Research Dossier on Melanotan-2

(Melanocortin Peptide)

Classification & Molecular Identity

Amino-acid sequence, molecular weight, structural motifs

Melanotan-2 (MT-II) is a cyclic heptapeptide melanocortin agonist:
Ac-Nle-c[Asp-His-D-Phe-Arg-Trp-Lys]-NH₂. It is conformationally constrained by a lactam bridge between the Aspside-chain and the Lys ε-amine, generating a 23-membered ring; Nle (norleucine) replaces Met at the N-terminus and D-Phe (position 7 of α-MSH numbering) enhances potency/stability. The cyclic lactam design was introduced to preserve the His-Phe-Arg-Trp core pharmacophore of α-MSH/NDP-MSH while improving potency and duration relative to linear peptides. American Chemical Society Publications+2American Chemical Society Publications+2

Physicochemical entries (e.g., PubChem) list formula C₅₀H₆₉N₁₅O₉; MT-II is typically water-soluble in research-grade buffers. PubChem+1

Discovery history (lab, year, species)

Cyclic α-MSH analogues with lactam bridges were designed in the late 1980s to create potent, longer-acting melanocortin ligands (notably MT-I and MT-II). The “MT-II” scaffold emerged from structure–activity optimization around the His-Phe-Arg-Trp core and was reported as “superpotent” in frog skin bioassays and mammalian models. American Chemical Society Publications+1

Endogenous vs synthetic origin

Endogenous melanocortins (e.g., α-MSH) are POMC-derived neuropeptides. Melanotan-2 is a fully synthetic α-MSH analogue (not a natural human sequence) built to agonize melanocortin receptors (MCRs) with increased potency/stability. Frontiers

Homologs, analogs, derivatives

• Melanotan-1 (MT-I; afamelanotide), a different α-MSH analogue (linear/less constrained) with human pharmacokinetic data in pigmentation studies. PubMed

• Bremelanotide (PT-141), a carboxylated metabolite/derivative of MT-II developed as a centrally acting MCR agonist for hypoactive sexual desire disorder (HSDD); FDA-approved (distinct labeling/indications). PMC+2PMC+2

• Tool agonists/antagonists in the melanocortin field (e.g., SHU-9119, an antagonist/partial agonist; tetrapeptide Ac-His-D-Phe-Arg-Trp-NH₂) are common SAR comparators. ScienceDirect+1

Historical Development & Research Trajectory

Key milestones

• Design & synthesis (late 1980s–1990s): Lactam-bridged α-MSH analogues including MT-II demonstrated potent melanocortin receptor agonism and pigmentation activity in preclinical systems. American Chemical Society Publications

• First human-oriented findings (1990s): Pilot observations revealed erectogenic and libido-related effects following MT-II exposure, prompting early Phase-1/2 investigations in men with psychogenic erectile dysfunction (ED). PubMed

• Central mechanism studies (1998–2003): Human double-blind crossover work and animal neuropharmacology mapped pro-erectile actions to central MCRs (MC3R/MC4R), including brain and distal spinal sites; nausea/yawning consistently appeared as common adverse events. PubMed+1

• Branching to derivatives (2000s–2010s): The clinical trajectory shifted to bremelanotide (PT-141), leveraging central MCR agonism with a distinct PK/route (intranasal or SC “as needed”) for HSDD. PMC+1

• Regulatory/public-health attention (2010s–2020s): Growing off-label/illicit use of “melanotan” products (especially nasal sprays) prompted safety warnings by regulators and dermatology societies regarding adverse effects and mole changes/melanoma concerns; MT-II products sold to consumers are unapproved in multiple jurisdictions. Therapeutic Goods Administration (TGA)+1

Paradigm shifts & controversies

1. From skin to CNS: Although engineered from a pigmentation hormone, MT-II became widely studied for central effects (sexual arousal/ED models; anorectic actions), underscoring MCR pleiotropy. PMC

2. Selectivity trade-offs: MT-II is a non-selective MCR agonist (not MC1R-specific). Its ability to engage MC3R/MC4R explains centrally mediated outcomes (libido, appetite) and dose-limiting nausea/yawning. PMC

