Description of PT-141

Synthetically modified peptide PT-141 is connected with alpha-melanocyte-stimulating hormone (α-MSH), which was invented in 1960s. PT-141, as a derivate of Melatonan 2 peptide, binds melanocortin receptors found mostly in the skin and central nervous system (MC-1R and MC-4R receptors). Especially, receptor MC-4R plays a crucial role in modulating sexual desire, which was found in numerous animal and human studies. Nowadays this compound is also known as women Viagra for hypoactive female sexual desire disorder (HSDD) treatment. Let us discuss further information gained from several researches of the peptide PT-141.

Research Confirmed Effects

1. PT-141 and Sexual Dysfunctions

PT-141 stimulates MC-4R receptor, which is responsible for sexual stimulation and behavior. Research has shown that male mice with melanocortin-4-receptor (MC-4R) deficiency tend to develop erectile dysfunction, suggesting a link between this receptor and sexual function. However, female mice carrying a mutation in the MC-4R gene exhibit fertility issues. Another study with male rats demonstrated that Melanotan 2, a melanocortin receptor agonist, induces penile erections via central and spinal melanocortin receptors, confirming its proerectile activity.

Erectile dysfunction (ED) is commonly linked to vascular issues, but recent research suggests a central role for melanocortin receptor agonists like PT-141 in treating ED. PT-141 was evaluated in both healthy male subjects and patients with inadequate responses to Viagra. In a study involving a double-blind, placebo-controlled crossover design, PT-141 was administered subcutaneously in doses ranging from 0.3 to 10 mg to assess its effectiveness. The results showed a statistically significant erectile response at doses over 1.0 mg in healthy males and 4 mg or 6 mg in ED patients. Furthermore, these effects were consistent even in patients with inadequate responses to PDE5 inhibitors like Viagra, because PT-141 works in different mechanism than Viagra.

[1] - [3]

2. PT-141 and Female Sexual Behavior

PT-141 is derived from Melatonan 2, which in combination with progesterone, could potentially be used to treat hypoactive sexual desire in women. PT-141 has shown promise in treating sexual dysfunction in both men and women. In a randomized, double-blind, placebo-controlled study, 342 men with erectile dysfunction who did not respond to sildenafil (Viagra) were administered PT-141 intranasally or a placebo before sexual stimulation. Results showed that 33.5% of patients in the PT-141 group experienced a positive clinical response compared to 8.5% in the placebo group. The study also found that patients in the PT-141 group reported higher satisfaction during intercourse. Another trial evaluated the efficacy of PT-141 in treating female sexual dysfunction in premenopausal women. The study found that patients treated with this peptide experienced an increase in satisfying sexual events, improvements in the female sexual function index, and a reduction in sexual distress compared to the placebo group. Despite some side effects like nausea and flushing, it showed potential as an alternative treatment for sexual dysfunction.

Female Sexual Dysfunction (FSD) is a condition that is often underdiagnosed and undertreated. PT-141, or called also Bremelanotide, marketed as Rekynda, is a melanocortin receptor agonist designed for on-demand treatment of hypoactive sexual desire disorder (HSDD) in pre-menopausal women. This investigational drug has completed two successful Phase 3 trials, meeting co-primary endpoints. AMAG Pharmaceuticals acquired exclusive North American rights to develop and commercialize Rekynda, with anticipated approval and launch by early 2019. HSDD affects approximately 15 million women in the United States, with a significant portion being pre-menopausal. Despite one existing HSDD therapy for pre-menopausal women, awareness and understanding of the condition are low. Rekynda, with its fast onset of action and potential safety, could offer an alternative for women with HSDD.

[4} - [8]

3. PT-141, Bremelanotide and Hemorrhage

BPC-157 je známy aj ako peptid proti vredovej chorobe, ktorý dokáže liečiť a chrániť rôzne poškodenia telesných orgánov a zároveň zachováva prirodzenú integritu slizničnej bariéry v tráviacom trakte. Tento peptid pôsobí vo veľkom rozsahu a má dokonca oveľa priaznivejšie účinky ako štandardné cytoprotektíva. BPC 157, ako prototyp cytoprotektívnej látky, by tak mal kontrolovať funkciu ciev v závislosti od poranenia, perforovaného defektu alebo cievnej obštrukcie.

4. PT-141 in Infections

In a study examining the synthetic melanocortin peptide, researchers discovered significant anti-fungal and anti-inflammatory effects against Candida albicans vaginitis. The study involved both in vitro and in vivo experiments, demonstrating that peptide dose-dependently inhibited Candida albicans colony formation. In a rat model of Candida albicans vaginitis, administration of agonist (CKPV)2 resulted in decreased survival of the fungal pathogen in the vaginal environment and reduced infiltration of macrophages into the sub-epithelial mucosa.

Further analysis revealed that the anti-fungal and anti-inflammatory effects of (CKPV)2 were associated with activation of melanocortin receptor-1 (MC-1R). This finding indicates that MC-1R activation is critical for the observed anti-fungal and anti-inflammatory effects of this receptor agonists.

