MT-2 (Melanotan 2)

MT-2 (Melanotan 2) is a cyclic non-selective melanocortin receptor agonist peptide developed at the University of Arizona by the laboratories of Mac E. Hadley and Victor J. Hruby in the 1980s. The molecule is a structural analog of α-melanocyte-stimulating hormone (α-MSH), the endogenous tridecapeptide melanocortin produced by post-translational processing of pro-opiomelanocortin (POMC) in the pituitary and in peripheral tissues. The peptide-engineering rationale was to produce a metabolically stable, potent, non-selective melanocortin receptor agonist that retained the broad melanocortin-receptor profile of α-MSH but with substantially extended duration of action and oral/parenteral bioavailability.

The molecule is a cyclic heptapeptide with sequence Ac-Nle-cyclo(Asp-His-D-Phe-Arg-Trp-Lys)-NH2, where the cyclization is via a lactam bridge between the Asp side chain and the Lys side chain. The structural modifications relative to the parent α-MSH sequence include replacement of the N-terminal serine and methionine with norleucine (Nle), the D-phenylalanine substitution at position 7 (a key potency-enhancing modification in melanocortin-agonist medicinal chemistry), and the lactam cyclization that constrains the conformation and provides resistance to proteolytic degradation. MT-2 binds with measurable affinity and agonist activity at all four cloned melanocortin receptor subtypes (MC1R, MC3R, MC4R, MC5R) and the receptor subtype MC2R (the ACTH-selective melanocortin receptor; engagement at this subtype is generally weak for MT-2).

This page is a research-only educational reference for MT-2 / Melanotan 2 as a research peptide for melanocortin-pharmacology research. The peptide is not approved as a medicine in any jurisdiction; the related but structurally distinct linear melanocortin-1-receptor-selective analog afamelanotide (Scenesse) is an approved medicine in some jurisdictions for erythropoietic protoporphyria — MT-2 is not afamelanotide and is not the approved medicine. No medical or therapeutic claims are made on this page, and no safety claims are made about non-research use.

MT-2 (Melanotan 2) is a cyclic heptapeptide analog of α-melanocyte-stimulating hormone (α-MSH). The structure is Ac-Nle⁴-c[Asp⁵,D-Phe⁷,Lys¹⁰]-α-MSH(4-10)-NH2, more compactly written as Ac-Nle-cyclo(Asp-His-D-Phe-Arg-Trp-Lys)-NH2 with an amide-capped C-terminus and a lactam bridge between the Asp side chain and Lys side chain. The molecular weight is approximately 1024 g/mol. The cyclization, the D-phenylalanine substitution, and the N-terminal acetylation and norleucine substitution were chosen through structure-activity-relationship work in the Hadley/Hruby laboratories as modifications that confer high potency, broad melanocortin-receptor agonist activity, and metabolic stability relative to the parent α-MSH sequence.

The molecule was designed and patented in the late 1980s with priority dating and US patent issuance reflecting work conducted at the University of Arizona under the original "Melanotan" naming convention. Two principal Melanotan analogs were developed: Melanotan-1 (afamelanotide; [Nle⁴,D-Phe⁷]-α-MSH), a linear MC1R-selective analog that was subsequently developed clinically and approved as Scenesse (afamelanotide) for erythropoietic protoporphyria by Clinuvel Pharmaceuticals; and Melanotan-2 (MT-2; the cyclic compound described on this page), a more conformationally constrained, non-selective melanocortin agonist developed for research-pharmacology applications. The two molecules are structurally and pharmacologically distinct; MT-2 is not afamelanotide.

The melanocortin receptor system is a family of five G-protein-coupled receptors (MC1R through MC5R) with distinct tissue distributions and physiological roles. MC1R is principally expressed in melanocytes (skin pigmentation) and immune cells. MC2R is the adrenocortical ACTH receptor mediating cortisol release. MC3R is expressed in CNS sites and peripheral tissues and is involved in energy homeostasis and inflammation. MC4R is expressed in hypothalamic and other CNS sites and is the principal receptor mediating melanocortin effects on food intake and energy expenditure (loss-of-function MC4R variants are the most common monogenic cause of human obesity). MC5R is expressed in exocrine glands and other peripheral tissues with less well-characterized function. MT-2 is a non-selective agonist at MC1R, MC3R, MC4R, and MC5R with relatively weak activity at MC2R.