3. Safety narrative: While afamelanotide (MT-I) has clinical PK and approved uses elsewhere, MT-II lacks contemporary, indication-level approvals; dermatology/regulatory sources caution about unregulated MT-II products, especially nasal sprays. Causality linking MT-II to melanoma remains uncertain, but mole changesand case reports fuel concern; authoritative sources recommend avoidance outside regulated research. DermNet®+1

Evolution of scientific interest

Research has diversified to receptor structural biology, ligand selectivity, and biased signaling, with MT-II still used as a reference MCR agonist in metabolism, sexual function, and pigmentation models. PMC

Mechanisms of Action

Primary & secondary receptor interactions

Melanotan-2 binds and activates melanocortin receptors MC1R–MC5R with nanomolar potency (exact K_i/EC₅₀ values vary by assay/species). Functionally:

• MC1R (melanocytes/skin): ↑ cAMP via Gs, stimulating melanogenesis (↑ tyrosinase, eumelanin synthesis).

• MC3R/MC4R (CNS): Modulate sexual behavior, erectile physiology, appetite/energy balance; erectogenic signals involve central and spinal circuits.

• MC5R (exocrine/immune): broader roles; contribution to MT-II pharmacology is context-dependent. PMC+2PMC+2

Human and animal studies localize pro-erectile effects to the hypothalamus and lumbosacral spinal cord; intrathecal MT-II in rodents induced erections more efficiently than intracerebroventricular dosing, and a central MC antagonist (SHU-9119) blocked responses. PubMed

Intracellular signaling pathways

All MCRs are Class-A GPCRs primarily coupled to Gs → adenylyl cyclase → cAMP/PKA, elevating CREB-dependent transcription. In melanocytes, this up-regulates melanogenesis genes (e.g., TYR). In CNS circuits (MC3R/MC4R), cAMP-PKA signaling modulates neuronal excitability and downstream neuropeptide systems governing appetite and sexual arousal (complex network effects). Frontiers

CNS vs peripheral effects

• CNS: MC3R/MC4R in hypothalamus/brainstem/spinal cord mediate appetite suppression, erectogenic and pro-libidinal effects in preclinical/early human studies. PMC

• Peripheral: MC1R in melanocytes drives pigmentation; MC1R/MC5R in immune/exocrine cells contribute to anti-inflammatory and other peripheral signatures (model-dependent). Frontiers

Hormonal, metabolic, immune interactions

• Metabolic: Central MT-II produces anorectic/weight-loss effects in rodents; chronic central MCR activation reduces adiposity in some models (translational relevance to humans Not established). PMC

• Sexual/endocrine: Human trials in psychogenic ED reported increased rigid erections and sexual desire vs placebo, consistent with central MC3R/MC4R activation. PubMed

• Immune/dermatology: The melanocortin system exerts anti-inflammatory actions broadly; for MT-II specifically, controlled human immunologic endpoints remain limited. Frontiers

Evidence grading (A–C)

• A (replicated core biology): Non-selective MT-II agonism at MCRs; cAMP/PKA signaling; MC1R-mediated melanogenesis; central MC3R/MC4R involvement in erection and appetite (animal + early human). PMC+2PubMed+2

• B (translational): Human psychogenic ED studies (double-blind crossover; erectogenic and libido effects; frequent nausea/yawning). PubMed

• C (uncertain): Long-term efficacy/safety, standardized human PK, and dermatologic risk-benefit at scale—Not established; nasal spray formulations marketed to consumers are unapproved and raise safety concerns. DermNet®+1

Pharmacokinetics & Stability

ADME profile (what is known)

• Absorption: Controlled human PK for MT-II itself is limited/Not established in peer-reviewed pharmacokinetic monographs. (By contrast, MT-I has reported human PK with t½ ~0.8–1.7 h beta-phase after SC dosing in volunteers; this is not directly generalizable to MT-II.) PubMed

• Distribution: As a small cyclic peptide, MT-II is expected to have limited V_d unless transported or retained by tissue receptors; CNS penetration in humans is unclear (evidence mainly indirect via pharmacodynamic effects).

