The melanotan research peptide family consists of synthetic analogues of α-melanocyte-stimulating hormone that act at the melanocortin receptors MC1R to MC5R. This guide covers Melanotan 1 (afamelanotide / NDP-α-MSH), Melanotan 2 and PT-141 (bremelanotide): their verified structures, the single-atom differences that separate them, receptor selectivity, and laboratory handling. Written for researchers characterising melanocortin pharmacology in vitro — research context only.
Key takeaways
- All three compounds derive from α-MSH, a 13-residue peptide cleaved from pro-opiomelanocortin (POMC). The core recognition motif shared by every melanocortin agonist is His-Phe-Arg-Trp.
- Melanotan 1 is afamelanotide, also written NDP-α-MSH or [Nle4, D-Phe7]-α-MSH: a linear 13-residue peptide, CAS 75921-69-6, C78H111N21O19, MW ≈1646.9 Da. It is described as MC1R-preferring.
- Melanotan 2 is a cyclic lactam heptapeptide, Ac-Nle-cyclo[Asp-His-D-Phe-Arg-Trp-Lys]-NH2, CAS 121062-08-6, C50H69N15O9, MW ≈1024.2 Da. It is a non-selective agonist across MC1R, MC3R, MC4R and MC5R.
- PT-141 (bremelanotide) is the same cyclic scaffold with a free C-terminal carboxylic acid instead of the amide: CAS 189691-06-3, C50H68N14O10, MW ≈1025.2 Da. It is described as an active metabolite of Melanotan 2 and acts principally at MC3R and MC4R.
- MC2R is the exception in the receptor family: it responds to ACTH and not to α-MSH-derived analogues, because it requires sequence outside the shared HFRW core.
- The two engineered substitutions in Melanotan 1 — norleucine for methionine at position 4 and D-phenylalanine for L-phenylalanine at position 7 — respectively remove an oxidisable side chain and impose protease resistance with a constrained conformation.
- These are research chemicals supplied for laboratory use only. Nothing here describes use by people, and no tanning, cosmetic or other in-vivo application is described or endorsed.
What are melanocortin peptides?
Melanocortin peptides are a family of signalling peptides cleaved from a single precursor protein, pro-opiomelanocortin, that act on five G-protein-coupled receptors designated MC1R through MC5R. The family includes α-, β- and γ-melanocyte-stimulating hormone and adrenocorticotropic hormone (ACTH), and all of them converge on the same second messenger: receptor activation couples through Gs to adenylyl cyclase and raises intracellular cyclic AMP.
What makes the system tractable for medicinal chemistry is its modularity. A short core motif — His-Phe-Arg-Trp — carries most of the receptor recognition, while flanking residues and conformational constraints tune which receptor subtype is preferred. Every compound in this guide is a variation on that theme.
The system also has endogenous antagonists, which is unusual for a peptide-hormone family. Agouti signalling protein and agouti-related peptide act as inverse agonists at melanocortin receptors, meaning tone is set by the balance of agonist and antagonist rather than by agonist concentration alone.
POMC processing and the origin of α-MSH
α-MSH is produced by proteolytic processing of POMC, a precursor that also yields ACTH, β-endorphin and other fragments depending on which prohormone convertases are expressed in a given tissue. α-MSH corresponds to the first 13 residues of ACTH, N-terminally acetylated and C-terminally amidated: Ac-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH2.
Two features of that native sequence are liabilities for laboratory work. The methionine at position 4 is readily oxidised to the sulfoxide, and the peptide is rapidly cleaved by serum and tissue proteases. Both liabilities were addressed by the medicinal chemistry that produced NDP-α-MSH.
The melanocortin receptor family MC1R–MC5R
The five melanocortin receptors are class A G-protein-coupled receptors that signal principally through Gs and cyclic AMP. They differ in tissue distribution and in which POMC-derived ligands they recognise, and that combination is what makes subtype selectivity the central question in melanocortin medicinal chemistry.
