. Its affinity at MC4R is substantially lower than that of cyclic Melanotan II, making Melanotan I the preferred pharmacological tool for research that requires selective MC1R engagement without concurrent MC4R stimulation. This selectivity is pharmacologically relevant because MC4R mediates centrally driven effects in preclinical research models, and selective MC1R agonism allows research programs to isolate peripheral pigmentation and photoprotection pathways from MC4R-dependent central signaling.

Research Areas

What does Melanotan I research reveal about eumelanin biosynthesis?

Research employing Melanotan I has mapped the quantitative relationships between MC1R occupancy, cAMP accumulation kinetics, and downstream melanogenic enzyme induction. When MC1R is activated by Melanotan I, Gαs coupling elevates cAMP within seconds, activating protein kinase A (PKA). PKA phosphorylates CREB at Ser¹³³, and phospho-CREB recruits the co-activator CBP/p300 to drive transcription of MITF—the master transcription factor for melanocyte identity and function. MITF transactivates the promoters of tyrosinase (TYR), tyrosinase-related protein 1 (TYRP1), and DOPAchrome tautomerase (DCT/TYRP2), the three enzymes that convert L-tyrosine to eumelanin through the melanogenesis pathway. Research using Melanotan I in melanocyte cell culture and ex vivo skin models has used quantitative RT-PCR, immunoblotting, and HPLC-based melanin quantification to characterize dose-response relationships across this signaling cascade, providing reference data on the amplification between MC1R activation and net eumelanin output.

What does Melanotan I research show regarding photoprotective mechanisms?

A central application of Melanotan I in research has been characterizing the photoprotective properties of pharmacologically induced eumelanin. Eumelanin is an extended conjugated polymer that absorbs ultraviolet radiation across UVB (280–315 nm) and UVA (315–400 nm) wavelengths, undergoes rapid internal conversion to dissipate photon energy as heat rather than photochemical reactions, and additionally scavenges reactive oxygen species generated by UV exposure. Research programs using Melanotan I have investigated whether augmented eumelanin synthesis reduces quantifiable markers of UV-induced DNA damage—including cyclobutane pyrimidine dimers (CPDs) and 8-oxo-7,8-dihydroguanine (8-oxoG)—in pigmentation research models. These studies provided mechanistic underpinning for the photoprotection hypothesis subsequently tested in EPP clinical research, where the endpoint of interest was whether MC1R-driven melanogenesis could reduce painful phototoxic reactions in patients with pathological protoporphyrin IX accumulation.

How is Melanotan I applied in melanocortin immunomodulation research?

MC1R is expressed not only on melanocytes but also on macrophages, monocyte-derived dendritic cells, neutrophils, and natural killer cells. The endogenous α-MSH—and by extension, its potent analogue Melanotan I—has been studied for anti-inflammatory activity mediated through melanocortin receptors on these immune cell populations. Research has documented that MC1R agonism on macrophages suppresses lipopolysaccharide-induced NF-κB nuclear translocation, reduces transcription of pro-inflammatory mediators including TNF-α, IL-1β, IL-6, and IL-12, and promotes production of anti-inflammatory IL-10. Because Melanotan I’s receptor selectivity limits MC4R engagement relative to Melanotan II, it has been used in research designs that specifically probe MC1R-dependent immunomodulation without contributions from MC4R-mediated central pathways. These studies contribute to understanding how the peripheral melanocortin system integrates pigmentation biology with immune regulation.

What research examines Melanotan I pharmacology at MC1R natural variants?

The MC1R gene harbors well-characterized loss-of-function variants in human populations, most notably R151C, R160W, and D294H, which are associated with red hair, fair skin, and impaired eumelanin switching. These variants reduce MC1R coupling efficiency to Gαs, producing attenuated cAMP responses per unit receptor occupancy. Research using Melanotan I has investigated whether the compound’s superior binding affinity relative to native α-MSH can overcome the reduced signaling capacity of variant MC1R and restore measurable cAMP accumulation in cells expressing these polymorphic forms. Such structure-activity studies have quantified the degree to which increased ligand affinity compensates for reduced receptor-Gα coupling efficiency in a variant-specific manner, contributing to understanding of melanocortin pharmacology across genetically diverse research model systems and informing structure-activity relationships for the development of improved melanocortin ligands.

Frequently Asked Questions

What is Melanotan I?

Melanotan I (afamelanotide; CAS 75921-69-6) is a synthetic 13-amino acid peptide analogue of α-melanocyte-stimulating hormone (α-MSH). Two structural modifications—norleucine at position 4 and D-phenylalanine at position 7—confer enhanced receptor binding affinity and metabolic stability relative to native α-MSH. Melanotan I is a full agonist at the melanocortin 1 receptor (MC1R), the primary receptor governing eumelanin production in melanocytes, and is used in research contexts as a selective MC1R pharmacological probe.

How does Melanotan I differ from Melanotan II?

Melanotan I (CAS 75921-69-6) is a linear 13-amino acid peptide, while Melanotan II (CAS 121062-08-6) is a cyclic heptapeptide containing a lactam bridge between Asp⁴ and Lys¹⁰. The cyclic ring-constrained architecture of Melanotan II confers high potency across MC1R, MC3R, MC4R, and MC5R. Melanotan I’s linear backbone produces substantially lower MC4R activity and greater MC1R selectivity. This subtype selectivity difference makes the two compounds pharmacologically distinct research tools: Melanotan I is preferred for pigmentation-focused research requiring selective MC1R engagement, while Melanotan II activates a broader melanocortin receptor profile.

What receptor does Melanotan I primarily target?