• Metabolism/clearance: Peptidic proteolysis and renal/hepatobiliary pathways are presumed; rat data report t½ ≈ 1.5 h (preclinical). Validated human t½ for MT-II: Not established. ScienceDirect

• Excretion: Not defined for MT-II; for MT-I ≤3.9% urinary recovery reported (context only). PubMed

Plasma half-life & degradation

• Human MT-II t½: Not established in peer-reviewed PK papers. Available translational work infers relatively short systemic residence from dosing paradigms and rapid onset of pharmacodynamic effects (nausea, flushing, spontaneous erections). PubMed

• Preclinical: Rat t½ ~1.5 h (one source). ScienceDirect

Stability (in vitro & in vivo); storage/reconstitution

MT-II’s lactam ring improves proteolytic resistance vs linear α-MSH peptides. Nonetheless, standardized, product-agnostic stability and shelf-life curves for research vials are not provided in peer-reviewed literature; routine peptide handling (cold chain, avoid repeated freeze–thaw, protect from light) is typical for research practice.

Preclinical Evidence

Animal & in vitro studies (selected)

Pigmentation & receptor pharmacology
MT-II activates MC1R to stimulate cAMP-dependent melanogenesis in melanocytes (inference from α-MSH analog literature and receptor-binding data). Receptor mapping and structural studies across MC1R–MC5R confirm MT-II as a potent but non-selective agonist. PMC

Central sexual/arousal physiology
Rodent experiments demonstrate that intracerebroventricular (i.c.v.) and intrathecal (i.th.) MT-II dose-dependently induce penile erections; spinal delivery is especially efficacious, and SHU-9119 (MC3R/MC4R antagonist) blocks responses, localizing a critical site of action to the lumbosacral spinal cord. PubMed

Appetite/weight studies
Chronic activation of central melanocortin signaling with MT-II reduces food intake and body mass in mice; given the very short t½ of α-MSH, MT-II provides a more stable tool to manipulate MC4R-dependent energy-balance circuits. Translational appetite-modulation claims in humans remain Not established. PMC

Investigational dose ranges (illustrative; preclinical)

• Rodent CNS studies: i.c.v./i.th. nmol doses evoked erectile responses (study-specific). PubMed

• Rodent metabolic studies: centrally administered MT-II suppressed food intake and reduced adiposity over days to weeks (regimen-dependent). PMC

Comparative efficacy/safety (preclinical)

• Efficacy: Robust CNS pharmacology (erection, appetite) and peripheral melanogenesis are consistently reproduced across labs.

• Safety: Rodent acute studies did not identify major toxicities at research exposures; comprehensive GLP toxicology for chronic systemic MT-II is limited in the public domain.

Limitations

Species differences in MCR distribution, CNS access, and emesis/nausea circuitry complicate extrapolation. Mechanistic attribution across five MCR subtypes is context-dependent; MT-II is not receptor-selective.

Human Clinical Evidence

Summary: Early, small, controlled human studies evaluated MT-II primarily in psychogenic ED; pigmentation was examined extensively with MT-I rather than MT-II. Contemporary, indication-defining trials for MT-II are scarce, and MT-II has no modern therapeutic approval. A derivative, bremelanotide (PT-141), progressed to regulatory approval (HSDD), highlighting central melanocortin pharmacology while not validating MT-II itself for any labeled treatment.

Psychogenic erectile dysfunction (ED)

• Double-blind, placebo-controlled, crossover (n=10): A single SC MT-II dose produced clinically apparent erections in 8/10 men; mean duration of tip rigidity ≥80% was 38.0 min with MT-II vs 3.0 min with placebo (p=0.0045). Nausea, stretching/yawning, and decreased appetite occurred more often with MT-II; none required treatment. Investigational dose used in study: 0.025 mg·kg⁻¹ SC. PubMed

• Larger human studies (cited in reviews): Erectogenic and libido-enhancing effects reproduced; severe nauseawas dose-limiting in a portion of subjects at 0.025 mg·kg⁻¹. PubMed

Sexual function: mechanistic bridging to PT-141

Central melanocortin agonism arising from MT-II research informed bremelanotide development—approved in the US for HSDD (distinct drug/product). Several randomized studies exist for bremelanotide; those findings cannot be directlyattributed to MT-II but provide context for class pharmacology (central MCR agonism impacting sexual desire/arousal). PMC+1

