PT-141

PT 141 Research

What is the research background of PT 141?

PT 141 is a synthetic peptide analog and an agonist of melanocortin receptors, mainly including MC3R and MC4R, which are predominantly expressed in the central nervous system ^[1].The discovery of PT 141 has brought new hope for the treatment of sexual dysfunction. Early studies on it indicated that administering PT 141 to rats and non-human primates led to penile erections. After systemic administration to rats, the activation of neurons in the hypothalamus was demonstrated by an increase in c-Fos immunoreactivity. Neurons in the same region of the central nervous system would take up the pseudorabies virus injected into the corpus cavernosum of the rat penis^[1] .PT 141 has the potential to treat sexual dysfunction. Studies have shown that after administering PT 141 to normal men and patients with erectile dysfunction, there was a rapid and dose-dependent increase in erectile activity. These results suggest that PT 141 has great potential as a new treatment for sexual dysfunction ^[1].

What is the mechanism by which PT 141 acts on melanocortin receptors?

The specific mechanism by which PT 141 (Bremelanotide) acts on melanocortin receptors is rather complex, and the following is a detailed elaboration of its mechanism:

The melanocortin receptor system consists of melanocortin peptides, unique receptors, accessory proteins, and endogenous antagonists. Melanocortin peptides are small peptide hormones that have been studied under various physiological and pathological conditions. Currently, there are five known types of melanocortin receptors, which are distributed in the central nervous system and some peripheral tissues. G protein-coupled melanocortin receptors usually transmit signals through adenylate cyclase and other downstream signaling pathways. Depending on the ligand, surface expression of the melanocortin receptor, receptor occupancy time, associated proteins, cell type, and other parameters, the signaling pathways are complex and pleiotropic. Although all five melanocortin receptors are coupled to Gs, they can occasionally also be coupled to Gq or Gi ^[2].

Binding of PT 141 to melanocortin receptors: 

PT 141 is a peptide analog. As a melanocortin receptor agonist, it can bind to central melanocortin receptors. PT 141, as a synthetic peptide analog of α-melanocyte-stimulating hormone, is an agonist of melanocortin receptors including MC3R and MC4R, which are mainly expressed in the central nervous system^[1] .

Effects on female rats: 

In female rats, PT 141 selectively stimulates courtship behavior without affecting lordosis, rhythm, or other sexual behaviors. PT 141 does not cause systemic motor activation and does not affect the perception of sexual rewards. This indicates that the central melanocortin system is important in regulating female sexual desire. The selective pharmacological effect on the appetitive sexual behavior of female rats has never been reported before, which also makes PT 141 potentially the first identified drug capable of treating female sexual desire disorders ^[3].

Effects on rats and non-human primates: Administration of PT 141 to rats and non-human primates leads to penile erections. Systemic administration of PT 141 activates neurons in the hypothalamus of rats, manifested as an increase in c-Fos immunoreactivity. Neurons in the same region of the hypothalamus will take up the pseudorabies virus injected into the corpus cavernosum of the rat penis ^[3].

Effects on human males: 

Administration of PT 141 to normal men and patients with erectile dysfunction leads to a rapid and dose-dependent increase in erectile activity. The results suggest that PT 141 is expected to become a new treatment for sexual dysfunction ^[3].

Effects on human females: In premenopausal women with sexual arousal disorder, after a single-dose intranasal administration of Bremelanotide (i.e., PT 141), more women reported moderate or high levels of sexual desire. Compared with the placebo, there was a more obvious trend of positive responses regarding the feelings of genital arousal after Bremelanotide treatment. Among the women who attempted sexual intercourse within 24 hours after treatment, significantly more women were more satisfied with the level of sexual arousal after using Bremelanotide compared with the placebo. However, after the administration of Bremelanotide, there was no significant change in vaginal vasocongestion when watching pornographic videos ^[4].

In conclusion, as a melanocortin receptor agonist, PT 141, by binding to melanocortin receptors, produces various physiological effects in animal models and humans, especially playing an important role in regulating sexual function.

