Melanotan II (MT-II) is a lactam-bridged cyclic heptapeptide analog of the α-melanocyte-stimulating hormone 4–10 region, developed within the University of Arizona College of Medicine melanocortin program. Receptor assays characterize it as an agonist at human MC1R, MC3R, MC4R, and MC5R rather than the ACTH-selective MC2R, and it is not an FDA-approved drug, cosmetic, or tanning agent.
Melanotan II is often described through outcomes—pigmentation, appetite, or sexual-function observations—but those labels hide the evidence architecture. A stronger guide starts with exact peptide identity, receptor pharmacology, the University of Arizona development lineage, and the difference between early MT-II studies and later approved products built from related but distinct molecules.
- MT-II is a lactam-cyclized seven-residue analog of the α-MSH 4–10 region.
- Human receptor data support agonism at MC1R, MC3R, MC4R, and MC5R; “nonselective” does not mean equal potency at every receptor.
- MC2R is the ACTH receptor and is not part of MT-II’s established receptor profile.
- The lineage begins with Sawyer, Hruby, Hadley, and colleagues at the University of Arizona College of Medicine and is documented in the Hadley/Dorr reviews.
- Early MT-II human studies were small, historical experiments; they do not create a modern approved indication.
- MT-II, afamelanotide, and bremelanotide are related melanocortin analogs but are not interchangeable molecules, formulations, or evidence objects.
Melanotan II at a Glance
| Field | Melanotan II record | Interpretation boundary |
|---|---|---|
| Common names | Melanotan II, MT-II, MTII | Do not collapse it into Melanotan I, afamelanotide, PT-141, or bremelanotide |
| Peptide design | Cyclic heptapeptide analog of the α-MSH 4–10 region | The lactam bridge and D-Phe substitution are identity-defining |
| CAS / formula / average molecular weight | 121062-08-6 / C50H69N15O9 / 1,024.18 g/mol | FDA Global Substance Registration System identity fields, not product-quality or activity claims |
| Human receptor profile | Agonist at MC1R, MC3R, MC4R, and MC5R | Assay potency varies by receptor and method; multi-receptor does not mean equal |
| MC2R relationship | MC2R is the ACTH receptor | Do not include MC2R in the established MT-II agonist profile |
| FDA status | No FDA-approved Melanotan II finished drug | Scenesse and Vyleesi contain different active molecules |
The FDA’s Global Substance Registration System record for Melanotan II provides substance identifiers, formula, and molecular weight. Registration in a substance database is not drug approval and does not establish safety, effectiveness, formulation quality, or a permitted personal use.
What Is Melanotan II?
Melanotan II is a lactam-bridged cyclic heptapeptide based on residues 4–10 of α-MSH. The historical study record writes the sequence as Ac-Nle-Asp-His-D-Phe-Arg-Trp-Lys-NH2, with cyclization between the Asp and Lys side chains.[1] Norleucine and D-phenylalanine substitutions, truncation, terminal modifications, and the lactam ring distinguish MT-II from native α-MSH.
These features were designed to restrict conformation and prolong activity relative to native peptide systems. They also mean that a label such as “α-MSH analog” describes ancestry, not equivalence. Native α-MSH, afamelanotide, MT-II, SHU9119, and bremelanotide each require their own identity and pharmacology records.
Reagent identity record
| Identity field | Value | Source record |
|---|---|---|
| CAS Registry Number | 121062-08-6 | FDA Global Substance Registration System; Apex catalog record |
| Molecular formula | C50H69N15O9 | FDA Global Substance Registration System; PubChem CID 92432 |
| Average molecular weight | 1,024.18 g/mol (PubChem CID 92432 reports 1024.2 g/mol for the same formula) | FDA Global Substance Registration System |
| Amino-acid sequence | Ac-Nle-cyclo(Asp-His-D-Phe-Arg-Trp-Lys)-NH2 | Written in the 1996 pilot Phase I report as Ac-Nle4-Asp5-His6-D-Phe7-Arg8-Trp9-Lys10 α-MSH4-10-NH2[1] |
| Ring chemistry | Lactam bridge closing the Asp5 and Lys10 side chains | Classified as a cyclic lactam MSH(4–10) analog in the receptor-selectivity study[5] |
| FDA substance identifier (UNII) | UPF5CJ93X7 | FDA Global Substance Registration System |
| Compound class | Cyclic α-MSH(4–10) analog; multi-receptor melanocortin agonist | IUPHAR/BPS Guide to Pharmacology ligand record |
| Physical form | Lyophilized powder; catalog storage note −20 °C long term | Apex catalog record — a handling note, not a use instruction |
The University of Arizona Melanocortin Lineage
The modern analog lineage traces to the University of Arizona College of Medicine program led by Victor Hruby, Mac Hadley, Robert Dorr, and colleagues. Two structure–activity papers set the chemistry that MT-II inherits. In 1980 Sawyer and coauthors described [Nle4,D-Phe7]-α-MSH — later developed as Melanotan-1/afamelanotide, not MT-II — roughly 26-fold more potent than native α-MSH in a mouse-melanoma adenylate-cyclase assay and resistant to degradation by serum enzymes (PMID 6777774); both of those substitutions still sit in the MT-II sequence.