Pigmentation

Human pigmentation/PK work has been better characterized for MT-I (afamelanotide) than MT-II. In healthy volunteers, MT-I increased skin tanning and displayed SC β-phase t½ ≈ 0.8–1.7 h with low urinary recovery; these PK values are not evidence for MT-II but illustrate α-MSH analogue behavior in humans. Definitive human PK for MT-II is Not established. PubMed

Safety signals/adverse events observed in human MT-II studies

• Common acute AEs: Nausea, facial flushing, decreased appetite, yawning/stretching; spontaneous erectionsin men (often several hours post-dose). PubMed+1

• Dose-limiting: Severe nausea in a subset at 0.025 mg·kg⁻¹ SC in ED studies. PubMed

• Long-term outcomes: Not established; modern, long-duration safety datasets for MT-II are lacking.

• Regulatory cautions about consumer products: Multiple agencies and dermatology resources warn against unapproved MT-II (especially nasal sprays), citing AEs (nausea/vomiting, flushing, priapism, blood-pressure effects) and concerns about mole changes/melanoma—with causality unproven but risk signals sufficient for public-health warnings. DermNet®+1

ClinicalTrials.gov IDs

• MT-II itself: Historic ED studies predate current registry norms; no active/late-phase interventional trialsdedicated to MT-II for labeled therapeutic use were identified at the time of writing.

• Bremelanotide derivative: e.g., NCT02338960 (HSDD efficacy, “as-needed” dosing) — derivative context only. ClinicalTrials.gov

Pharmacokinetics & Stability — Evidence Gaps (Explicit)

• Human MT-II PK (t½, Vd, CL, bioavailability by route): Not established in peer-reviewed PK studies. (Preclinical rat t½ ≈ 1.5 h has been reported.) ScienceDirect

• Nasal formulation PK: Not established; many consumer nasal sprays are unregulated, with unknown content, excipients, and bioavailability. Regulatory communications advise avoidance. Therapeutic Goods Administration (TGA)

• Chronic exposure: Not established; available human reports largely involve single or short-course exposures.

Comparative Context

Related peptides & small molecules

• MT-I (afamelanotide): α-MSH analogue with pigmentation indications and human PK literature. PubMed

• Bremelanotide (PT-141): Centrally acting melanocortin agonist (MC3R/MC4R) for HSDD; evidence base includes Phase-3 data; distinct from MT-II. PMC

• Selective MC1R ligands/tetrapeptides: Useful for pigmentary/anti-inflammatory research while avoiding broad MC3R/MC4R engagement; contemporary tool-compound guidance emphasizes receptor selectivity for clean mechanistic readouts. American Chemical Society Publications

Advantages (research perspective)

• Potent, robust MCR agonist spanning MC1R-MC5R—a practical positive control for melanocortin pathway activation.

• Central pharmacology (sexual behavior, appetite) is well demonstrated in preclinical and small controlled human ED studies. PubMed

Disadvantages/constraints

• Non-selectivity complicates receptor-level interpretation and increases off-target (unwanted) axis activation (e.g., nausea via central pathways).

• Human PK & long-term safety unknown; consumer products unregulated; dermatologic risks (mole changes, melanoma concern) remain unresolved yet worrisome to regulators/clinicians. DermNet®+1

Research category placement

• Best regarded as a broad-spectrum melanocortin tool agonist for mechanistic experiments in pigmentation, neuroendocrine, and sexual function research, with attention to dose-limiting AEs in translational settings.

Research Highlights

• Structure–activity: The lactam-bridged MT-II design (Asp–Lys ring) preserves the His-Phe-Arg-Trp core, increasing potency and metabolic stability vs linear α-MSH. American Chemical Society Publications

• Central pro-erectile pharmacology: Double-blind crossover trial showed erections in 8/10 men, ↑ rigidity time vs placebo; nausea/yawning common. Investigational dose used in study: 0.025 mg·kg⁻¹ SC. PubMed

• Spinal mechanism: Rodent work localizes a strong erectogenic site of action to lumbosacral spinal cord; antagonist SHU-9119 blocks responses. PubMed

• Metabolic tool: MT-II is a potent anorectic in rodents, widely used to probe MC4R-dependent energy-balance circuits. PMC

• Safety discourse: Dermatology/regulatory bodies warn against unapproved MT-II (especially nasal sprays) due to AEs and oncodermatologic concerns; causal links to melanoma remain inconclusive, but risk signals justify caution. DermNet®+1

Conflicting/uncertain areas

• Human PK and dose–exposure relationships for MT-II—Not established.