Dose–response effects of PT-141 on sexual behavior in bilevel chambers. (Top) Effects on solicitations in females primed with estrogen and progesterone (EP) or estrogen alone (E alone). Post hoc tests revealed that both the 100- and 200-g/kg doses increased the number of solicitations significantly compared to saline-treated controls (P values＜0.05). (Middle) Effects on pacing in females primed with EP or E alone. (Bottom) Effects on lordosis quotients in females primed with EP or E alone. Data are means SEM. *, P ＜0.05 from control.

Source:PubMed^[3]

What are the specific potential benefits of PT 141 for male low sexual desire and erectile difficulties?

Improvement of erectile function:

Numerous studies have shown that PT 141 has a certain therapeutic effect on male erectile dysfunction. For example, in some clinical trials, it was found to be able to induce penile erections^[5] (Shadiack A M, 2007). In a Phase IIb study of male diabetic patients with erectile dysfunction, the patients were randomly assigned to receive placebo or different doses of PT 141. The results showed that in the groups with higher doses of PT 141 (12.5mg and 15mg), there was a significant improvement in the Erectile Function (EF) domain of the International Index of Erectile Function (IIEF), with a clear difference compared to the placebo group^[5] .

The mechanism by which PT 141 improves erectile function may be related to its role as a melanocortinergic drug, binding to melanocortin receptors in the central nervous system, especially in the hypothalamus. This binding may regulate the neural pathways related to erection, thus promoting penile erection^[5] .

Good tolerability and safety:

According to the clinical experience of Bremelanotide, the administration of melanocortin agonists (such as Bremelanotide) is well tolerated ^[6]. It is not associated with the hypotension observed with the current phosphodiesterase-5 inhibitors used for the treatment of erectile dysfunction.

Clinical effect studies:

Evaluation in healthy male subjects and patients with erectile dysfunction: 

After subcutaneous administration in healthy male subjects and patients with erectile dysfunction (ED) who reported insufficient response to Viagra, the cyclic heptapeptide melanocortin analog PT 141 was evaluated ^[7](Rosen R C, 2004). Doses ranging from 0.3 to 10 mg were administered to healthy male subjects, and doses greater than 1.0 mg produced a statistically significant erectile response. ED patients received placebo, 4 or 6mg PT 141 in a crossover design in the presence of visual sexual stimulation (VSS). At both doses, the erectile response induced by PT 141 was statistically significant. PT 141 was safe and well tolerated in both studies. In patients who did not have an adequate response to PDE5 inhibitors, the erectile potential, tolerability, and ability of PT 141 to cause significant erections suggest that PT 141 may provide another treatment option for ED for a potentially wide range of patients.

Effect of combination with sildenafil: 

Nineteen erectile dysfunction patients who self-reported a response to Viagra or Levitra were given 25mg sildenafil and 7.5mg intranasal PT 141, 25mg sildenafil and intranasal placebo spray, and placebo tablets and intranasal placebo spray in a randomized crossover design ^[8](Diamond L E, 2005). The erectile response to two 30-minute visual sexual stimulations was evaluated by RigiScan. The results showed that the erectile response induced by the combination of PT 141 and sildenafil was significantly greater than that induced by sildenafil alone. The combination was safe and well tolerated, without causing new adverse events or an increase in the frequency or severity of adverse events. The conclusion is that the combination of intranasal PT 141 and phosphodiesterase 5 inhibitors may provide a treatment option for patients who are ineffective or have poor tolerance at higher doses of monotherapy.