In 1982 the same group reported a conformationally restricted cyclic α-MSH analog with superagonist activity.[2] Measured against native α-MSH, that cyclic analog was more than 10,000-fold more potent at darkening frog (Rana pipiens) skin, roughly 30-fold more potent on lizard (Anolis carolinensis) melanophores in vitro, and about 3-fold more potent in a cell-free Cloudman S-91 mouse-melanoma membrane adenylate-cyclase preparation. Those are amphibian, reptile, and mouse-cell measurements, not human results — and the 1982 molecule was not itself MT-II.
Hadley, Hruby, Blanchard, and Dorr’s 1998 review documents the discovery and development of Melanotan I and Melanotan II.[3] Hadley and Dorr’s 2006 historical synthesis follows the program through clinical studies and commercialization.[4] Palatin Technologies licensed the program and developed bremelanotide, also called PT-141. That development history does not make bremelanotide and MT-II the same peptide.
Which Melanocortin Receptors Does MT-II Activate?
There are five melanocortin receptor subtypes: MC1R through MC5R. MT-II’s established human profile covers MC1R, MC3R, MC4R, and MC5R. Schiöth and colleagues compared cyclic MSH analogs in cells expressing the human MC1, MC3, MC4, and MC5 receptors and found that the cyclic lactams, MT-II among them, held higher overall affinity for the MC receptors than any of the cyclic disulphide analogs tested.[5] Those four subtypes are different proteins — the cloned MC3-R is only 43% identical to the melanocyte MSH receptor, a sequence comparison reported without a species in the abstract (PMID 8415620) — so reaching all of them is not the same as treating them alike. The current IUPHAR/BPS Guide to Pharmacology MT-II record curates full-agonist activity at those four human receptors.
“Nonselective” is a shorthand for multi-receptor activity, not a claim that every receptor sees the same potency, efficacy, tissue exposure, or downstream outcome. Assay format, species, receptor expression, ligand concentration, and readout can change reported values. For that reason, this guide uses a qualitative receptor map and leaves numerical values with their source assays.
MC2R is the ACTH receptor. It has a distinct ligand requirement and is not included in the established MT-II receptor set. Listing “MC1R–MC5R” as though MT-II activates all five equally is inaccurate.
The melanocortin receptor family on record
The five subtypes were cloned and localized between 1992 and 1994. Each row reports what the cited paper measured, in the system it measured it in.
| Receptor · source | System reported | Reported finding · PMID |
|---|---|---|
| MC1R and MC2R · Mountjoy 1992 | Cloned murine and human MSH receptors; cloned human ACTH receptor | Established melanocortin receptors as a distinct G-protein-coupled receptor subfamily and separated the MSH receptor from the ACTH receptor · PMID 1325670 |
| MC3R · Roselli-Rehfuss 1993 | Cloned receptor, species not stated in the abstract; hypothalamic and limbic expression, arcuate POMC neurons | MC3-R is 43% identical to the melanocyte MSH receptor, couples strongly to adenylyl cyclase, and is potently activated by γ-MSH peptides that lack melanotropic activity · PMID 8415620 |
| MC4R · Gantz 1993 | Cloned human receptor expressed in transfected COS-1 and L-cells | Expressed primarily in brain and notably absent from adrenal cortex, melanocytes and placenta; gene mapped to chromosome 18q21.3; melanocortin response profile distinct from the three receptors cloned before it · PMID 8392067 |
| MC4R distribution · Mountjoy 1994 | Adult rat brain | MC4-R mRNA found across cortex, thalamus, hypothalamus, brainstem and spinal cord, including both parvicellular and magnocellular paraventricular neurons — a far broader distribution than MC3-R · PMID 7854347 |
| MC5R · Gantz 1994 | Cloned mouse receptor; mouse tissue Northern blot | cAMP potency rank α-MSH > β-MSH > ACTH > γ-MSH, with the melanocortin core heptapeptide alone inactive; mRNA detected in mouse skeletal muscle, lung, spleen and brain · PMID 8185570 |
What Does the Published MT-II Evidence Actually Show?