• Long-term dermatologic risk from MT-II exposure—Conflicting/uncertain (regulatory concern vs paucity of causal trials). DermNet®

• Selectivity questions: MT-II activates multiple MCRs; receptor-specific outcomes require selective ligands or knockouts for clean attribution. American Chemical Society Publications

Potential Research Applications (no clinical claims; research-use framing)

1. Melanocortin receptor mapping & bias
   Use MT-II as a positive control alongside selective MC1R/MC4R ligands to dissect G-protein vs β-arrestinbias, receptor trafficking, and downstream transcriptomics in melanocytes, hypothalamic neurons, and spinal circuits. American Chemical Society Publications

2. Pigmentation pathway dissection
   Compare α-MSH, MT-I, and MT-II in human melanocyte cultures and 3D skin equivalents for cAMP dynamics, TYR expression, and eumelanin content; quantify MC1R variants (e.g., loss-of-function alleles) on response magnitude. (Context from MC1R/α-MSH literature.) MDPI

3. Spinal sexual reflexes
   Combine intrathecal MT-II with electrophysiology or functional imaging in rodent spinal preparations to map MCR-expressing interneurons; probe blockade with SHU-9119 or genetic MC4R disruption. PubMed

4. Energy-balance circuitry
   Deploy MT-II in MC3R/MC4R neuronal cultures and in vivo metabolic assays to quantify feeding and thermogenic outputs, with RNA-seq to capture hypothalamic network responses and crosstalk with NPY/AgRPpathways. PMC

5. Comparative toxicology & formulation science
   Contrast SC vs intranasal lab formulations in validated animal models, measure systemic exposure and CNS levels, and standardize nausea surrogates (rodent pica, ferret emesis model) to characterize exposure–AErelationships (research only).

Safety & Toxicology

Preclinical toxicity

Published rodent studies broadly describe tolerability at investigational exposures but are not GLP-style, chronic toxicology packages. Reports from ED and CNS literature emphasize nausea and yawning/stretching as prominent, centrally mediated effects. PubMed

Known/theoretical molecular risks

• Non-selective MCR agonism: Engagement of MC3R/MC4R contributes to nausea, blood-pressure and autonomic effects in some settings; dose-response is steep. PMC

• Dermatologic considerations: MC1R activation increases melanin; case reports/observational concerns include atypical mole changes; causality for melanoma induction is not established, yet regulatory guidance warns against consumer use. DermNet®+1

• Formulation risks: Nasal sprays marketed online are unregulated, with unknown identity/purity and excipients; regulators highlight serious AE risk and advise avoidance. Therapeutic Goods Administration (TGA)

Human safety observations

• ED trials: Transient nausea, yawning, decreased appetite, flushing; spontaneous erections; most AEs resolved without intervention at the investigational dose (0.025 mg·kg⁻¹ SC). PubMed

• Dermatology sources: Document common short-term AEs (flushing, nausea/vomiting) and caution about priapism in men; long-term dermatologic safety Not established. DermNet®

Data gaps

• Human MT-II PK, chronic safety, and DDIs (Not established).

• Reproductive toxicity, carcinogenicity, immunogenicity—formal datasets Not established in the public domain.

Limitations & Controversies

• Evidence imbalance: Robust preclinical & small early human ED studies vs. limited modern, well-controlled therapeutic programs for MT-II.

• Safety messaging vs causality: Dermatology/regulatory warnings are precautionary amid inconclusive causal links to melanoma; nonetheless, unregulated consumer products constitute a public-health risk. DermNet®+1

• Mechanistic complexity: Non-selective MCR activation complicates attribution; selective ligands or genetic tools are often preferable for pathway dissection. American Chemical Society Publications

Future Directions

1. Human PK/PD characterization
   Rigorous Phase 1 studies to define t½, CL, Vd, bioavailability by SC vs IN routes, with exposure–AE modeling (e.g., Emax or indirect-response models for nausea/yawning).

