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What Is Melanotan II?

Melanotan II (MT-II, CAS 121062-08-6) is a synthetic cyclic heptapeptide lactam analogue of alpha-melanocyte-stimulating hormone (α-MSH) with molecular weight 1024.19 g/mol and molecular formula C₅₀H₆₉N₁₅O₉. PubChem CID: 92432. The structure is: Ac-Nle-cyclo[Asp-His-D-Phe-Arg-Trp-Lys]-NH₂, where the cyclic constraint is formed by an intramolecular lactam bond between the Asp-4 carboxyl group and the Lys-10 epsilon-amine, and Nle (norleucine) substitutes for Met at position 4 of native α-MSH. Melanotan II is a non-selective melanocortin receptor agonist with activity at MC1R, MC3R, MC4R, and MC5R, and was developed at the University of Arizona as part of a systematic structure-activity relationship programme to produce potent, stable melanocortin receptor agonists for pharmacological research.

Chemical Properties

Property	Value
CAS Number	121062-08-6
Molecular Formula	C₅₀H₆₉N₁₅O₉
Molecular Weight	1024.19 g/mol
Structure Type	Cyclic heptapeptide lactam
Ring Closure	Asp-4 carboxyl to Lys-10 epsilon-amine lactam bond
N-Terminus	Acetylated (Ac-Nle)
C-Terminus	C-terminal amide (-NH₂)
Key Substitutions vs α-MSH	Nle⁴ (for Met), D-Phe⁷ (for L-Phe), cyclic lactam
Receptor Targets	MC1R, MC3R, MC4R, MC5R (non-selective melanocortin agonist)
PubChem CID	92432

Historical Development and Discovery

Melanotan II was developed at the University of Arizona by Victor Hruby, Mac Hadley, and colleagues as part of a systematic programme to produce potent, metabolically stable analogues of α-melanocyte-stimulating hormone (α-MSH) for melanocortin receptor research. Native α-MSH (a 13-amino acid peptide: Ac-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH₂) has a short plasma half-life due to rapid proteolytic degradation and receptor desensitisation, limiting its research utility. The Arizona group applied three structural strategies to overcome these limitations: (1) substitution of Nle for the oxidation-sensitive Met at position 4; (2) substitution of D-Phe for L-Phe at position 7, improving receptor potency and DPP-IV resistance; and (3) cyclisation via a Asp-4/Lys-10 intramolecular lactam bond, constraining the peptide backbone into the bioactive conformation and dramatically improving potency and stability.

The resulting compound — originally designated MT-II or Melanotan-2 — demonstrated markedly increased potency and plasma half-life compared to native α-MSH, enabling its use as a pharmacological tool for investigating melanocortin receptor biology. Melanotan I (afamelanotide) is a linear analogue produced by the same programme (Nle⁴-D-Phe⁷-α-MSH), lacking the cyclic lactam; Melanotan II is the more potent cyclic variant and is distinct from Melanotan I in both structure and receptor selectivity profile.

Chemical Architecture and Structural Features

Structural Element	Details
Cyclic Lactam	Asp-4 (carboxyl) to Lys-10 (epsilon-amine); reduces conformational flexibility, stabilises pharmacophore
Nle⁴ Substitution	Norleucine replaces Met⁴ of α-MSH; eliminates oxidation-sensitive thioether side chain
D-Phe⁷ Substitution	D-configuration Phe at position 7; key pharmacophore residue; improves MC-R potency and DPP-IV resistance
Core Pharmacophore	His-D-Phe-Arg-Trp (positions 6–9); conserved in native α-MSH as His-Phe-Arg-Trp; minimal sequence required for MC-R binding
N-Terminal Acetylation	Ac-Nle; acetyl group at N-terminus stabilises against aminopeptidase cleavage
C-Terminal Amide	-NH₂; protects against carboxypeptidase cleavage
Net Charge	+2 at physiological pH (Arg, His ionisable; Asp partially neutralised in lactam)