Pigmentation observations
A 1996 pilot Phase I report studied MT-II in three healthy male volunteers (n=3) under a single-blind, alternating-day design in which each subject received either MT-II or saline.[1] Subcutaneous injections were given each weekday for two consecutive weeks, starting at 0.01 mg/kg; two subjects were escalated in 0.005 mg/kg increments to 0.03 mg/kg and one to 0.025 mg/kg.
Two of the three subjects showed increased pigmentation of the face, upper body, and buttock one week after dosing ended, recorded by quantitative reflectance as well as visual assessment. The same report logged Grade II somnolence and fatigue in one of the two subjects dosed at 0.03 mg/kg, mild nausea at most dose levels, and a stretching-and-yawning complex that tracked spontaneous erections lasting 1 to 5 hours after dosing. The authors recommended 0.025 mg/kg/day for subsequent Phase I work. Three subjects and a study-specific formulation: a historical dose-finding observation, not general safety evidence and not an approved indication.
Sexual-function observations
A later double-blind, placebo-controlled crossover study enrolled ten men (n=10) whose erectile dysfunction had no known organic cause and monitored penile rigidity by RigiScan across a 6-hour window.[6] Clinically apparent erections developed in 8 of 10 men on MT-II. Mean duration of tip rigidity above 80% was 38.0 minutes on MT-II versus 3.0 minutes on vehicle placebo (p=0.0045), at a dose of 0.025 mg/kg. Transient nausea, stretching and yawning, and decreased appetite were reported more often on MT-II than on placebo, and none required treatment.
A larger summary from the same group, covering 20 men and adding a sexual-desire endpoint, sits in the claim map below. Neither study approved MT-II, and neither transfers Vyleesi’s finished-drug evidence onto it.
Appetite and energy-balance models
MT-II has also been used as an experimental MC4R-pathway probe in rodent models. Schuhler and colleagues gave intracerebroventricular MTII to male Siberian hamsters just before lights off; food intake fell significantly against vehicle across the 6-hour observation period, and the same response appeared in age-matched animals held in short photoperiod for 9 wk, by which point body weight had significantly decreased.[7] There was no clear difference between long- and short-photoperiod hamsters in either the size of the response or the dose needed for half-maximal inhibition of feeding, and MTII significantly increased grooming in both states.
The authors read that null difference as evidence against the melanocortin pathway driving seasonal weight change in this species. These are hamster central-administration data; they do not establish a human weight-management use. A rat paraventricular result on the same pathway sits in the claim map below.
The existence of an early human paper does not establish a favorable benefit–risk profile. Study size, era, formulation, population, comparator, adverse-event collection, and regulatory review all matter. This guide reports the record without converting it into advice.
Additional reported findings
Each row names the compound, model, species, and endpoint, so nothing is silently carried across from a neighbouring molecule.