2. Receptor-selective analogs
   Systematic comparison of MT-II with selective MC1R (dermatology) and MC4R (central) ligands to reduce off-target effects; deploy biased agonists to modulate cAMP vs β-arrestin pathways. American Chemical Society Publications

3. Spinal circuit mapping
   Combine MT-II with cell-type-specific MC3R/MC4R manipulations to resolve spinal vs supraspinal control of erectile physiology and autonomic outputs. PubMed

4. Metabolic applications (mechanistic)
   Use MT-II in hypothalamic organoids and in vivo metabolic phenotyping to define energy-balance nodes and potential tachyphylaxis; avoid efficacy extrapolation without human trials. PMC

5. Safety & regulatory science
   If pursued experimentally, establish quality-controlled MT-II (identity/purity), characterize impurities/degradants, and build GLP safety packages to address chronic exposure, oncodermatologicmonitoring, and CNS AEs.

References

1. Al-Obeidi F, Hruby VJ, et al. Potent and prolonged-acting cyclic lactam analogs of α-melanotropin: design based on molecular dynamics. J Med Chem. 1989. American Chemical Society Publications

2. Zhang C, et al. Selective cyclized α-MSH derivatives (lactam bridging overview). ACS Omega. 2020. American Chemical Society Publications

3. Yuan XC, et al. Ligands for melanocortin receptors: beyond melanocyte pigmentation. Pharmacol Ther. 2022 (PMC). (Receptor pharmacology; MT-II potencies across MC1R/3R/4R). PMC

4. Wessells H, et al. Synthetic melanotropic peptide initiates erections in men with psychogenic ED: double-blind, placebo-controlled crossover. J Urol. 1998;160:389–393. Investigational dose: 0.025 mg·kg⁻¹ SC. PubMed

5. Wessells H, et al. MT-II induces penile erection via brain and spinal melanocortin receptors. Neuroscience.2003;118:755–762. (Central & spinal mechanisms; blockade by SHU-9119). PubMed

6. Olney JJ, et al. Protective effects of the melanocortin receptor system in brain. J Neuroimmune Pharmacol. 2013 (PMC). (MC3R/MC4R CNS distribution context). PMC

7. Côté I, et al. Chronic activation of central melanocortin system reduces food intake & body mass. Front Neurosci.2016 (PMC). (MT-II anorectic tool). PMC

8. Royalty JE, et al. Investigation of safety, tolerability, pharmacokinetics, and PD of melanocortin agents. J Clin Pharmacol. 2014. (Class context; MT-II/PT-141 human experience summarized). Wiley Online Library

9. Edinoff AN, et al. Bremelanotide for treatment of female HSDD. Psychopharmacol Bull. 2022 (PMC). (Derivative of MT-II; approved indication). PMC

10. ClinicalTrials.gov: NCT02338960 (Bremelanotide efficacy/safety in HSDD; derivative context). ClinicalTrials.gov

11. DermNet NZ. Melanotan-II. (Adverse effects & cautions; consumer product warnings). DermNet®

12. TGA (Australia). Don’t risk using tanning products containing “melanotan”. (Regulatory safety communication; 2025). Therapeutic Goods Administration (TGA)

13. Ugwu SO, et al. Skin pigmentation and pharmacokinetics of melanotan-I in humans. Clin Pharmacol Ther. 1997. (MT-I human PK; not directly MT-II). PubMed

14. Boeglin D, et al. Aza-scanning of melanocortin agonists; cyclic peptide preferences. Chem Biol Drug Des. 2006. (Conformational/analog insights relevant to MT-II). Wiley Online Library

15. Yang Y, et al. Molecular signatures of human melanocortin receptors for ligand binding. J Pharm Biomed Anal.2017. (Receptor determinants; SHU-9119 reference). ScienceDirect

Notes on amounts/designs:
• 0.025 mg·kg⁻¹ SC — investigational dose used in study Wessells 1998 (ED trial). PubMed
• Rat t½ ≈ 1.5 h — preclinical half-life reference. ScienceDirect
• MT-I human PK (t½ 0.8–1.7 h β-phase) — context for α-MSH analog behavior; not MT-II. PubMed

⚠️ Disclaimer This peptide is intended strictly for laboratory research use. It is not FDA-approved or authorized for human use, consumption, or therapeutic application.