Research Mechanisms

• MC1R Agonism (Melanogenesis Research): MC1R is expressed primarily on melanocytes and is the principal receptor mediating melanogenesis — the biosynthesis of melanin pigments. MC1R activation by Melanotan II drives cAMP-mediated signalling (Gs-coupled), promoting eumelanin (brown/black pigment) synthesis over phaeomelanin (red/yellow pigment). MC1R research using Melanotan II investigates pigmentation biology, UV response, and melanocyte cellular biology.
• MC4R Agonism (CNS Research): MC4R is expressed in hypothalamic nuclei (paraventricular nucleus, arcuate nucleus) and brainstem regions, and is studied as a Gs-coupled GPCR in CNS pharmacology research. Melanotan II is a potent MC4R agonist used as a pharmacological tool for characterizing hypothalamic melanocortin signalling pathways, second messenger cascades, and downstream MC4R receptor biology in experimental systems.
• MC3R Receptor Pharmacology (Hypothalamic Pharmacology): MC3R is expressed in the hypothalamus and peripheral tissues including the gastrointestinal tract and immune cells, where it participates in GPCR signalling research alongside MC4R. Melanotan II’s activity at MC3R contributes to its utility in hypothalamic pharmacology research, though MC3R pharmacology is distinct from and complementary to MC4R.
• MC5R Agonism (Exocrine Research): MC5R is expressed in exocrine glands (sebaceous, lacrimal, parotid) and immune cells. Melanotan II’s activity at MC5R has made it a tool for investigating exocrine gland biology and immune cell melanocortin signalling, though this receptor is less studied than MC1R and MC4R in the context of MT-II research.
• Cyclic Lactam Pharmacophore Constraint: The Asp/Lys intramolecular lactam bond in Melanotan II constrains the peptide backbone, locking the His-D-Phe-Arg-Trp pharmacophore into a conformation with higher intrinsic receptor affinity than the linear α-MSH parent. This structural constraint is a key example of backbone cyclisation as a peptide drug design strategy and has been extensively studied in melanocortin SAR research.
• D-Phe-Mediated Potency Enhancement: Substitution of L-Phe with D-Phe at position 7 of the α-MSH core is one of the most studied pharmacophore modifications in melanocortin peptide research. The D-configuration at this position is critical for high-affinity melanocortin receptor binding and for resistance to proteolytic cleavage at the Phe-Arg bond, significantly extending the effective research half-life of the compound.

Research Areas

What Is the Difference Between Melanotan I and Melanotan II?

Melanotan I (afamelanotide; CAS 75921-69-6) and Melanotan II (CAS 121062-08-6) were both developed at the University of Arizona from the same α-MSH analogue programme. The key structural difference is cyclisation: Melanotan I is a linear 13-amino acid analogue (Ac-Ser-Tyr-Ser-Nle-Glu-His-D-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH₂) sharing Nle⁴ and D-Phe⁷ modifications with the native α-MSH sequence. Melanotan II is a shorter (heptapeptide), cyclic lactam version (Ac-Nle-cyclo[Asp-His-D-Phe-Arg-Trp-Lys]-NH₂) lacking the non-pharmacophore residues and constrained by the Asp/Lys intramolecular lactam. The cyclisation in Melanotan II confers greater potency at melanocortin receptors and a broader receptor activity profile, including more pronounced MC4R activity compared to Melanotan I.

Melanocortin Receptor Pharmacology Research

Melanotan II has been a foundational pharmacological tool in melanocortin receptor biology research since the early 1990s. Its non-selective activity across MC1R, MC3R, MC4R, and MC5R — combined with high potency and metabolic stability relative to native α-MSH — makes it a reference agonist for characterising melanocortin receptor expression, signalling kinetics, second messenger cascades, and receptor desensitisation and internalisation in experimental systems. Selective and non-selective melanocortin agonists and antagonists have been developed partly in response to the pharmacological profiles established using Melanotan II as a research benchmark.

Backbone Cyclization as a Peptide Design Strategy

Melanotan II’s intramolecular Asp/Lys lactam constraint is one of the earliest and most extensively studied applications of backbone cyclization in peptide medicinal chemistry. The technique locks the His-D-Phe-Arg-Trp pharmacophore into a conformation with higher intrinsic melanocortin receptor affinity than the linear α-MSH parent. SAR research using Melanotan II as the parent scaffold has produced structure-activity data relevant to cyclic peptide design across receptor families, and the Asp/Lys lactam approach has been replicated in peptide drug design programmes investigating other GPCR ligands.

Cyclic Peptide Structure-Activity Relationship Research

Melanotan II is a benchmark compound in the field of cyclic peptide medicinal chemistry. The Asp/Lys intramolecular lactam approach demonstrated in MT-II has informed peptide drug design programmes across multiple therapeutic areas, establishing backbone cyclisation as a validated strategy for improving peptide receptor potency, metabolic stability, and selectivity. SAR studies using MT-II as the parent scaffold — examining the contribution of D-Phe configuration, Nle substitution, lactam ring size, and pharmacophore residue identity to melanocortin receptor binding — have produced extensive structure-activity data relevant to cyclic peptide research broadly.

Frequently Asked Questions

What is the CAS number for Melanotan II?

The CAS number for Melanotan II is 121062-08-6. The molecular formula is C₅₀H₆₉N₁₅O₉ and the molecular weight is 1024.19 g/mol. Melanotan II (MT-II) is also known by the notation Ac-Nle-cyclo[Asp-His-D-Phe-Arg-Trp-Lys]-NH₂. PubChem CID: 92432.

What melanocortin receptors does Melanotan II bind?

