Melanocortin Peptides: Afamelanotide, Melanotan II, and PT-141

Melanotan I, Melanotan II, and PT-141 are sold as a tanning-and-libido set. They are three different melanocortin ligands.

Afamelanotide (Melanotan I) is the linear analog [Nle4, D-Phe7]-alpha-MSH. Melanotan II is a cyclic lactam analog. PT-141 (bremelanotide) came out of the Melanotan II program as a melanocortin agonist studied for sexual function. They do not have the same receptor mix, the same trial record, or the same regulatory status.

This page stays with verified papers. It does not publish a tanning protocol.

Research notice: Research-grade peptides discussed here are not approved for human consumption, medical treatment, or diagnosis. FDA-approved medicines studied in the papers below are separate from research-grade material.

At a glance

Receptor family

Mountjoy, Robbins, Mortrud, and Cone cloned the murine and human MSH receptors and a human ACTH receptor. Those genes define the melanocortin G-protein-coupled receptor family that later papers split into MC1R through MC5R.

Pigmentation pharmacology in this class is classically MC1R. Sexual-function pharmacology in the PT-141 papers is framed as central MC3R/MC4R. This page does not invent a complete selectivity table for research-grade vials. Receptor claims below are what the cited papers actually say.

Afamelanotide (Melanotan I)

Sawyer, Sanfilippo, Hruby et al. (1980) described [Nle4, D-Phe7]-alpha-MSH as a highly potent alpha-melanotropin with ultralong biological activity. That analog is afamelanotide / Melanotan I.

Langendonk, Balwani, Anderson et al. (N Engl J Med, 2015) ran two multicenter, randomized, double-blind, placebo-controlled trials of subcutaneous implants containing 16 mg of afamelanotide in erythropoietic protoporphyria. Patients received an implant every 60 days (five implants in the EU study, n=74; three in the US study, n=94). The primary endpoint was hours of direct sunlight without pain.

In the US study, median pain-free time after 6 months was 69.4 hours with afamelanotide versus 40.8 hours with placebo (P=0.04). In the EU study, median pain-free time after 9 months was 6.0 hours versus 0.8 hours (P=0.005), and phototoxic reactions were 77 versus 146 (P=0.04). Quality of life improved with afamelanotide in both trials. Adverse events were mostly mild; serious adverse events were not thought to be related to the study drug.

The 16 mg implant and 60-day interval are trial methods for that product, not a protocol for research-grade powder. This site does not currently have a Melanotan I / afamelanotide peptide page.

Melanotan II

Al-Obeidi, Castrucci, Hadley, and Hruby (1989) designed cyclic lactam analogues of alpha-MSH. Dorr, Lines, Levine et al. (1996) gave the lactam-bridged heptapeptide they named Melanotan-II (Ac-Nle4-Asp5-His6-D-Phe7-Arg8-Trp9-Lys10-NH2) to three healthy men in a single-blind, alternating-day, placebo-controlled phase I study. They reported Grade II somnolence and fatigue at the highest amount tested in one of two subjects, mild nausea at most dose levels, a stretching and yawning complex that appeared to correlate with spontaneous penile erections, and increased pigmentation in the face, upper body, and buttock in two of three subjects one week after dosing ended. n=3. Those amounts are trial methods, not a tanning schedule.

Wessells, Fuciarelli, Hansen et al. (1998) ran a double-blind, placebo-controlled crossover study in 10 men with psychogenic erectile dysfunction. Clinically apparent erections developed in 8 of 10 men after Melanotan-II. Mean duration of tip rigidity greater than 80% was 38.0 minutes versus 3.0 minutes with placebo (P=0.0045). Nausea, stretching and yawning, and decreased appetite were reported more often after Melanotan-II. Wessells et al. (2000) extended human erectile-function observations in related papers.

Hadley and Dorr (2006) reviewed the clinical history: Melanotan I for tanning studies, Melanotan II for erectile-function studies, and PT-141 as a later analog then entering trials. Melanotan II is not an approved drug in the sources cited.

Melanotan II peptide page.

PT-141 (bremelanotide)

Molinoff, Shadiack, Earle, Diamond, and Quon (2003) described PT-141 as a synthetic peptide analogue of alpha-MSH and an agonist at melanocortin receptors including MC3R and MC4R. Administration to rats and nonhuman primates produced penile erections. In normal men and in patients with erectile dysfunction, they reported a rapid, dose-dependent increase in erectile activity. Rosen, Diamond, Earle et al. (2004) evaluated subcutaneous PT-141 in healthy men and in patients with an inadequate response to sildenafil; Diamond, Earle, Rosen et al. (2004) evaluated intranasal PT-141. Those papers are ED pharmacology. The amounts they tested are study methods.

Clayton, Althof, Kingsberg et al. (2016) ran a randomized, placebo-controlled dose-finding trial of subcutaneous bremelanotide in premenopausal women with female sexual dysfunctions (efficacy n=327). For the 1.25/1.75 mg pooled group versus placebo, mean changes were +0.7 versus +0.2 satisfying sexual events per month, +3.6 versus +1.9 on the Female Sexual Function Index total score, and -11.1 versus -6.8 on the Female Sexual Distress Scale-Desire/Arousal/Orgasm total score. Adverse events: nausea, flushing, headache.

Kingsberg, Clayton, Portman et al. (2019) reported two identical phase 3 RECONNECT trials in premenopausal women with hypoactive sexual desire disorder. Of 1,267 women randomized, 1,202 were in the efficacy population. Coprimary endpoints were the Female Sexual Function Index-desire domain and Female Sexual Distress Scale item 13. Desire increased versus placebo (study 301: 0.30; study 302: 0.42; integrated 0.35). Distress decreased (integrated -0.33). Nausea, flushing, and headache occurred in 10% or more on bremelanotide in both studies.

