Melanotan-2

Overview

Melanotan II is up to 1000 times more potent than endogenous α-MSH, binding to the body’s melanocortin receptors in varying degrees, exerting varied effects. MT-II binds primarily to the MC1 and MC4 receptors, and to a lesser extent to MC3. Here is a rundown of the receptors in play:

• 1. MC1triggers the darkening of the skin and hair.
  2. MC3 is involved in the regulation of appetite and energy.
  3. MC4 affects sexual behavior and male erectile function.

Increased rate of skin tanning: 

Melanotan II is known to stimulate the production of melanin, the substance in the skin that determines the rate of tanning and helps prevent sunburn. A 2015 review of melanotan use and associated clinical outcomes identified eighteen clinical trials and twenty-one clinical case presentations demonstrating melanotan II’s action as a synthetic tanning agent.

Although the precise intracellular signaling cascades remain incompletely understood, current data suggest that receptor interactions might lead to the elevated synthesis of eumelanin. This might offer a potential pathway for the development of sunless tanning models in a controlled research environment.  These pathways are further enhanced with the exposure to UV radiation.

Treatment of erectile dysfunction (ED): 

In a seminal study on the effects of MT-II on sexual function by Wessells H et al., the peptide was administered to 20 men with erectile dysfunction. The study measured penile rigidity and levels of sexual desire, while side effects were self-reported. According to the authors, 17 out of 20 men experienced the desired outcome of penile erection [6].

A 2006 study by Giuliano et al. found that injections of melanotan 2 (0.1, 0.3, and 1 mg/kg) elicited erectile events in anesthetized rats. Researchers noted that MT-2 also shortened the latency of the first erectile event to occur, concluding that the peptide recruited the central and peripheral melanocortin pathways to achieve this effect [7].

However, as noted by Mahiques-Santos, while melanotan II has been investigated as a potential ED treatment, it has been largely superseded by a nasally administered molecule (PT-141, link), an active metabolite of the molecule [1]. There is nonetheless strong research interest in MT-2 as a potential treatment of erectile dysfunction.

Melanotan 2 and Hunger

There is good evidence to suggest that MT-2 can reduce fat storage and hunger behavior in animal models. Researchers have found that the melanocortin-4 receptor (MC-4R) plays a role in food preferences and intake and that MT-2 is a potent agonist of MC-4R.

Administration of MT-2 to mice causes significant reductions in how much food they consume, but also changes their preference for fatty foods. Mice given MT-2 ignore fatty foods, which they would otherwise prefer. Similarly, mice devoid of the MC-4R receptor consume fatty foods almost exclusively and are immune to the effects of MT-2.

The effects of MT-2 are similar to those of the hormone leptin, sometimes called the satiety hormone because it reduces cravings and food intake. Leptin, however, has never been useful in the treatment of obesity, even in individuals who are leptin deficient. This is likely because there are two pathways for satiety, called leptin-dependent and leptin-independent pathways. Research suggests MT-2 is more effective in stimulating both pathways and thus may be a more effective exogenous treatment for reducing hunger.

Melanotan 2 and Autism

The newest research finding for MT-2 indicates that the peptide can reverse certain autistic features in a commonly used mouse model of autism spectrum disorder (ASD).

There is no treatment for the condition, but recent search has indicated that oxytocin therapy mav be useful in mitigating some of the behavioral problems associated with ASD. Using a mouse model of maternal immune activation known to lead to autism, researchers investigated whether MT2, which is known to stimulate oxytocin release, could counteract ASD or reduce common ASD behaviors. Their research revealed that administration of MT-2 reverses the decreased communication, impaired social interaction, and repetitive behaviors associated with autism in this particular model. In fact, the researchers found that MT-2 administration increased the expression of oxytocin receptors in specific parts of the brain, suggesting a direct correlation between oxytocin signaling in those areas and ASD-specific behaviors.

