Melanotan II (MT-2) — Peptide Protocol Wiki reference

Mechanism of Action # Mechanistic overview.

Skin & Hair Cosmetic & Anti-Wrinkle Melanotan-1 Melanotan-1 (Afamelanotide): Approved alpha-MSH analog.

Covers melanocortin mechanism, Scenesse for EPP, photoprotective tanning, and safety data.

Melanotan-2: Tanning and Sexual Health Peptide | Peptide Protocol Wiki Skip to main content 🧬 Peptide Protocol Wiki Peptides Side Effects New Learn Directory Tools Blog News About ⌘K ⌘K 🌱 New to Peptides?

Start the 7-step beginner guide Peptides Side Effects New Directory Learn Tools Blog News About Melanotan-2 📋 Overview 🧬 Molecule 🔄 Similar ⚠️ Side Effects 💉 Dosing 🔬 Research 🚨 Risks 👥 Community 📊 Community Data Home Peptides Melanotan-2 Skin & Hair Reproductive Health preclinical Melanotan-2 Also known as: MT-2, MT2, MT-II, MT, Melanotan II Compare with 2 peptide s Research compiled by Peptide Protocol Wiki 📅 Updated February 1, 2026 Citations Verified TL;DR Melanotan-2 is a synthetic cyclic heptapeptide analog of alpha-melanocyte-stimulating hormone (alpha-MSH) that acts as a non-selective melanocortin receptor agonist.

It was developed at the University of Arizona and has been studied for melanogenesis stimulation, sexual dysfunction, and appetite modulation.

The evidence base for Melanotan‑2 is limited to small, short human trials showing erectogenic activity and increased sexual desire, and early observations of tanning.

Browse all skin peptides → Table of Contents 📌 TL;DR • Potent melanocortin receptor agonist stimulating melanogenesis • Precursor compound to PT-141 (bremelanotide) for sexual dysfunction • Investigated for appetite suppression via MC4R activation • Cyclic structure confers enhanced stability over linear analogs Community-Reported Side Effects Anecdotal ?

nce Skin tanning, sexual function enhancement, and appetite suppression 💉 Dosing Amount Loading: 0.25-0.5 mg daily; Maintenance: 0.5-1.0 mg 1-2 times per week Frequency Daily during loading (1-3 weeks); 1-2 times per week for maintenance Duration Loading: 2-4 weeks; Maintenance: ongoing as desired Step-wise Titration 💊 Administration Route SC Schedule Daily during loading (1-3 weeks); 1-2 times per week for maintenance Timing Evening dosing preferred (nausea is common, sleeping through it reduces discomfort) 📅 Cycle Duration Loading: 2-4 weeks; Maintenance: ongoing as desired Repeatable Yes Loading phase followed by maintenance Preparation & Storage Diluent: Bacteriostatic water ⚗️ Suggested Bloodwork ( 4 tests) CMP with liver enzymes When: Baseline Why: Baseline metabolic function Blood pressure When: Baseline Why: MT-2 can affect blood pressure Blood pressure When: Weekly during loading Why: Monitor cardiovascular effects Blood pressure When: Ongoing Why: Hypertension or hypotension episodes ⚠️ Hypertension or hypotension episodes 💡 Key Considerations → Start with low dose (0.25 mg) and titrate up to assess tolerance → UV exposure enhances tanning effect but is not required → Contraindication: Avoid in melanoma or high melanoma risk; contraindicated in uncontrolled hypertension; use extreme caution with cardiovascular disease Subscribe to unlock this content Get weekly peptide research summaries, new study alerts, and

Restore access No thanks, continue reading Related Reading Peptide Melanotan-1 alpha-MSH analog for photoprotection Peptide PT-141 bremelanotide melanocortin agonist Article 8 Peptides for Skin Health and Rejuvenation: Research Guide How Melanotan-2 works at the cellular level Overview of Melanotan-2 benefits and applications Scientific Details Molecular Formula C50H69N15O9 Molecular Weight 1024.18 Da CAS Number 121062-08-6 Sequence Ac-Nle-c[Asp-His-D-Phe-Arg-Trp-Lys]-NH2 What is Melanotan-2?

Melanotan-2 (MT‑II; Ac‑Nle‑Asp‑His‑D‑Phe‑Arg‑Trp‑Lys‑NH2) is a cyclic α‑MSH analogue that acts as a nonselective melanocortin receptor agonist, primarily engaging class A GPCRs MC1R–MC5R to elevate cAMP via Gs and trigger downstream kinase and transcriptional programs in a tissue‑specific manner (pigmentary, metabolic, and behavioral).

In addition, systemic MT‑II can activate mast cells to release histamine, producing H1 receptor–mediated hypothermia independent of canonical melanocortin receptors (off‑target).

Receptor binding profile and selectivity.

ocortin receptors with the following approximate Ki values: MC1R ≈ 0.67 nM, MC4R ≈ 6.6 nM, MC3R ≈ 34 nM, and MC5R ≈ 46 nM, indicating highest affinity at MC1R and MC4R with lower affinity at MC3R/MC5R; MC2R is not activated by MSH analogues.

Functionally, MT‑II reduces food intake in wild‑type mice, and this anorexigenic effect is abolished in MC4R‑deficient mice, implicating MC4R as the principal mediator of the appetite‑suppressing action.

Canonical signaling pathways.