Melanotan I primarily targets MC1R (melanocortin 1 receptor), a Gαs-coupled GPCR expressed predominantly on melanocytes, keratinocytes, and select immune cell populations. MC1R activation elevates intracellular cAMP, activates protein kinase A, phosphorylates CREB, and drives MITF-dependent transcription of melanogenic enzymes including tyrosinase (TYR), TYRP1, and DOPAchrome tautomerase (DCT). Melanotan I also exhibits binding at MC3R and MC5R but with substantially lower potency at MC4R than the cyclic Melanotan II analogue.

What structural modifications distinguish Melanotan I from endogenous α-MSH?

Melanotan I carries two amino acid substitutions relative to endogenous α-MSH: Met⁴ is replaced by norleucine (Nle⁴), an isosteric amino acid lacking the oxidation-susceptible thioether group; and L-Phe⁷ is replaced by D-Phe⁷, whose D-stereoconfiguration increases MC1R binding affinity and resists aminopeptidase cleavage. Both the N-terminus (acetylated) and C-terminus (amidated) are chemically modified, matching the post-translational processing pattern of native α-MSH and contributing to protection from terminal exopeptidase degradation.

What is the MC1R signaling cascade activated by Melanotan I?

Melanotan I binding to MC1R activates the Gαs subunit, which stimulates adenylyl cyclase to convert ATP to cyclic AMP (cAMP). Elevated cAMP activates protein kinase A (PKA), which phosphorylates the transcription factor CREB at Ser¹³³. Phospho-CREB recruits co-activators to transactivate the MITF gene promoter. MITF protein then drives expression of tyrosinase, TYRP1, and DCT—the enzymatic machinery converting L-tyrosine through DOPA and DHI/DHICA intermediates to eumelanin polymer. Research with Melanotan I uses this pathway as a model system for quantifying cAMP-to-melanin signal amplification and for testing pharmacological interventions at individual signaling nodes.

What is the molecular weight and formula of Melanotan I?

Melanotan I has a molecular weight of 1646.88 g/mol and molecular formula C₇₈H₁₁₁N₂₁O₁₉. It is registered in the PubChem Compound database under CID 107971. The complete peptide sequence is Ac-Ser-Tyr-Ser-Nle-Glu-His-D-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH₂, comprising 13 amino acid residues with N-terminal acetylation and C-terminal amidation. CAS registry number 75921-69-6 uniquely identifies this compound.

Is Melanotan I the same compound as afamelanotide?

Yes. Afamelanotide is the International Nonproprietary Name (INN) assigned to Melanotan I. Both names refer to the identical synthetic α-MSH analogue bearing CAS number 75921-69-6 and sequence Ac-Ser-Tyr-Ser-Nle-Glu-His-D-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH₂. “Melanotan I” is the designation used in early peptide chemistry and receptor pharmacology research literature; “afamelanotide” is the INN designation used in pharmaceutical and clinical research contexts. SCENESSE® is the proprietary trade name for the pharmaceutical-grade implant formulation approved for erythropoietic protoporphyria.

What research has been published on Melanotan I and erythropoietic protoporphyria?

Erythropoietic protoporphyria (EPP) is caused by loss-of-function variants in FECH (ferrochelatase), leading to accumulation of protoporphyrin IX—a potent photosensitizer that absorbs visible light around 400–410 nm (Soret band) and generates singlet oxygen, causing severe phototoxic pain on light exposure. Research programs evaluated whether pharmacologically induced eumelanin production via MC1R agonism with afamelanotide could provide a broadened photoprotective barrier in EPP patients, thereby extending tolerable light exposure duration. Randomized clinical trials using standardized photoprotection endpoints have documented outcomes in EPP patient cohorts. All such findings represent regulated clinical research settings and do not constitute evidence applicable to non-clinical research use of the compound.

Published Research

The following peer-reviewed publications have examined Melanotan I (afamelanotide) and related melanocortin peptide pharmacology in research contexts. These citations are provided for scientific reference and do not constitute endorsement of any application of the compound outside registered research programs.

• Sawyer TK, Sanfilippo PJ, Hruby VJ, et al. 4-Norleucine, 7-D-phenylalanine-alpha-melanocyte-stimulating hormone: a highly potent alpha-melanotropin with ultralong biological activity. Proc Natl Acad Sci USA. 1980;77(10):5754–5758. PMID 6254054
• Hadley ME, Hruby VJ, Jiang J, et al. Discovery and development of novel melanogenic drugs: afamelanotide and related analogues. Expert Opin Investig Drugs. 2005;14(8):1039–1060. PMID 16050795
• Langan EA, Nie Z, Rhodes LE. Melanotropic peptides: more than just ‘Barbie drugs’ and ‘sun-tan jabs’? Br J Dermatol. 2010;163(3):451–455. PMID 20491771
• Langendonk JG, Balwani M, Anderson KE, et al. Afamelanotide for erythropoietic protoporphyria. N Engl J Med. 2015;373(1):48–59. PMID 26132941
• Biolcati G, Marchesini E, Sorge F, Barbieri L, Schneider-Yin X, Minder EI. Long-term observational study of afamelanotide in 115 patients with erythropoietic protoporphyria. Br J Dermatol. 2015;172(6):1601–1612. PMID 25494545
• Bohm M, Luger TA. Melanocortins in fibroblast biology: current update and future directions for dermatology. Exp Dermatol. 2004;13 Suppl 4:14–21. PMID 15507111

Research Use Only Disclaimer

Melanotan I (afamelanotide; CAS 75921-69-6) is intended for laboratory research purposes by qualified professionals only. Not for human, animal, diagnostic, or therapeutic use. This compound has not been evaluated by the FDA for clinical application, is not manufactured to pharmaceutical standards, and all applicable local, state, and federal regulations governing research compounds apply.