| Receptor | Principal tissue | Endogenous ligand | Studied role in the literature |
|---|---|---|---|
| MC1R | Melanocytes, some immune cells | α-MSH | Melanogenesis and pigment-type switching; anti-inflammatory signalling |
| MC2R | Adrenal cortex | ACTH exclusively | Steroidogenesis — not activated by α-MSH-derived analogues |
| MC3R | Central nervous system, some peripheral tissue | γ-MSH, α-MSH | Energy homeostasis, lean-mass accrual, inflammatory modulation |
| MC4R | Hypothalamus and wider CNS | α-MSH | Energy balance; loss-of-function variants associated with early-onset obesity |
| MC5R | Exocrine tissue including sebaceous glands | α-MSH | Exocrine secretion; least characterised of the five |
Melanotan 1 (afamelanotide, NDP-α-MSH)
Melanotan 1 is the linear 13-residue analogue Ac-Ser-Tyr-Ser-Nle-Glu-His-D-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH2, known in the literature as afamelanotide, NDP-α-MSH or [Nle4, D-Phe7]-α-MSH. It carries CAS 75921-69-6, molecular formula C78H111N21O19 and a molecular weight of approximately 1646.9 Da. It is described as binding predominantly to MC1R.
Two substitutions distinguish it from native α-MSH, and both are textbook examples of peptide engineering:
- Met4 → Nle (norleucine). Norleucine is isosteric with methionine but replaces the sulfur-containing side chain with a plain hydrocarbon. This removes the oxidation liability entirely without changing the residue’s size or hydrophobicity.
- L-Phe7 → D-Phe. Inverting the stereochemistry at a single centre both blocks proteolysis at that position — proteases are stereospecific — and restricts the local backbone conformation, stabilising the bioactive presentation of the HFRW core.
The combination produced a compound with markedly greater potency and duration than the native hormone in the original pharmacological characterisation, and it is the parent scaffold from which the cyclic analogues were subsequently developed. Afamelanotide has since been taken forward as a licensed pharmaceutical in some territories — a research-context observation about the licensed form, not a description of the research chemical supplied here.
Melanotan 2: the cyclic lactam
Melanotan 2 is a conformationally constrained heptapeptide, Ac-Nle-cyclo[Asp-His-D-Phe-Arg-Trp-Lys]-NH2, with CAS 121062-08-6, formula C50H69N15O9 and molecular weight approximately 1024.2 Da. It is described in the literature as a non-selective agonist across MC1R, MC3R, MC4R and MC5R.
The cyclisation is a side-chain-to-side-chain lactam: the γ-carboxyl of aspartic acid is joined to the ε-amino group of lysine. This is a standard strategy for reducing conformational entropy in a peptide — the ring restricts the number of shapes the backbone can adopt, which typically raises potency and improves metabolic stability at the cost of subtype discrimination.
That trade-off explains the pharmacological profile precisely. By locking the HFRW core into a compact presentation, the design gained potency and duration but lost the selectivity that the extended linear scaffold of Melanotan 1 retains for MC1R. Where Melanotan 1 is a tool for probing MC1R, Melanotan 2 is a broad-spectrum melanocortin agonist and needs a receptor panel to interpret any result obtained with it.
PT-141 (bremelanotide) and one atom of difference
PT-141, also called bremelanotide, is Ac-Nle-cyclo[Asp-His-D-Phe-Arg-Trp-Lys]-OH: the identical cyclic scaffold to Melanotan 2, terminating in a free carboxylic acid rather than a primary amide. Its CAS number is 189691-06-3, formula C50H68N14O10 and molecular weight approximately 1025.2 Da — one dalton heavier, reflecting the replacement of –NH2 with –OH.
PT-141 is described as an active metabolite of Melanotan 2, formed by hydrolysis of the C-terminal amide. Its reported receptor profile is agonism across the family with the exception of MC2R, acting principally at MC3R and MC4R rather than at MC1R.
The practical significance for a laboratory is analytical. A one-dalton difference between a parent compound and its metabolite is easily resolved by a modern mass spectrometer but is invisible on a UV chromatogram alone. Any batch characterisation that relies solely on HPLC retention time and peak area cannot distinguish these two compounds with confidence.
Why cyclisation costs selectivity
A flexible linear peptide can adopt a different bound conformation at each receptor subtype, allowing sequence outside the core to discriminate between them. A rigid ring presents essentially the same shape to every subtype, so recognition collapses onto the shared core motif.
Why the D-amino acid matters analytically
D-Phe and L-Phe are indistinguishable by mass and nearly so by ordinary reversed-phase HPLC. Confirming stereochemistry requires a chiral method or a co-injection against a characterised reference — a genuine limitation of standard certificates of analysis.