The use of PT 141 is of great significance in many aspects, especially bringing new hope to numerous patients in the field of sexual health. For premenopausal women suffering from acquired and generalized hypoactive sexual desire disorder (HSDD), PT 141 is a major breakthrough. Previously, such patients often endured the psychological pressure caused by low sexual desire in their daily lives, which severely affected their emotional state and intimate relationships with their partners. The emergence of PT 141 has changed this situation. By regulating the pathways in the brain involved in the sexual response, it significantly improves the sexual desire of patients. Clinical research data show that after using Bremelanotide, there are obvious differences in the average changes of the Female Sexual Function Index - Desire domain (FSFI-D) and the 13th item score of the Female Sexual Distress Scale - Desire/Arousal/Orgasm (FSDS-DAO) from the baseline to the end of the study (EOS).

This intuitively reflects its positive effects in enhancing patients' sexual desire and alleviating related distress, greatly improving the quality of life of premenopausal women with HSDD and helping them regain confidence and the joy of life.

Moreover, PT 141 also shows potential positive effects on male sexual dysfunction. In terms of improving male low sexual desire, many patients reported a significant increase after using it, being able to regain their interest in sexual activity. And regarding erectile difficulties, some patients' erectile function has been improved to a certain extent after use, enhancing the effect of penile erection, enabling them to complete sexual behavior more smoothly in sexual life and improving their sexual experience.

This undoubtedly relieves the physical and mental burden for the male group that has been troubled by sexual dysfunction for a long time, repairs the psychological trauma caused by sexual function problems, and also helps to maintain the harmony and stability of family relationships.

From a macroscopic perspective of medical research, the use of PT 141 provides valuable practical evidence for in-depth exploration of the mechanisms related to human sexual health.

The research process of its mechanism of action has prompted researchers to conduct more in-depth explorations of the neural pathways in the brain related to the sexual response, melanocortin receptors, etc., promoting the progress of basic research in the field of sexual health, laying the foundation for the development of more treatment methods and drugs for sexual dysfunction, further enriching the medical treasury, and taking a solid step forward for medicine in overcoming the challenges of sexual health problems.

Relevant Citations

[1] Molinoff P B, Shadiack A M, Earle D, et al. PT-141: A melanocortin agonist for the treatment for the of sexual dysfunction[J]. The New York Academy of Science, 2003,994:96-102.DOI:10.1111/j.1749-6632.2003.tb03167.x.

[2] Gebrie A. The melanocortin receptor signaling system and its role in neuroprotection against neurodegeneration: Therapeutic insights[J]. Annals of the New York Academy of Sciences, 2023,1527(1):30-41.DOI:10.1111/nyas.15048.

[3] Pfaus J G, Shadiack A, Van Soest T, et al. Selective facilitation of sexual solicitation in the female rat by a melanocortin receptor agonist[J]. Proceedings of the National Academy of Sciences of the United States of America, 2004,101(27):10201-10204.DOI:10.1073/pnas.0400491101.

[4] Diamond L E, Earle D C, Heiman J R, et al. An effect on the subjective sexual response in premenopausal women with sexual arousal disorder by bremelanotide (PT-141), a melanocortin receptor agonist[J]. Journal of Sexual Medicine, 2006,3(4):628-638.DOI:10.1111/j.1743-6109.2006.00268.x.

[5] Shadiack A M, Sharma S D, Earle D C, et al. Melanocortins in the treatment of male and female sexual dysfunction[J]. Current Topics in Medicinal Chemistry, 2007,7(11):1137-1144.

[6] Steidle C P, Zinner N R, Karlin G, et al. Phase IIB study of bremelanotide in the treatment of ED in diabetic males[J]. Journal of Urology, 2007,177(4):388.DOI:10.1016/S0022-5347(18)31391-0.

[7] Rosen R C, Diamond L E, Earle D C, et al. 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®[J]. International Journal of Impotence Research, 2004,16(2):135-142.DOI:10.1038/sj.ijir.3901200.

[8] Diamond L E, Earle D C, Garcia W D, et al. Co-administration of low doses of intranasal PT-141, a melanocortin receptor agonist, and sildenafil to men with erectile dysfunction results in an enhanced erectile response[J]. Urology, 2005,65(4):755-759.DOI:10.1016/j.urology.2004.10.060.