Research-grade PT-141 is not the labeled product used in RECONNECT.

PT-141 peptide page.

What is not claimed here

• A cancer-prevention claim. Langendonk measured pain-free sun time and phototoxic reactions in EPP, not melanoma incidence.
• A ranking of which analog "tans faster" or "has fewer sides" outside the papers above.
• Mole-darkening advice, stacking of two melanocortins, or a research-vial dose copied from the 16 mg implant or from RECONNECT.
• Head-to-head RCTs of afamelanotide versus Melanotan II versus PT-141. None are in the sources below.

Peptide pages, vendors, and calculator

• Melanotan II
• PT-141
• Vendors listing Melanotan II: /stores?peptides=melanotan-ii
• Vendors listing PT-141: /stores?peptides=pt-141
• Reconstitution math (no dose advice): /tools/peptide-calculator?peptide=melanotan-ii or PT-141

Category hubs: tanning peptides, sexual improvement peptides.

References

1. Sawyer TK, Sanfilippo PJ, Hruby VJ, et al. 4-Norleucine, 7-D-phenylalanine-alpha-melanocyte-stimulating hormone: a highly potent alpha-melanotropin with ultralong biological activity. Proc Natl Acad Sci U S A. 1980;77(10):5754-5758. PMID: 6777774. DOI: 10.1073/pnas.77.10.5754.
2. Al-Obeidi F, Castrucci AM, Hadley ME, Hruby VJ. Potent and prolonged acting cyclic lactam analogues of alpha-melanotropin: design based on molecular dynamics. J Med Chem. 1989;32(12):2555-2561. PMID: 2555512. DOI: 10.1021/jm00132a010.
3. Mountjoy KG, Robbins LS, Mortrud MT, Cone RD. The cloning of a family of genes that encode the melanocortin receptors. Science. 1992;257(5074):1248-1251. PMID: 1325670. DOI: 10.1126/science.1325670.
4. Dorr RT, Lines R, Levine N, et al. Evaluation of melanotan-II, a superpotent cyclic melanotropic peptide in a pilot phase-I clinical study. Life Sci. 1996;58(20):1777-1784. PMID: 8637402. DOI: 10.1016/0024-3205(96)00160-9.
5. Wessells H, Fuciarelli K, Hansen J, et al. Synthetic melanotropic peptide initiates erections in men with psychogenic erectile dysfunction: double-blind, placebo controlled crossover study. J Urol. 1998;160(2):389-393. PMID: 9679884.
6. Wessells H, Gralnek D, Dorr R, Hruby VJ, Hadley ME, Levine N. Effect of an alpha-melanocyte stimulating hormone analog on penile erection and sexual desire in men with organic erectile dysfunction. Urology. 2000;56(4):641-646. PMID: 11018622. DOI: 10.1016/s0090-4295(00)00680-4.
7. Wessells H, Levine N, Hadley ME, Dorr R, Hruby V. Melanocortin receptor agonists, penile erection, and sexual motivation: human studies with Melanotan II. Int J Impot Res. 2000;12 Suppl 4:S74-S79. PMID: 11035391. DOI: 10.1038/sj.ijir.3900582.
8. Molinoff PB, Shadiack AM, Earle D, Diamond LE, Quon CY. PT-141: a melanocortin agonist for the treatment of sexual dysfunction. Ann N Y Acad Sci. 2003;994:96-102. PMID: 12851303. DOI: 10.1111/j.1749-6632.2003.tb03167.x.
9. Rosen RC, Diamond LE, Earle DC, Shadiack AM, Molinoff PB. Evaluation of the safety, pharmacokinetics and pharmacodynamic effects of subcutaneously administered PT-141, a melanocortin receptor agonist, in healthy male subjects and in patients with an inadequate response to Viagra. Int J Impot Res. 2004;16(2):135-142. PMID: 14999221. DOI: 10.1038/sj.ijir.3901200.
10. Diamond LE, Earle DC, Rosen RC, Willett MS, Molinoff PB. Double-blind, placebo-controlled evaluation of the safety, pharmacokinetic properties and pharmacodynamic effects of intranasal PT-141, a melanocortin receptor agonist, in healthy males and patients with mild-to-moderate erectile dysfunction. Int J Impot Res. 2004;16(1):51-59. PMID: 14963471. DOI: 10.1038/sj.ijir.3901139.
11. Hadley ME, Dorr RT. Melanocortin peptide therapeutics: historical milestones, clinical studies and commercialization. Peptides. 2006;27(4):921-930. PMID: 16412534. DOI: 10.1016/j.peptides.2005.01.029.
12. Langendonk JG, Balwani M, Anderson KE, et al. Afamelanotide for Erythropoietic Protoporphyria. N Engl J Med. 2015;373(1):48-59. PMID: 26132941. DOI: 10.1056/NEJMoa1411481.
13. Clayton AH, Althof SE, Kingsberg S, et al. Bremelanotide for female sexual dysfunctions in premenopausal women: a randomized, placebo-controlled dose-finding trial. Womens Health (Lond). 2016;12(3):325-337. PMID: 27181790. DOI: 10.2217/whe-2016-0018.
14. Kingsberg SA, Clayton AH, Portman D, et al. Bremelanotide for the Treatment of Hypoactive Sexual Desire Disorder: Two Randomized Phase 3 Trials. Obstet Gynecol. 2019;134(5):899-908. PMID: 31599840. DOI: 10.1097/AOG.0000000000003500.