Melanotan II

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A 7-residue macrocyclic peptide retaining the His-Phe-Arg-Trp recognition motif of native alpha-MSH, closed by a side-chain lactam bridge between aspartate and lysine. Characterized in the primary literature as a non-selective melanocortin receptor agonist. For laboratory characterisation only.

Melanotan II is a synthetic cyclic heptapeptide analog of alpha-MSH, designed at the University of Arizona in the early 1990s. A side-chain lactam bridge closes the macrocycle and confers resistance to enzymatic degradation relative to the linear parent peptide. It is characterized in the published in-vitro literature as a non-selective agonist across MC1R, MC3R, MC4R and MC5R, with minimal activity at MC2R. No compound containing Melanotan II has been approved by any regulatory agency.

Melanocortin-1 receptor Ki ≈ 1.4 nM Full agonist (in vitro)

Competitive binding assays in human MC1R-overexpressing HEK293 cells using radiolabeled NDP-alpha-MSH report low-nanomolar affinity. MC1R is expressed on melanocytes and regulates eumelanin versus phaeomelanin synthesis.

Melanocortin-3 receptor High affinity Full agonist (in vitro)

Reported in the primary literature as a full agonist at MC3-R. The receptor is implicated in energy homeostasis and is expressed on immune cell populations.

Melanocortin-4 receptor High affinity Full agonist (in vitro)

Full agonist activity reported at MC4-R. Intracerebroventricular administration inhibited feeding across four murine models of hyperphagia, a finding central to the subsequent MC4R energy-balance literature.

Melanocortin-5 receptor High affinity Full agonist (in vitro)

Engagement reported in cAMP accumulation assays. MC5R is expressed in peripheral tissues and associated with exocrine and sebaceous secretion.

Melanocortin-2 receptor (ACTH receptor) Ki > 1 μM Minimal activity (in vitro)

The pharmacologically notable exclusion. Reported affinity above 1 micromolar separates Melanotan II activity from the adrenocorticotropic / corticosteroid axis.

Binding and functional values are from in-vitro assays reported in peer-reviewed literature. In-vitro characterisation only — no clinical or therapeutic claim is expressed or implied. Research use only.

In-vitro receptor binding · cyclic analog series Hruby et al., J Med Chem 1995

Murine hyperphagia models · intracerebroventricular administration Fan et al., Nature 1997

Randomized controlled trial · fair-skinned subjects Barnetson et al., Br J Dermatol 2006

Double-blind, placebo-controlled crossover · psychogenic ED Wessells et al., Urology 1998

Dose-escalation tolerability pilot Dorr et al., Life Sci 1996

Reference chemistry and regulatory status only. Literature on one of these compounds does not transfer to the others; citations should be checked against the compound actually studied.

Melanotan II is a synthetic cyclic heptapeptide analog of alpha-melanocyte-stimulating hormone (alpha-MSH). It has molecular formula C50H69N15O9 and mass 1024.2 g/mol, with published sequence Ac-Nle-c[Asp-His-D-Phe-Arg-Trp-Lys]-NH2. Three modifications distinguish it from the corresponding alpha-MSH fragment: norleucine at position 4 in place of an oxidation-sensitive methionine, D-phenylalanine at position 7, and a side-chain lactam bridge between aspartate and lysine that closes the macrocycle. Common synonyms in the literature include MT-II, MT-2, and Ac-[Nle4, Asp5, D-Phe7, Lys10]-alpha-MSH (4-10)-NH2.

Note on structure: the ring is a lactam (amide) bridge, not a disulfide. The sequence contains no cysteine residues. Several secondary sources describe the cyclization incorrectly.

Investigation of Melanotan II is limited in scale, concentrated in the 1990s and 2000s, and comprises in-vitro receptor pharmacology, animal models, and small early-phase human studies rather than large randomized trials. Published work spans structure-activity research, establishing the cyclization strategy and its receptor-binding consequences; melanogenesis research, including a randomized controlled trial examining eumelanin synthesis in fair-skinned subjects and a phase-I pilot characterizing tolerability; feeding-behavior research, in which intracerebroventricular administration was reported to inhibit feeding across four murine models of hyperphagia; and erectile-response research in a double-blind placebo-controlled crossover design. Nausea and flushing are reported as dose-limiting across the human studies. None of this material establishes therapeutic outcomes in humans, and no Phase 3 trial has been completed or published.

Melanotan II is supplied as a lyophilized powder, soluble in water and saline. Reconstitution is typically performed with bacteriostatic water per laboratory SOP. Protect from light and moisture, and minimize freeze-thaw cycles by aliquoting for extended storage. Vendor storage guidance for this compound is not consistent — published recommendations range from 2–8 °C to −20 °C for lyophilized material. Because the compound has no approved formulation, no official monograph exists; follow the guidance supplied with your specific lot alongside your own laboratory protocol.

Melanotan II is not approved for any indication by the FDA, EMA, MHRA, TGA, or Health Canada, and has never been submitted for regulatory review in any jurisdiction. It is not eligible for pharmaceutical compounding under sections 503A or 503B of the Federal Food, Drug, and Cosmetic Act. Regulatory agencies in the United States, United Kingdom and Australia have issued public warnings regarding this compound, and published case reports in the dermatology and emergency medicine literature describe serious adverse events associated with non-research use.

Three structurally distinct melanocortin analogs frequently conflated in secondary sources. Reference chemistry and regulatory status only — no comparative-effectiveness claim expressed or implied.