Melanotan research peptide comparison table
The table below sets out verified identity data and reported receptor selectivity for the three compounds. Selectivity descriptions reflect how the compounds are characterised in the published literature.
| Property | Melanotan 1 (afamelanotide) | Melanotan 2 | PT-141 (bremelanotide) |
|---|---|---|---|
| Structure | Linear, 13 residues | Cyclic lactam, 7 residues | Cyclic lactam, 7 residues |
| Sequence | Ac-Ser-Tyr-Ser-Nle-Glu-His-D-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH2 | Ac-Nle-cyclo[Asp-His-D-Phe-Arg-Trp-Lys]-NH2 | Ac-Nle-cyclo[Asp-His-D-Phe-Arg-Trp-Lys]-OH |
| CAS number | 75921-69-6 | 121062-08-6 | 189691-06-3 |
| Molecular formula | C78H111N21O19 | C50H69N15O9 | C50H68N14O10 |
| Molecular weight | ≈1646.9 Da | ≈1024.2 Da | ≈1025.2 Da |
| C-terminus | Amide (Val-NH2) | Amide | Free carboxylic acid |
| Reported selectivity | MC1R-preferring | Non-selective: MC1R, MC3R, MC4R, MC5R | MC1R–MC5R except MC2R; principally MC3R/MC4R |
| Other names | NDP-α-MSH, [Nle4, D-Phe7]-α-MSH, MT-1 | MT-II, MT-2 | Bremelanotide, PT-141 |
| Modified residues | Nle4, D-Phe7 | Nle, D-Phe, Asp–Lys lactam | Nle, D-Phe, Asp–Lys lactam |
Solution preparation: concentration reference
The following is a concentration reference for laboratory solution preparation. It converts a stated vial mass and a chosen diluent volume into a working concentration for assay calculations. It is not a dosing table and has no application outside a laboratory.
| Mass in vial | Diluent volume | Concentration | Amount in 0.1 mL | Approx. molarity (MW 1025) |
|---|---|---|---|---|
| 10 mg | 1 mL | 10 mg/mL | 1,000 mcg | ≈9.8 mM |
| 10 mg | 2 mL | 5 mg/mL | 500 mcg | ≈4.9 mM |
| 10 mg | 5 mL | 2 mg/mL | 200 mcg | ≈2.0 mM |
| 10 mg | 10 mL | 1 mg/mL | 100 mcg | ≈0.98 mM |
| 5 mg | 1 mL | 5 mg/mL | 500 mcg | ≈4.9 mM |
| 5 mg | 2 mL | 2.5 mg/mL | 250 mcg | ≈2.4 mM |
For Melanotan 1 the molarity column should be recalculated on 1646.9 Da, which gives roughly 6.1 mM for a 10 mg/mL preparation. Receptor-binding and cAMP assays typically operate in the nanomolar range, so several serial dilution steps separate a laboratory stock from an assay concentration.
General technique is covered in our guide to how to reconstitute research peptides, and diluent choice in the bacteriostatic water guide.
Stability and laboratory handling
Melanocortin analogues are relatively robust as lyophilised solids and considerably less so in solution. Three chemistry-specific points are worth noting.
First, tryptophan is photolabile. Every compound here contains a tryptophan in its core motif, and Trp is among the most light-sensitive proteinogenic residues. Amber glass or foil wrapping is a reasonable default for solutions.
Second, the cyclic compounds are not immune to hydrolysis. The amide-to-acid conversion that turns Melanotan 2 into PT-141 is exactly the kind of slow hydrolytic change that a solution held at room temperature and non-neutral pH can undergo, which means a stored Melanotan 2 solution can drift towards a mixture over time.
Third, arginine and lysine residues give these peptides a strong positive charge, which promotes adsorption to glass and to some plastics at low concentration. Low-bind tubes and carrier protein where the assay permits are standard mitigations.
Quality control for cyclic and D-amino acid peptides
Certificates of analysis for this family have to answer questions that a simple linear peptide does not raise. A meaningful certificate should address all four of the following.
- Correct mass, with resolution to distinguish close analogues. Melanotan 2 and PT-141 differ by one dalton. The mass-spectrometric data should be specific enough to tell them apart.
- Evidence of cyclisation. A cyclic lactam is 18 daltons lighter than the corresponding linear peptide, because ring closure eliminates a molecule of water. A linear impurity is therefore mass-detectable.
- Purity by RP-HPLC with the integration table shown, not just a headline percentage.
- Counter-ion and net peptide content. Arginine-rich peptides are typically supplied as acetate or trifluoroacetate salts, and the salt is a meaningful proportion of vial mass.