The published research on MT-2 includes characterization of receptor pharmacology (binding affinity and functional agonism at each of the cloned melanocortin receptor subtypes), preclinical pharmacology in rodent models of melanocortin signaling (effects on melanogenesis in melanocyte cultures and on skin pigmentation in animals, effects on food intake and body weight in MC4R-relevant rodent models, effects on cardiovascular and inflammatory endpoints in MC3R/MC4R-relevant models, and effects on erectile function in melanocortin-erectile research), and characterization of the conformational properties of the cyclized peptide by NMR and computational structural methods.

It is important to distinguish MT-2 from the approved medicine afamelanotide (Melanotan-1, Scenesse): the two are structurally distinct (cyclic non-selective vs. linear MC1R-selective), are pharmacologically distinct (non-selective vs. MC1R-selective), and have entirely different regulatory status (MT-2 is not approved for any indication; afamelanotide is an approved medicine for a specific narrow indication in some jurisdictions). MT-2 is also distinguished from an MC4R-preferring melanocortin analog (an MC4R-preferring linear melanocortin-agonist peptide that has been approved as Vyleesi for a specific indication); the two molecules are again structurally and pharmacologically distinct.

Pro-opiomelanocortin (POMC) and its peptide products including α-, β-, and γ-melanocyte-stimulating hormones and adrenocorticotropic hormone (ACTH) were characterized biochemically through the 1950s and 1960s with foundational structural work by Li and others establishing the amino acid sequences. The melanocortin receptor subtypes were cloned and characterized in the late 1980s and early 1990s, with the five-receptor family (MC1R through MC5R) and the distinct endogenous antagonists agouti and agouti-related peptide (AgRP) establishing the molecular framework for melanocortin pharmacology.

The Melanotan project at the University of Arizona under Mac E. Hadley (cell biology / melanocyte biology) and Victor J. Hruby (peptide chemistry / structure-activity relationships) was initiated in the 1980s with the goal of developing α-MSH analogs that retained or enhanced the melanogenic and other melanocortin-receptor-mediated activities of α-MSH but with substantially improved metabolic stability and duration of action. The structure-activity work proceeded through systematic modification of the α-MSH sequence with substitutions at key positions and through cyclization strategies to constrain the active conformation. Two principal compounds emerged from this program: Melanotan-1 ([Nle⁴,D-Phe⁷]-α-MSH; a linear analog with the two key potency-enhancing substitutions) and Melanotan-2 (the cyclic non-selective compound described on this page).

Melanotan-1 was subsequently developed clinically for erythropoietic protoporphyria (a rare photodermatosis in which patients are extremely sensitive to sunlight) by Clinuvel Pharmaceuticals as afamelanotide, which received marketing approval in the EU in 2014 and in the US in 2019 under the trade name Scenesse. Afamelanotide functions as an MC1R agonist promoting melanogenesis in the skin and providing a photoprotective effect in patients with the rare disease. The clinical development of MT-2 (the cyclic non-selective compound) did not advance to approval for any indication; its principal application has been in academic and preclinical pharmacology research.

The MT-2 compound has been the subject of considerable non-research and non-medical use outside of regulatory frameworks, particularly in contexts related to skin tanning. This non-research use is outside the scope of this educational reference and is not endorsed by Dr Jays Peptides. Several regulatory authorities have issued warnings or advisories regarding non-research use of MT-2 specifically because of safety concerns observed in non-controlled use contexts; the research-supply context of this page is academic and laboratory melanocortin-pharmacology research, not non-research use.

In the broader melanocortin-pharmacology research landscape, MT-2 remains a useful pharmacological tool for in-vitro receptor binding and functional assays, for in-vivo rodent studies of non-selective melanocortin signaling, and as a structural starting point for the design of receptor-subtype-selective melanocortin agonists. The non-selective profile of MT-2 has historically been a limitation for therapeutic translation (clinical development of melanocortin agonists has generally favored receptor-subtype-selective approaches) but is useful in research contexts where broad melanocortin engagement is the experimental objective.

The melanocortin system consists of five G-protein-coupled receptors (MC1R through MC5R) and a set of endogenous peptide ligands derived by post-translational processing of pro-opiomelanocortin (POMC). The principal endogenous agonists are α-melanocyte-stimulating hormone (α-MSH, a 13-amino-acid peptide), β-MSH, γ-MSH, and adrenocorticotropic hormone (ACTH, a 39-amino-acid peptide with N-terminal sequence identical to the active core of α-MSH). The two endogenous antagonists are agouti (peripheral, principally targeting MC1R) and agouti-related peptide (AgRP, CNS, principally targeting MC3R and MC4R). The receptor subtypes signal through Gαs and cyclic AMP elevation, with downstream effects depending on the cellular and physiological context.