[9]

5. PT-141 and Cancer

Cutaneous phototype, traditionally associated with skin pigmentation and the ratio of eumelanin to pheomelanin, is mainly determined by polymorphisms in the melanocortin 1 receptor (MC-1R). However, recent studies suggest that MC1R signaling has broader implications, beyond just melanin production. MC-1R not only stimulates eumelanin synthesis but also activates antioxidant pathways, DNA repair, and cell survival mechanisms. Emerging research indicates that MC-1R is linked to the activation of nuclear receptors, opening new avenues for understanding photoprotection and skin phototypes. These discoveries suggest that skin phototype is a 'biochemical fingerprint' influenced by multiple factors, including but not limited to melanin content, impacting individual responses to sun exposure and related risks.

Ultraviolet (UV) light exposure is a significant risk factor for basal cell carcinoma, squamous cell carcinoma, and melanoma, particularly in people with fair skin and blue eyes who tend to sunburn rather than tan. However, the patterns of UV exposure that lead skin cancer differ, as do the intracellular molecular pathways involved. Specific variants of the MC-1R gene have been identified to play a direct role in the development of different types of skin cancers, independent of their role in influencing a pigmentary phenotype. These variants are also linked to interactions with genes that regulate immune-inflammatory responses, DNA repair, or apoptosis. The impact of UV exposure and MC-1R gene variants highlights the complex relationship between environmental and genetic factors in the etiology of skin cancers. Understanding these connections could lead to targeted prevention strategies and treatments for those at higher risk and PT-141 could play a role in this field.

[10], [11]

References

1. androck, A. Schulz, C. Merkwitz, T. Schöneberg, K. Spanel-Borowski, and A. Ricken, “Reduction in corpora lutea number in obese melanocortin-4-receptor-deficient mice,” Reprod. Biol. Endocrinol. RBE, vol. 7, p. 24, Mar. 2009.
2. R. C. Rosen, L. E. Diamond, D. C. Earle, A. M. Shadiack, and P. B. Molinoff, “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., vol. 16, no. 2, pp. 135–142, Apr. 2004. [PubMed]
3. H. Wessells, V. J. Hruby, J. Hackett, G. Han, P. Balse-Srinivasan, and T. W. Vanderah, “Ac-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-NH2 induces penile erection via brain and spinal melanocortin receptors,” Neuroscience, vol. 118, no. 3, pp. 755–762, 2003. [PubMed]
4. A.-S. Rössler, J. G. Pfaus, H. K. Kia, J. Bernabé, L. Alexandre, and F. Giuliano, “The melanocortin agonist, melanotan II, enhances proceptive sexual behaviors in the female rat,” Pharmacol. Biochem. Behav., vol. 85, no. 3, pp. 514–521, Nov. 2006. [PubMed]
5. M. R. Safarinejad and S. Y. Hosseini, “Salvage of sildenafil failures with bremelanotide: a randomized, double-blind, placebo controlled study,” J. Urol., vol. 179, no. 3, pp. 1066–1071, Mar. 2008. [PubMed]
6. A. H. Clayton et al., “Bremelanotide for female sexual dysfunctions in premenopausal women: a randomized, placebo-controlled dose-finding trial,” Womens Health Lond. Engl., vol. 12, no. 3, pp. 325–337, 2016. [PubMed]
7. M. K. Miller, J. R. Smith, J. J. Norman, and A. H. Clayton, “Expert opinion on existing and developing drugs to treat female sexual dysfunction,” Expert Opin. Emerg. Drugs, vol. 23, no. 3, pp. 223–230, 2018. [PubMed]
8. “AMAG Pharmaceuticals and Palatin Technologies Enter Into Exclusive Licensing Agreement for North American Rights to RekyndaTM (bremelanotide), a Potential Treatment for a Common Female Sexual Disorder – AMAG Pharmaceuticals.” . [MarketWatch]
9. H. Ji et al., “The Synthetic Melanocortin (CKPV)2 Exerts Anti-Fungal and Anti-Inflammatory Effects against Candida albicans Vaginitis via Inducing Macrophage M2 Polarization,” PLoS ONE, vol. 8, no. 2, Feb. 2013. [PLOS ONE]
10. V. Maresca, E. Flori, and M. Picardo, “Skin phototype: a new perspective,” Pigment Cell Melanoma Res., vol. 28, no. 4, pp. 378–389, Jul. 2015. [PubMed]
11. L. Feller, R. a. G. Khammissa, B. Kramer, M. Altini, and J. Lemmer, “Basal cell carcinoma, squamous cell carcinoma and melanoma of the head and face,” Head Face Med., vol. 12, p. 11, Feb. 2016. [PubMed]
12. 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. doi:10.2217/whe-2016-0018
13. T. R. McMillan, M. A. M. Forster, L. I. Short, A. P. Rudecki, D. L. Cline, and S. L. Gray, “Melanotan II, a melanocortin agonist, partially rescues the impaired thermogenic capacity of pituitary adenylate cyclase-activating polypeptide deficient mice,Exp. Physiol. , vol. 106, no. 2, pp. 427–437, Feb. 2021, doi: 10.1113/EP088838.”
14. C. Spana, R. Jordan, and S. Fischkoff, “Effect of bremelanotide on body weight of obese women: Data from two phase 1 randomized controlled trials,Diabetes Obes. Metab., vol. 24, no. 6, pp. 1084–1093, Jun. 2022, doi: 10.1111/dom.14672. ”