References

1. Mahiques-Santos L. Melanotan [Melanotan]. Actas Dermosifiliogr. 2012 May;103(4):257-9. Spanish. doi: 10.1016/j.ad.2011.08.002. Epub 2011 Nov 1. PMID: 22051769.
2. Hadley ME, Dorr RT. Melanocortin peptide therapeutics: historical milestones, clinical studies and commercialization. Peptides. 2006 Apr;27(4):921-30. doi: 10.1016/j.peptides.2005.01.029. Epub 2006 Jan 18. PMID: 16412534.
3. Dorr RT, Ertl G, Levine N, Brooks C, Bangert JL, Powell MB, Humphrey S, Alberts DS. Effects of a superpotent melanotropic peptide in combination with solar UV radiation on tanning of the skin in human volunteers. Arch Dermatol. 2004 Jul;140(7):827-35. doi: 10.1001/archderm.140.7.827. PMID: 15262693.
4. Brennan, R., Wells, J. G., & Van Hout, M. C. (2014). An unhealthy glow? A review of melanotan use and associated clinical outcomes. Performance Enhancement & Health, 3(2), 78–92.
5. Dorr RT, Lines R, Levine N, Brooks C, Xiang L, Hruby VJ, Hadley ME. Evaluation of melanotan-II, a superpotent cyclic melanotropic peptide in a pilot phase-I clinical study. Life Sci. 1996;58(20):1777-84. doi: 10.1016/0024-3205(96)00160-9. PMID: 8637402.
6. 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 Oct;12 Suppl 4:S74-9. doi: 10.1038/sj.ijir.3900582. PMID: 11035391.
7. Giuliano F, Clément P, Droupy S, Alexandre L, Bernabé J. Melanotan-II: Investigation of the inducer and facilitator effects on penile erection in anaesthetized rat. Neuroscience. 2006;138(1):293-301. doi: 10.1016/j.neuroscience.2005.11.008. Epub 2005 Dec 19. PMID: 16360286.
8. Minakova E, Lang J, Medel-Matus JS, Gould GG, Reynolds A, Shin D, Mazarati A, Sankar R. Melanotan-II reverses autistic features in a maternal immune activation mouse model of autism. PLoS One. 2019 Jan 10;14(1):e0210389. doi: 10.1371/journal.pone.0210389. PMID: 30629642; PMCID: PMC6328175.
9. Cousen P, Colver G, Helbling I. Eruptive melanocytic naevi following melanotan injection. Br J Dermatol. 2009 Sep;161(3):707-8. doi: 10.1111/j.1365-2133.2009.09362.x. Epub 2009 Jul 2. PMID: 19575725.
10. Langan EA, Nie Z, Rhodes LE. Melanotropic peptides: more than just ‘Barbie drugs’ and ‘sun-tan jabs’? Br J Dermatol. 2010 Sep;163(3):451-5. doi: 10.1111/j.1365-2133.2010.09891.x. Epub 2010 Jun 9. PMID: 20545686.
11. Evans-Brown M, Dawson RT, Chandler M, McVeigh J. Use of melanotan I and II in the general population. BMJ. 2009 Feb 17;338:b566. doi: 10.1136/bmj.b566. PMID: 19224885.
12. Langan EA, Ramlogan D, Jamieson LA, Rhodes LE. Change in moles linked to use of unlicensed “sun tan jab”. BMJ. 2009 Jan 27;338:b277. doi: 10.1136/bmj.b277. PMID: 19174439.
13. Dreyer BA, Amer T, Fraser M. Melanotan-induced priapism: a hard-earned tan. BMJ Case Rep. 2019 Feb 21;12(2):e227644. doi: 10.1136/bcr-2018-227644. PMID: 30796078; PMCID: PMC6388891.
14. Ryakhovsky, Vladimir V et al. “The first preparative solution phase synthesis of Melanotan II.” Beilstein Journal of Organic Chemistry vol. 4 (2008): 39. doi:10.3762/bjoc.4.39. https://pubmed.ncbi.nlm.nih.gov/19043625/
15. Mac E. Hadley, Discovery that a melanocortin regulates sexual functions in male and female humans, Peptides, Volume 26, Issue 10, 2005, Pages 1687-1689, ISSN 0196-9781, https://doi.org/10.1016/j.peptides.2005.01.023
16. King, Stephen H et al. “Melanocortin receptors, melanotropic peptides and penile erection.” Current topics in medicinal chemistry vol. 7,11 (2007): 1098-1106. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2694735/
17. Peters, Björn, et al. “Melanotan II: a possible cause of renal infarction: review of the literature and case report.” CEN case reports vol. 9,2 (2020): 159-161. doi:10.1007/s13730-020-00447-z. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7148395/
18. Ter Laak, Mariël P, et al. “The potent melanocortin receptor agonist melanotan-II promotes peripheral nerve regeneration and has neuroprotective properties in the rat.” European Journal of Pharmacology vol. 462,1-3 (2003): 179-83. doi:10.1016/s0014-2999(02)02945-x. https://pubmed.ncbi.nlm.nih.gov/12591111/
19. Wessells, H et al. “Melanocortin receptor agonists, penile erection, and sexual motivation: human studies with Melanotan II.” International journal of impotence research vol. 12 Suppl 4 (2000): S74-9. doi:10.1038/sj.ijir.3900582. https://pubmed.ncbi.nlm.nih.gov/11035391/