MC1R is principally expressed in melanocytes, where its activation by α-MSH (or by exogenous agonists like MT-2) elevates intracellular cAMP, activates the microphthalmia-associated transcription factor (MITF), and drives expression of melanogenic enzymes (tyrosinase, TYRP1, DCT). The downstream biochemistry includes the switch from pheomelanin synthesis (red/yellow pigmentation pathway) to eumelanin synthesis (brown/black pigmentation pathway) — the basis for the skin-pigmentation effect of melanocortin agonists. Loss-of-function MC1R variants in humans are associated with red-hair / fair-skin phenotype and increased melanoma risk. MC1R is also expressed in immune cells and contributes to anti-inflammatory melanocortin signaling.

MC2R is the ACTH-selective receptor in the adrenal cortex; it mediates ACTH-driven cortisol release in the hypothalamic-pituitary-adrenal axis. MC2R signaling is the basis for the use of ACTH and synthetic ACTH analogs (cosyntropin) in clinical endocrinology. MT-2 has relatively weak activity at MC2R compared with the other receptor subtypes.

MC3R is expressed in CNS sites (hypothalamic arcuate, ventromedial, and other nuclei) and in peripheral tissues including macrophages. CNS MC3R contributes to regulation of energy homeostasis and feeding behavior (although the relative roles of MC3R and MC4R in this regulation are an active area of research). Peripheral MC3R on macrophages contributes to anti-inflammatory melanocortin signaling.

MC4R is expressed principally in hypothalamic and other CNS sites and is the principal receptor mediating melanocortin effects on food intake and energy expenditure. Loss-of-function MC4R variants are the most common monogenic cause of human obesity, with both heterozygous and homozygous mutation carriers showing characteristic phenotypes. MC4R is also expressed in CNS sites mediating effects on erectile function (the basis for the development of MC4R-preferring agonists for sexual-function indications) and on autonomic and cardiovascular signaling.

MC5R is expressed in exocrine glands (sebaceous, lacrimal, and others) and in other peripheral tissues with less well-characterized function. MC5R signaling has been studied in lipid-metabolism and inflammation contexts.

MT-2 binds and activates MC1R, MC3R, MC4R, and MC5R with broadly similar potency in published receptor pharmacology and shows weak activity at MC2R. The non-selective receptor profile distinguishes MT-2 from the receptor-subtype-selective melanocortin agonists that have been developed for specific therapeutic applications: afamelanotide (Melanotan-1) is MC1R-selective and developed for skin photoprotection in erythropoietic protoporphyria; an MC4R-preferring melanocortin analog is MC4R-preferring and developed for sexual-function indication; setmelanotide is MC4R-selective and developed for syndromic obesity associated with specific upstream POMC-pathway variants. MT-2's non-selective profile makes it useful in research contexts where broad melanocortin engagement is the experimental objective, but limits its translational utility for any specific receptor-subtype-targeted application.

The cyclic structure of MT-2 — the lactam bridge between Asp⁵ and Lys¹⁰ — constrains the conformation of the receptor-binding pharmacophore (the central His-D-Phe-Arg-Trp motif that is the conserved active core of melanocortin agonists) and provides substantial resistance to proteolytic degradation. NMR and computational structural studies have characterized the conformational properties of cyclic Melanotan analogs and have informed subsequent generations of melanocortin-agonist medicinal chemistry.

MT-2 (Melanotan 2) is a cyclic heptapeptide with sequence Ac-Nle-cyclo(Asp-His-D-Phe-Arg-Trp-Lys)-NH2 and amide-capped C-terminus. The cyclization is via a lactam bridge between the Asp⁵ side chain carboxyl group and the Lys¹⁰ side chain amine. The N-terminus is acetylated. The molecular weight is approximately 1024 g/mol.

The structural modifications relative to the parent α-MSH sequence include: N-terminal acetylation and replacement of Ser-Tyr-Ser-Met (positions 1-4 of α-MSH) with the single norleucine (Nle) residue (positions 1-3 truncated and Met⁴ replaced with Nle for resistance to oxidative degradation of the methionine sulfur); the conserved active-core His-D-Phe-Arg-Trp motif with the key D-phenylalanine substitution at position 7 (replacing the natural L-Phe; this single chirality inversion is the most important potency-enhancing modification in melanocortin-agonist medicinal chemistry); and the lactam cyclization between Asp⁵ and Lys¹⁰ that constrains the conformation and provides proteolytic resistance.

The cyclization rigidifies the bioactive conformation of the central pharmacophore, increasing receptor-binding affinity and reducing the entropic cost of receptor engagement compared with the linear parent peptide. The amide-capped C-terminus removes the free C-terminal carboxylate and provides additional resistance to C-terminal exopeptidase degradation.