| Compound · model · species | Endpoint | Reported result · PMID |
|---|---|---|
| Melanotan II · double-blind placebo-controlled crossover, 6-hour RigiScan monitoring · human, 20 men with psychogenic or organic erectile dysfunction | Penile rigidity without sexual stimulation; self-reported desire; adverse effects | Erection in 17 of 20 men; mean 41 minutes of tip rigidity above 80%; increased desire after 68% of MT-II doses versus 19% of placebo doses (P<0.01); severe nausea in 12.9% of subjects at 0.025 mg/kg · PMID 11035391 |
| MTII, with an α-MSH comparator arm · paraventricular-nucleus microinjection · rat | Nocturnal and NPY-stimulated food intake; conditioned taste aversion | Co-administration with NPY of 1 pmol MTII or 600 pmol α-MSH into the paraventricular nucleus each caused a significant decrease in NPY-induced feeding; neither peptide caused conditioned taste aversion at feeding-suppressive doses, while intracerebroventricular α-MSH caused weak aversion · PMID 11179607 |
| α-MSH and ACTH acting at MC1R, the pigmentation receptor MT-II engages · cultured melanocytes · human | cAMP, tyrosinase activity, proliferation, UV-induced apoptosis | α-MSH and ACTH equipotent and more potent than β-MSH, with γ-MSH weakest; melanocyte cultures carrying Arg160Trp, Arg151Cys or Asp294His loss-of-function MC1R variants failed to raise cAMP, tyrosinase activity or proliferation and were more vulnerable to UV cytotoxicity · PMID 12851336 |
| MC1R receptor genetics · population and pigment-cell review · human | Loss-of-function variant frequency and phenotype | The review reports recent work suggesting up to 30% of the population harbours MC1R loss-of-function variants (no cohort, ancestry, or n given); most red-haired individuals are compound heterozygotes or homozygotes across as many as five frequent loss-of-function alleles, making MC1R a determinant of sun sensitivity and skin-cancer risk · PMID 10885670 |
| Melanotan II · single subcutaneous self-administration of internet-purchased material · human case report, 39-year-old man | Systemic toxicity, rhabdomyolysis, renal function | A 6 mg injection — six times the amount the patient reported using initially — was followed by heart rate peaking at 146 beats per minute, creatine kinase climbing from 1,760 IU/L to 17,773 IU/L over 12 hours, creatinine of 2.25 mg/dL, and 3 days in intensive care; mass spectrometry confirmed the injected material against a purchased Melanotan II standard · PMID 23121206 |
Two rows describe MC1R itself; MC1R pharmacology is what the pigmentation lane rests on.
Melanotan II vs Afamelanotide and Bremelanotide
| Entity | Identity and lineage | Regulatory record |
|---|---|---|
| Melanotan II / MT-II | Cyclic heptapeptide α-MSH analog from the Arizona program | No FDA-approved finished drug |
| Melanotan I / afamelanotide | Linear α-MSH analog; distinct from MT-II | Scenesse implant approved under NDA 210797 |
| PT-141 / bremelanotide | Related cyclic melanocortin analog developed by Palatin; distinct from MT-II | Vyleesi finished drug approved under NDA 210557 |
FDA approved Scenesse (afamelanotide), NDA 210797, on October 8, 2019 for a specified erythropoietic-protoporphyria indication. FDA approved Vyleesi (bremelanotide), NDA 210557, on June 21, 2019 for a specified hypoactive-sexual-desire-disorder indication. Those approvals belong to the named active molecules, sponsors, formulations, evidence packages, and labels.
MT-II is not the active ingredient in either approval. Similar lineage, overlapping receptor activity, or a shared development history does not transfer formulation, labeling, indication, clinical evidence, or regulatory status.
That rule is also why this page does not carry the clinical literature for its neighbours. The Melanotan-1 tanning trials, the afamelanotide programme behind the Scenesse implant, and the bremelanotide arousal studies are real evidence — for those molecules. Those results belong on their own records.
Regulatory and Analytical Boundaries
Approval status, stated explicitly
Melanotan II is not approved by the FDA as a drug, cosmetic, or tanning agent, and it has no FDA-approved indication. A CAS number, a UNII, a substance-database entry, and a certificate of analysis are identity and analytical facts; none of them is an approval.
That absence of approval sits beside a published harm signal. The 2012 clinical-toxicology case in the claim map above documented sympathomimetic toxicity, rhabdomyolysis, and renal dysfunction after a single self-injection of internet-purchased material later confirmed by mass spectrometry. One case report is not an incidence estimate, but it is an adverse-event record attached to unregulated use of this exact compound.
Supplying a chemical reagent to qualified laboratories is a different act from marketing a drug. Research-use labeling must stay consistent across the page, product record, checkout context, and supporting documentation; therapeutic, cosmetic, or personal-use claims would change the regulatory context.
What the analytical record can and cannot settle
For analytical review, separate identity, purity, and activity. Mass spectrometry can support expected mass identity. HPLC can report chromatographic purity under a stated method. Neither result proves receptor activation, sterility, safety, an approved formulation, or equivalence to Scenesse or Vyleesi. A lot-specific certificate must match the exact lot and material under evaluation.