Melanotan II is a non-selective melanocortin receptor agonist with activity at MC1R (primary melanogenesis receptor on melanocytes), MC3R (hypothalamic and peripheral energy regulation), MC4R (CNS: hypothalamic hypothalamic signalling, autonomic regulation), and MC5R (exocrine glands, immune cells). It does not have significant activity at MC2R (the ACTH receptor), which is selective for the full ACTH sequence. Melanotan II’s non-selective MC1R–MC5R profile distinguishes it from receptor-selective melanocortin research tools.

What is the structure of Melanotan II?

Melanotan II has the structure Ac-Nle-cyclo[Asp-His-D-Phe-Arg-Trp-Lys]-NH₂. It is a cyclic heptapeptide lactam: the ring is formed by a bond between the Asp-4 carboxyl side chain and the Lys-10 epsilon-amine, cyclising the peptide backbone. The N-terminus is acetylated (Ac-Nle) and the C-terminus is amidated (-NH₂). The critical pharmacophore residues — His, D-Phe, Arg, Trp — correspond to positions 6–9 in native α-MSH and are conserved in Melanotan II within the cyclic constraint.

What is the difference between Melanotan I and Melanotan II?

Melanotan I (afamelanotide, CAS 75921-69-6) is a linear 13-amino acid α-MSH analogue. Melanotan II (CAS 121062-08-6) is a shorter, cyclic heptapeptide lactam with greater potency at melanocortin receptors due to its backbone cyclisation. Melanotan II has more pronounced MC4R activity than Melanotan I, while Melanotan I is more MC1R-selective. The two compounds were developed by the same University of Arizona research group as part of an α-MSH analogue programme aimed at improving potency, stability, and receptor selectivity for melanocortin research.

What is the molecular weight of Melanotan II?

The molecular weight of Melanotan II (MT-II) is 1024.19 g/mol. The molecular formula is C₅₀H₆₉N₁₅O₉. The CAS number is 121062-08-6 and the PubChem CID is 92432. The compound is a cyclic heptapeptide lactam with an N-terminal acetyl group and C-terminal amide modification.

Why is D-Phe important in Melanotan II?

The D-Phe at position 7 (corresponding to Phe-7 of native α-MSH) is one of the most important pharmacophore modifications in Melanotan II. D-configuration Phe at this position: (1) dramatically improves binding affinity at melanocortin receptors relative to L-Phe; (2) confers resistance to proteolytic cleavage at the Phe-Arg bond; and (3) positions the phenylalanine side chain in the optimal spatial orientation for engagement with the hydrophobic pocket of melanocortin receptor binding sites. The importance of D-Phe at this position is among the most studied single-residue SAR findings in melanocortin peptide pharmacology.

What does Nle substitution do in Melanotan II?

Nle (norleucine) at position 4 of Melanotan II replaces Met⁴ present in native α-MSH. Norleucine is the straight-chain C6 amino acid isomer of leucine, without the thioether side chain of methionine. The Nle⁴ substitution eliminates the oxidation-sensitive methionine sulfide, which in native α-MSH is susceptible to oxidation to methionine sulfoxide under aqueous storage conditions — a modification that reduces receptor binding activity. By replacing Met with Nle, Melanotan II achieves greater chemical stability in solution without compromising pharmacophore geometry, since Met and Nle have similar hydrophobic bulk at this position.

What is the PubChem CID for Melanotan II?

The PubChem CID for Melanotan II is 92432. The compound is catalogued under CAS 121062-08-6 with molecular formula C₅₀H₆₉N₁₅O₉ and molecular weight 1024.19 g/mol. Melanotan II (Ac-Nle-cyclo[Asp-His-D-Phe-Arg-Trp-Lys]-NH₂) is a synthetic cyclic heptapeptide lactam and non-selective melanocortin receptor agonist developed at the University of Arizona.

Published Research

• Sawyer TK, et al. (1982). 4-Norleucine, 7-D-phenylalanine-alpha-melanocyte-stimulating hormone: a highly potent alpha-melanotropin with ultralong biological activity. PNAS. PMID: 6285339
• Hadley ME, et al. (1996). Cyclic melanotropin peptides: discovery of superpotent and prolonged acting receptor agonists. PMID: 8695556
• Hruby VJ, et al. (1987). Cyclic conformationally constrained analogues of α-melanotropin: design and structure-activity relationships. J Med Chem. PMID: 3625708
• Hruby VJ, et al. (1995). Emerging approaches in the molecular design of receptor-selective peptide ligands. Biochemistry. PMID: 7711015
• Al-Obeidi F, et al. (1989). Potent and prolonged acting cyclic lactam analogues of α-melanotropin: design based on molecular dynamics. J Med Chem. PMID: 2542556
• Mountjoy KG, et al. (1992). The cloning of a family of genes that encode the melanocortin receptors. Science. PMID: 1325167

Research Use Only Disclaimer

Melanotan II (CAS 121062-08-6) 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.