20. Minakova E, Lang J, Medel-Matus JS, Gould GG, Reynolds A, Shin D, Mazarati A, Sankar R. Melanotan-II reverses autistic features in a maternal immune activation mouse model of autism. PLoS One. 2019 Jan 10;14(1):e0210389. Doi: 10.1371/journal.pone.0210389. PMID: 30629642; PMCID: PMC6328175.
21. Dorr RT, Lines R, Levine N, Brooks C, Xiang L, Hruby VJ, Hadley ME. Evaluation of melanotan-II, a superpotent cyclic melanotropic peptide in a pilot phase-I clinical study. Life Sci. 1996;58(20):1777-84. doi: 10.1016/0024-3205(96)00160-9. PMID: 8637402.
22. Minakova, E., et al. (2019). Melanotan-II reverses autistic features in a maternal immune activation mouse model of autism. PLoS ONE, 14(1), e0210389. DOI: 10.1371/journal.pone.0210389. Available: https://www.ncbi.nlm.nih.gov/pubmed/30629642
23. van der Klaauw, A., et al. (2015). Role of melanocortin signaling in the preference for dietary macronutrients in human beings. Lancet, 385(Suppl 1), S12. DOI: 10.1016/S0140-6736(15)60327-0. Available: https://www.ncbi.nlm.nih.gov/pubmed/26312834
24. Shimizu, H., Inoue, K., & Mori, M. (2007). The leptin-dependent and -independent melanocortin signaling system: regulation of feeding and energy expenditure. Journal of Endocrinology, 193(1), 1–9. DOI: 10.1677/JOE-06-0144. Available: https://www.researchgate.net/publication/24019710_The_Role_of_Leptin-Melanocortin_System_and_Human_Weight_Regulation_Lessons_from_Experiments_of_Nature
25. Bjørbaek, C., & Hollenberg, A. N. (2002). Leptin and melanocortin signaling in the hypothalamus. Vitamins and Hormones, 65, 281–311. DOI: 10.1016/S0083-6729(02)65008-X. Available: https://www.ncbi.nlm.nih.gov/pubmed/12481551
26. Guo, F., Bakal, K., Minokoshi, Y., & Hollenberg, A. N. (2004). Leptin signaling targets the thyrotropin-releasing hormone gene promoter in vivo. Endocrinology, 145(5), 2221–2227. DOI: 10.1210/en.2003-1316. Available: https://www.ncbi.nlm.nih.gov/pubmed/14764630
27. Lee, Y. H., Wang, M.-Y., Yu, X.-X., & Unger, R. H. (2016). Glucagon is the key factor in the development of diabetes. Diabetologia, 59(7), 1372–1375. DOI: 10.1007/s00125-016-3935-3. Available: https://www.ncbi.nlm.nih.gov/pubmed/27115412
28. Toda, C., et al. (2009). Distinct effects of leptin and a melanocortin receptor agonist injected into medial hypothalamic nuclei on glucose uptake in peripheral tissues. Diabetes, 58(12), 2757–2765. DOI: 10.2337/db09-0743. Available: https://www.ncbi.nlm.nih.gov/pubmed/19752162
29. York, D. A., Boghossian, S., & Park-York, M. (2011). Melanocortin activity in the amygdala influences alcohol intake. Pharmacology Biochemistry and Behavior, 98(1), 112–119. DOI: 10.1016/j.pbb.2010.12.010. Available: https://www.ncbi.nlm.nih.gov/pubmed/21167196
30. Navarro, M., Carvajal, F., Lerma-Cabrera, J. M., Cubero, I., Picker, M. J., & Thiele, T. E. (2015). Evidence that melanocortin receptor agonist Melanotan-II synergistically augments the ability of naltrexone to blunt binge-like ethanol intake in male C57BL/6J mice. Alcoholism: Clinical and Experimental Research, 39(8), 1425–1433. DOI: 10.1111/acer.12764. Available: https://www.ncbi.nlm.nih.gov/pubmed/26108334
31. Wessells, H., et al. (1998). Synthetic melanotropic peptide initiates erections in men with psychogenic erectile dysfunction: double-blind, placebo controlled crossover study. Journal of Urology, 160(2), 389–393. DOI: 10.1016/S0022-5347(01)62903-3. Available: https://www.ncbi.nlm.nih.gov/pubmed/9679884
32. Wessells, H., Hruby, V. J., Hackett, J., Han, G., Balse-Srinivasan, P., & Vanderah, T. W. (2003). MT-II induces penile erection via brain and spinal mechanisms. Annals of the New York Academy of Sciences, 994, 90–95. DOI: 10.1111/j.1749-6632.2003.tb03166.x
33. Wessells, H., et al. (1998). Synthetic melanotropic peptide initiates erections in men with psychogenic erectile dysfunction: double-blind, placebo controlled crossover study. International Journal of Impotence Research, 10(2), 57–61. Available: https://www.nature.com/articles/3900371.pdf
34. Islam, M. T., et al. (2022). Vasopressin neurons in the paraventricular hypothalamus promote wakefulness via lateral hypothalamic orexin neurons. Current Biology, 32(16), 3471–3483. DOI: 10.1016/j.cub.2022.07.020. Available: https://www.ncbi.nlm.nih.gov/pubmed/35907397
35. Lau, J. K. Y., et al. (2021). Melanocortin receptor activation alleviates amyloid pathology and glial reactivity in an Alzheimer’s disease transgenic mouse model. Scientific Reports, 11(1), 4359. DOI: 10.1038/s41598-021-83932-4. Available: https://www.ncbi.nlm.nih.gov/pubmed/33623128