Across MCR subtypes, the dominant coupling is Gs → adenylyl cyclase → cAMP → PKA with downstream phosphorylation of CREB and transcriptional effects; additional subtype‑specific modalities have been reported, including phosphoinositide/PLC signaling for MC3R and context‑dependent JAK/STAT linkages for MC5R.

At MC4R, agonists differ in temporal cAMP signaling and desensitization; MT‑II belongs to a subset that can induce prolonged cAMP signaling after agonist withdrawal, a ligand‑dependent kinetic property that may contribute to persistent physiological effects.

In melanocytes, MT‑II activation of MC1R elevates cAMP and PKA activity, increases the micropthalmia‑associated transcription factor (MITF), and upregulates melanogenic enzymes, notably tyrosinase, leading to increased eumelanin synthesis and tanning/photoprotection.

MT‑II is an MC1R agonist in melanocytes, though somewhat weaker than afamelanotide for MC1R‑driven cAMP, consistent with its broader receptor

CNS mechanisms: appetite and arousal (MC3R/MC4R).

In the hypothalamus, melanocortin signaling from POMC neurons decreases food intake via MC4R‑expressing neurons; MT‑II’s anorexigenic effect requires MC4R, aligning with central melanocortin control of energy balance.

Ligand‑dependent persistence of MC4R cAMP signaling may influence in vivo durability of responses.

MT‑II and related analogues also elicit prosexual behaviors in rodents and are clinically translated as bremelanotide (PT‑141), consistent with central melanocortin mechanisms involving MC4R/MC3R in arousal circuits.

Peripheral mechanisms: MC5R and exocrine/metabolic actions.

MC5R is broadly expressed in exocrine glands (sebaceous, lacrimal, preputial) and in skeletal muscle and adipose tissue.

Genetic studies show MC5R is required for normal exocrine secretion and hair/skin lipid content; agonism can modulate lipid mobilization in adipocytes and glucose uptake/thermogenesis in muscle.

MT‑II can activate MC5R but is less potent than selective MC5R agonists; thus, some peripheral metabolic or secretory effects of MT‑II may be mediated through MC5R where expressed.

Off‑target mechanism: mast cell activation and histamine H1 signaling.

Systemic (e.g., intraperitoneal) MT‑II in mice provokes transient hypometabolism/hypothermia that persists in mice lacking MC1R, MC3R, MC4R, or MC5R, demonstrating a non‑melanocortin receptor mechanism.

‑II elevates plasma histamine, and pharmacological or genetic blockade of histamine H1 receptors markedly attenuates the response, establishing a mast cell → histamine → H1R pathway.

MT‑II activates mast cells via MRGPRB2‑dependent and independent mechanisms; route of administration modulates this confounder, with subcutaneous dosing reducing histamine‑mediated hypothermia while preserving central MC4R‑dependent hypermetabolism.

Integrated mechanism of action.

MT‑II is a nonselective melanocortin agonist with highest functional relevance at MC1R (pigmentation via cAMP/PKA→MITF→tyrosinase) and MC4R (central appetite suppression and energy balance with ligand‑dependent cAMP kinetics), and contributory actions at MC3R and MC5R depending on tissue expression and signaling context.

Systemically, MT‑II can additionally activate mast cells to release histamine and trigger H1R‑mediated hypothermia, an off‑target mechanism independent of MC1R/3R/4R/5R that is important for interpreting in vivo pharmacology.

Therapeutic Applications # Key evidence summary Context Indication / Model Study design & population Intervention & dose Primary endpoints Efficacy outcomes (with numbers) Adverse events / safety notes Preclinical Erectogenic mechanism (rats, rabbits) Animal studies: intracerebral/intrathecal/IV in awake rats; anesthetized rabbit ICP recordings MT-II administered centrally/systemically (various experimental doses; potent MC4 agonist) Penile erection frequency; intracavernosa

l pressure (ICP); pharmacologic blockade (NOS inhibitor, nerve ablation) Dose-dependent increases in spontaneous erections in rats; MT-II–associated ICP rises in rabbits abolished by pudendal nerve ablation and blocked b...

Animal autonomic behaviors (yawning, grooming) noted; demonstrates central (MC4) and NO-dependent mechanism with minimal direct peripheral cavernos...

Clinical (psychogenic ED) Erectile dysfunction (psychogenic) Double-blind, placebo-controlled crossover; 10 men with psychogenic ED; RigiScan monitoring over 6 hours Subcutaneous MT-II, 0.025–0.157 mg/kg (reported range) Rigidity ( 80%), erection duration, onset time 8/10 men developed erections 80% rigidity; mean duration ~38 min vs ~3 min for placebo; onset range 15–270 min Dose-dependent nausea, stretching, yawning, decreased appetite; mild at lower dose (0.025 mg/kg) Clinical (organic ED) Erectile dysfunction (organic) Similar clinical trial in men with organic ED (trial type as above) MT-II injections (dose not specified in excerpt) % erections post-injection; rigidity score; tip rigidity duration; subjective sexual desire Erections after 63% of drug injections vs 5% placebo; mean responder rigidity score 6.9/10; tip rigidity 80% lasting ~45 min vs ~2 min for placebo...

Adverse events similar (nausea, autonomic effects); tolerability concerns documented Clinical (tanning origin) Sunless tanning / photoprotection (origin of MT-II trials) Phase I tanning trial in humans (healthy volunteers); pro-ere