The Apex catalog record for Melanotan II states a ≥99% purity specification, with identity and purity verified by reversed-phase HPLC and mass spectrometry and documented on a per-lot certificate. Read that as the specification the material is released against, not a measured value for a particular vial; the operative document is the certificate matching the lot in hand.
The PT-141 and bremelanotide research guide owns bremelanotide intent. The specialty research hub places the broader melanocortin family, while the COA guide, HPLC guide, and mass-spectrometry guide own analytical-method interpretation.
Frequently Asked Questions
What is Melanotan II?
Melanotan II is a lactam-cyclized seven-residue analog of the α-MSH 4–10 region developed within the University of Arizona melanocortin program.
Which receptors does Melanotan II activate?
Human receptor data support agonism at MC1R, MC3R, MC4R, and MC5R. The ACTH-selective MC2R is not part of the established MT-II agonist profile.
Does nonselective mean MT-II affects every melanocortin receptor equally?
No. Nonselective means MT-II has multi-receptor activity across MC1R, MC3R, MC4R, and MC5R. Potency and assay response differ by receptor, species, method, and experimental system.
Is Melanotan II the same as Melanotan I or afamelanotide?
No. Melanotan II is a cyclic heptapeptide, while Melanotan I and afamelanotide refer to a different linear analog and evidence record.
Is Melanotan II the same as PT-141 or bremelanotide?
No. Bremelanotide is a related but distinct melanocortin analog developed from the Arizona program. Vyleesi’s approval and formulation do not transfer to MT-II.
Is Melanotan II FDA approved?
No. There is no FDA-approved Melanotan II finished drug. Scenesse contains afamelanotide and Vyleesi contains bremelanotide, which are different active molecules.
What can a Melanotan II certificate of analysis establish?
A lot-specific certificate can report identity and analytical results under stated methods. It cannot prove receptor activity, sterility, safety, efficacy, approval, or equivalence to a finished drug.
What did the early human Melanotan II studies actually measure?
Two small studies. A 1996 pilot Phase I report followed three healthy male volunteers through subcutaneous doses of 0.01 to 0.03 mg/kg and recorded increased pigmentation by quantitative reflectance in two of the three. A 1998 double-blind crossover study in ten men with psychogenic erectile dysfunction recorded a mean 38.0 minutes of RigiScan tip rigidity above 80% versus 3.0 minutes on placebo (p=0.0045) at 0.025 mg/kg.
What adverse events are documented with unregulated Melanotan II use?
A 2012 clinical-toxicology case report describes a 39-year-old man who injected 6 mg of internet-purchased Melanotan II and developed sympathomimetic toxicity, rhabdomyolysis with creatine kinase reaching 17,773 IU/L, and renal dysfunction requiring 3 days of intensive care. Mass spectrometry confirmed the material was Melanotan II. One case report is not an incidence estimate.
References
- Dorr RT, et al. Evaluation of melanotan-II, a superpotent cyclic melanotropic peptide in a pilot phase-I clinical study. Life Sci. 1996;58(20):1777-84. PMID: PMID 8637402.
- Sawyer TK, et al. [half-Cys4,half-Cys10]-alpha-Melanocyte-stimulating hormone: a cyclic alpha-melanotropin exhibiting superagonist biological activity. Proc Natl Acad Sci U S A. 1982;79(6):1751-5. PMID: PMID 6281785.
- Hadley ME, et al. Discovery and development of novel melanogenic drugs. Melanotan-I and -II. Pharm Biotechnol. 1998;11:575-95. PMID: PMID 9760697.
- Hadley ME, et al. Melanocortin peptide therapeutics: historical milestones, clinical studies and commercialization. Peptides. 2006;27(4):921-30. PMID: PMID 16412534.
- Schiöth HB, et al. Selectivity of cyclic [D-Nal7] and [D-Phe7] substituted MSH analogues for the melanocortin receptor subtypes. Peptides. 1997;18(7):1009-13. PMID: PMID 9357059.
- Wessells H, et al. Synthetic melanotropic peptide initiates erections in men with psychogenic erectile dysfunction: double-blind, placebo controlled crossover study. J Urol. 1998;160(2):389-93. PMID: PMID 9679884.
- Schuhler S, et al. Decrease of food intake by MC4-R agonist MTII in Siberian hamsters in long and short photoperiods. Am J Physiol Regul Integr Comp Physiol. 2003;284(1):R227-32. PMID: PMID 12388479.