GenoPept publishes per-batch third-party certificates at /coa-certificates/. Our guide on how to read a peptide certificate of analysis walks through each field.
Melanocortin peptides in the GenoPept store
Frequently asked questions
What is the difference between Melanotan 1 and Melanotan 2?
Melanotan 1 (afamelanotide, NDP-α-MSH) is a linear 13-residue peptide of about 1646.9 Da that binds predominantly to MC1R. Melanotan 2 is a cyclic lactam heptapeptide of about 1024.2 Da that acts non-selectively across MC1R, MC3R, MC4R and MC5R. They share the His-Phe-Arg-Trp core motif and both use norleucine and D-phenylalanine substitutions, but they are structurally distinct molecules.
How does PT-141 differ from Melanotan 2 chemically?
PT-141 (bremelanotide) has the identical cyclic scaffold but terminates in a free carboxylic acid rather than a primary amide. That single change makes it one dalton heavier — about 1025.2 Da versus 1024.2 Da — and shifts the reported receptor preference towards MC3R and MC4R. PT-141 is described in the literature as an active metabolite of Melanotan 2.
What are the melanocortin receptors?
MC1R to MC5R are five class A G-protein-coupled receptors that signal through Gs and cyclic AMP. MC1R is found on melanocytes, MC2R in the adrenal cortex, MC3R and MC4R in the central nervous system, and MC5R in exocrine tissue. MC2R is unique in responding to ACTH alone and is not engaged by α-MSH-derived analogues.
Why is norleucine used instead of methionine?
Norleucine is isosteric with methionine — the same size and similar hydrophobicity — but its side chain is a plain hydrocarbon with no sulfur. Methionine oxidises readily to the sulfoxide, which changes a peptide’s mass and chromatographic behaviour and can reduce activity. Substituting norleucine removes that liability without perturbing how the residue packs against the receptor.
Why do these peptides contain a D-amino acid?
D-phenylalanine at position 7 does two things. Proteases are stereospecific, so a D-residue blocks cleavage at that position and greatly extends the peptide’s survival in biological matrices. It also constrains the local backbone geometry, helping to hold the His-Phe-Arg-Trp core in the conformation that the receptor recognises.
What is afamelanotide?
Afamelanotide is the international non-proprietary name for the compound also called Melanotan 1 or NDP-α-MSH: Ac-Ser-Tyr-Ser-Nle-Glu-His-D-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH2, CAS 75921-69-6. It has been developed as a licensed pharmaceutical in some territories. The material supplied by GenoPept is a research chemical, not the licensed pharmaceutical form.
How can a certificate of analysis distinguish Melanotan 2 from PT-141?
By mass. The two compounds differ by one dalton, which a modern mass spectrometer resolves easily but which is invisible on a UV chromatogram. A certificate reporting only HPLC retention time and peak area cannot separate them with confidence. Cyclisation itself is also mass-detectable: a cyclic lactam is 18 daltons lighter than its linear counterpart because ring closure eliminates water.
Do melanocortin peptides need protection from light?
It is prudent. Every compound in this family contains a tryptophan residue in its core recognition motif, and tryptophan is among the most photolabile proteinogenic amino acids. Amber vials or foil wrapping for solutions, together with cold, dry, dark storage of the lyophilised solid, is the standard laboratory approach for peptides containing Trp.
References
- Hadley ME, Dorr RT. Melanocortin peptide therapeutics: historical milestones, clinical studies and commercialization. Peptides. 2006;27(4):921-930. PubMed
- Reference entry: Afamelanotide — sequence, molecular formula, molar mass, CAS 75921-69-6 and MC1R selectivity. Reference entry
- Reference entry: Melanotan II — lactam cyclisation, molecular formula, molar mass, CAS 121062-08-6 and receptor profile. Reference entry
- Reference entry: Bremelanotide — sequence Ac-Nle-cyclo[Asp-His-D-Phe-Arg-Trp-Lys]-OH, molecular formula, CAS 189691-06-3 and MC3R/MC4R profile. Reference entry
- Reference entry: Melanocortin receptor — the MC1R to MC5R family, MC2R selectivity for ACTH, and agouti / AGRP inverse agonism. Reference entry
Research-grade melanocortin peptides, batch-verified
GenoPept supplies Melanotan 1, Melanotan 2 and PT-141 as lyophilised vials with a per-batch third-party certificate of analysis covering HPLC purity and mass-spectrometric identity, dispatched from the UK, strictly for laboratory research.