Melanotan 2 (MT-II) is a synthetic cyclic heptapeptide analogue of alpha-melanocyte-stimulating hormone (α-MSH). It is a non-selective agonist at the melanocortin receptors MC1R, MC3R, MC4R and MC5R, and it is used as a reference agonist in melanocortin receptor pharmacology and in melanocyte cell culture. NuVion supplies Melanotan 2 as a laboratory chemical for in vitro research use only.
Key facts
| Type/class | Synthetic cyclic peptide, α-MSH analogue, melanocortin receptor agonist |
| Amino acid count | 7 |
| Sequence | Ac-Nle-cyclo[Asp-His-D-Phe-Arg-Trp-Lys]-NH2 |
| Molecular formula | C50H69N15O9 |
| Molecular weight | 1024.2 g/mol |
| CAS number | 121062-08-6 |
| Synonyms | MT-II, MT-2, Melanotan II |
| Supplied form | Lyophilised powder in a sealed vial |
Melanotan 2
$59 AUD
View productResearch use only. Not for human or veterinary use.
Structure and chemistry
α-MSH is a 13-residue peptide (Ac-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH2) cleaved from the precursor proopiomelanocortin (POMC). The shortest sequence that still activates melanocortin receptors is the His-Phe-Arg-Trp tetrapeptide at positions 6 to 9. Melanotan 2 keeps this core together with the flanking residues 4 to 10 and introduces four changes. Met4 is replaced by norleucine (Nle), which removes the oxidisable thioether side chain. Phe7 is replaced by D-phenylalanine, which raises receptor affinity and blocks cleavage by chymotrypsin-like proteases. Glu5 is replaced by Asp and Gly10 by Lys, and the side chains of these two residues are joined through a lactam (amide) bond that closes the ring. The N-terminus is acetylated and the C-terminus is a primary amide, so the peptide carries no free terminal charges.
The lactam bridge holds the His-D-Phe-Arg-Trp segment in a beta-turn, which is close to the conformation the linear hormone adopts when bound to the receptor. This constraint explains why MT-II binds with higher affinity and gives a longer-lasting response in cell assays than α-MSH itself. The scaffold has also been the starting point for other melanocortin ligands. SHU9119, an MC3R and MC4R antagonist, is MT-II with D-2-naphthylalanine in place of D-Phe7, and bremelanotide (PT-141) is the same ring with a C-terminal carboxylic acid in place of the amide.
The molecule contains no cysteine and no methionine, so disulfide scrambling and thioether oxidation are not concerns. The tryptophan indole is sensitive to light and to oxidation, which is the main reason the lyophilised powder and any solution are kept away from light. With arginine and histidine free and the lysine side chain consumed in the lactam, the peptide carries a net positive charge at neutral pH and dissolves readily in water and aqueous buffers.
Mechanism of action
The melanocortin receptors are a family of five class A G protein-coupled receptors, MC1R to MC5R. MC2R responds only to adrenocorticotropic hormone (ACTH) and is not activated by MT-II. At MC1R, MC3R, MC4R and MC5R, MT-II is a full agonist with nanomolar EC50 values in cAMP assays, and at MC1R and MC4R its affinity is higher than that of α-MSH. Because it does not discriminate between these four subtypes, it is used to define the maximal response in an assay before selective ligands are tested against it.
All four MT-II-responsive receptors couple mainly to Gs. Agonist binding activates adenylyl cyclase, intracellular cAMP rises, and protein kinase A (PKA) phosphorylates the transcription factor CREB. In melanocytes, CREB drives expression of microphthalmia-associated transcription factor (MITF), which in turn switches on the genes for tyrosinase (TYR), tyrosinase-related protein 1 (TYRP1) and dopachrome tautomerase (DCT). These three enzymes convert tyrosine to eumelanin inside melanosomes, so MC1R activation by MT-II raises tyrosinase activity and melanin content in cultured melanocytes and pigmented cell lines. MC1R signalling also activates ERK1/2 through a cAMP-independent route involving c-Src and the KIT receptor.