Research-grade MT-2 is produced by solid-phase peptide synthesis (SPPS) followed by side-chain deprotection and on-resin or solution-phase lactam cyclization. The product is purified by reversed-phase HPLC to ≥98% purity and verified by analytical HPLC and mass spectrometry. The peptide is supplied as a sterile lyophilized powder in sealed vials for reconstitution. Lyophilized storage is at -20 °C or below in moisture-protected containers; reconstituted solutions in aqueous diluent are stored refrigerated and used within a short window per standard peptide-stability practice.

In published melanocortin-pharmacology research, MT-2 has been used in several principal applications:

In-vitro melanocortin receptor pharmacology. Recombinant MC1R, MC3R, MC4R, and MC5R expressed in heterologous cell systems (HEK293, COS-7, CHO) are used for radioligand binding assays (with [125I]NDP-α-MSH or related tracers), for cAMP accumulation functional assays, and for β-arrestin recruitment assays. MT-2 is a standard reference agonist in this work due to its broad non-selective potency profile across the receptor subtypes.

Cultured melanocyte and melanocyte-cell-line research. B16 mouse melanoma cells, primary human melanocytes, and other melanocyte cell models are treated with MT-2 to investigate melanogenic responses (tyrosinase induction, melanin accumulation, MITF activation, expression of melanogenic-pathway genes).

Preclinical rodent pharmacology. MT-2 is administered to rodents in studies of melanocortin signaling in various physiological contexts, including melanocortin effects on food intake and body weight (MC3R/MC4R-mediated), on cardiovascular and autonomic parameters (MC3R/MC4R-mediated), on inflammation (MC1R/MC3R-mediated), and on erectile function (MC4R-mediated). The non-selective receptor profile is informative in studies seeking to engage multiple receptor subtypes simultaneously.

Structure-activity research and conformational characterization. MT-2 has been used as a structural template for the design of additional melanocortin-agonist analogs with modifications targeting improved receptor-subtype selectivity, altered pharmacokinetic properties, or specific signaling-bias profiles. NMR and X-ray crystallographic structural studies of MT-2 and related cyclic Melanotan analogs have characterized the bioactive conformation of the pharmacophore.

Comparative pharmacology. MT-2 is used as a comparison reference in research characterizing newer melanocortin-agonist compounds, including the linear MC1R-selective afamelanotide, the MC4R-preferring an MC4R-preferring melanocortin analog, and the MC4R-selective setmelanotide. The comparative receptor pharmacology is informative for understanding the structure-activity basis of receptor-subtype selectivity.

All applications are research-supply context: laboratory and analytical use in cells, isolated receptors, and preclinical animal models. The peptide is not for human consumption and is not for any non-research use. Several regulatory authorities have issued warnings regarding non-research use of MT-2; the research context of this page does not extend to or endorse such non-research use.

MT-2 sits within the melanocortin-agonist landscape alongside the endogenous melanocortin peptides and the subsequent generation of receptor-subtype-selective synthetic melanocortin agonists.

MT-2 (Melanotan 2) is a cyclic non-selective melanocortin-receptor-agonist peptide developed at the University of Arizona by the Hadley and Hruby laboratories in the 1980s as a structural analog of α-melanocyte-stimulating hormone (α-MSH). The structure is Ac-Nle-cyclo(Asp-His-D-Phe-Arg-Trp-Lys)-NH2 with a lactam bridge between Asp⁵ and Lys¹⁰. The peptide is a potent agonist at MC1R, MC3R, MC4R, and MC5R with weak activity at MC2R. The structural modifications — N-terminal acetylation, norleucine replacement of methionine, D-phenylalanine substitution at position 7, and the lactam cyclization — confer high potency, broad receptor engagement, and substantial resistance to proteolytic degradation.

MT-2 has been used in published melanocortin-pharmacology research for in-vitro receptor binding and functional assays, for cultured melanocyte studies of melanogenic responses, and for preclinical rodent studies of melanocortin signaling in energy homeostasis, inflammation, and erectile function. The molecule is structurally and pharmacologically distinct from the linear MC1R-selective afamelanotide (Melanotan-1, Scenesse), which is an approved medicine for erythropoietic protoporphyria; MT-2 is not afamelanotide.

This page is research educational only. MT-2 is not approved as a medicine in any jurisdiction. Research-supply MT-2 is intended for laboratory and academic melanocortin-pharmacology research; it is not for human consumption and is not for any non-research use. Regulatory advisories regarding non-research use of Melanotan compounds have been issued by multiple authorities; the research-supply context of this page does not extend to or endorse such non-research use.