At MC4R, MT-II activates the same Gs-cAMP-PKA axis, and MC4R also couples to Gq-phospholipase C and to the inward rectifier potassium channel Kir7.1 in a G protein-independent manner. Agonist occupancy at MC4R recruits beta-arrestin 2 and drives receptor internalisation. The endogenous antagonists agouti signalling protein (ASIP, at MC1R and MC4R) and agouti-related protein (AgRP, at MC3R and MC4R) compete with MT-II for the orthosteric site and, at MC4R, act as inverse agonists that lower basal cAMP.
Research applications
Melanotan 2 sits in the Reproductive Signalling category alongside the other melanocortin ligands. Typical in vitro uses include:
- Competitive radioligand binding at recombinant MC1R, MC3R, MC4R and MC5R in HEK293 or CHO cell membranes, using MT-II to displace iodinated NDP-α-MSH and derive Ki values
- cAMP accumulation and CRE-luciferase reporter assays, where MT-II serves as the reference full agonist for EC50 and maximal-response comparisons
- Melanin content and tyrosinase activity assays in B16 cells and human primary melanocytes, including MITF, TYR, TYRP1 and DCT expression by qPCR or western blot
- Beta-arrestin recruitment, receptor internalisation and ERK1/2 phosphorylation assays used to profile biased signalling at MC4R
- Structure-activity relationship work on cyclic melanocortin ligands, with MT-II as the parent scaffold and SHU9119 as the matched antagonist
- RP-HPLC and LC-MS method development for lactam-bridged peptides
Handling in the laboratory
The lyophilised powder is reconstituted with bacteriostatic water added slowly down the wall of the vial, then swirled until the solid dissolves. The reconstitution calculator converts the vial content and the chosen volume of water into a working concentration. Keep the sealed vial dry, away from light and refrigerated as stated in the product documentation. Once reconstituted, keep the solution refrigerated, protect it from light, and use it within the period given in the documentation. Each lot is characterised by RP-HPLC for purity and by mass spectrometry for identity, so the observed mass can be checked against the expected 1024.2 g/mol.
Testing and supply from NuVion
NuVion’s Melanotan 2 comes from GMP-audited manufacture and is supplied lyophilised in sealed vials. Most batches are independently tested by Janoshik Analytical for purity by RP-HPLC and identity by mass spectrometry, and the Certificate of Analysis for a tested batch is published on the product page and in the COA library. Orders are dispatched from within Australia.
Related compounds
Melanotan 1 (afamelanotide) is the linear [Nle4, D-Phe7]-α-MSH analogue with selectivity for MC1R, and PT-141 (bremelanotide) is the free-acid form of the MT-II ring that is studied for its MC4R and MC3R activity. Together the three compounds cover the selective and non-selective ends of melanocortin agonist pharmacology.
Frequently asked questions
What is Melanotan 2 used for in research?
It is a reference agonist for the melanocortin receptor family. Laboratories use it in receptor binding and cAMP assays to set the maximal response against which selective agonists and antagonists are compared, and in melanocyte culture to study the MC1R-cAMP-MITF-tyrosinase pathway.
How does Melanotan 2 differ from Melanotan 1?
Melanotan 1 is a linear 13-residue analogue with the Nle4 and D-Phe7 substitutions and is selective for MC1R. Melanotan 2 is a seven-residue lactam-cyclised fragment that activates MC1R, MC3R, MC4R and MC5R with similar potency. The two are often run side by side to separate MC1R-dependent responses from those involving other subtypes.
Is Melanotan 2 a therapeutic good in Australia?
No. Melanotan 2 from NuVion is a laboratory chemical for in vitro research. It is not included in the Australian Register of Therapeutic Goods and has not been assessed by the TGA. It is not for human or veterinary use.
How should Melanotan 2 be stored?
Keep the lyophilised powder in its sealed vial, dry, away from light and refrigerated according to the product documentation. After reconstitution with bacteriostatic water, refrigerate the solution, protect it from light and use it within the period stated in the documentation. The tryptophan residue makes light protection more important for this compound than for many other short peptides.
Research use only. This product is a laboratory chemical supplied for in vitro research. It is not included in the Australian Register of Therapeutic Goods and has not been assessed by the Therapeutic Goods Administration for quality, safety or efficacy. It is not for human or veterinary use, and nothing on this page is a representation about therapeutic use.
