Bremelanotide Peptide and HSDD Related-Research

Bremelanotide, also known as PT-141, is a synthetic cyclic heptapeptide derived from Melanotan II (MT-II), a synthetic analog of the melanocortin hormone α-melanocyte-stimulating hormone (α-MSH).^[1][2] It was initially investigated for its potential role in addressing hypoactive sexual desire disorder (HSDD) in female research models, as evaluated in Phase IIb clinical trials by qualified researchers. Research has also explored its potential applications in managing acute hemorrhage, suggesting broader physiological interactions beyond its primary area of study.

 

Mechanism of Action

The biological activity of Bremelanotide is hypothesized to be mediated through its selective agonism of melanocortin receptors, particularly MC3R and MC4R.^[3] MC3R is predominantly expressed in the hypothalamus and has been linked to energy homeostasis, metabolic regulation, and neuroendocrine modulation. Research suggests that MC3R activity may impact feeding behavior, glucose metabolism, and lipid balance, though the precise regulatory mechanisms remain under investigation.

Conversely, MC4R is believed to play a critical role in suppressing hunger hormone signaling and regulating energy expenditure. Preclinical data suggest that its activation within the CNS may contribute to neurogenic control of metabolic functions, potentially impacting the regulation of adipose stores. In addition, MC4R has been proposed to have a role in reproductive signaling. Receptor activation is often hypothesized to impact neuroendocrine pathways linked to reproductive physiology.

Preliminary studies suggest that Bremelanotide’s binding to MC3R and MC4R may lead to neuronal activation in the hypothalamus. This may potentially trigger downstream signaling cascades associated with autonomic and neuroendocrine responses. Laboratory studies of murine research models suggest that this interaction may contribute to behavioral responses related to copulatory arousal. However, further research is necessary to elucidate the exact mechanisms underlying these findings.

 

Scientific Research and Studies

 

Early Investigations of Bremelanotide Peptide

An early 2000s study^[4] investigated the potential neuropharmacological impacts of Bremelanotide in murine models, focusing on its possible role in modulating mating behavior. The study involved observing female murine models to study behavioral responses following peptide exposure.

Observations suggested that while research models exhibited increased solicitation related to mating behavior, there were no notable alterations in motor activity, lumbar lordosis, or other mating-related behaviors. Based on these findings, researchers hypothesized that Bremelanotide does not act as a general motor stimulant but may potentially exert selective pharmacological impacts on the central nervous system (CNS), particularly through melanocortin receptor activation. The study further suggested that central melanocortin pathways might be integral to neurochemical mechanisms underlying copulation-related arousal.

Researchers further noted the stability and selectivity of this response across varied experimental conditions, citing, “The ability of PT-141 to enhance solicitation in two distinctive testing environments indicates that the effect [appears] selective and stable, and suggests that central melanocortin systems are part of the neurochemical network that evokes appetitive sexual behavior in female rats.” These findings provided preliminary data that suggests the role of melanocortin receptors in modulating copulatory motivation may warrant further investigation into the underlying neuroendocrine mechanisms.

 

Neurophysiological Interactions of Bremelanotide in the Central Nervous System

Studies on the Bremelanotide peptide have focused on its potential interactions within the central nervous system (CNS), particularly in brain regions implicated in neuroendocrine and behavioral responses. Preclinical studies utilizing murine models with elevated levels of reproductive hormones have reportedly displayed behavioral modifications following peptide introduction. According to reports, these studies have primarily assessed appetitive behaviors, such as increased locomotion and solicitation, alongside consummatory responses, including lordosis.

Experimental findings suggest that Bremelanotide exposure may be associated with heightened hunger-related behaviors without significantly altering consummatory responses. These studies report that the peptide’s impacts were observed following both peripheral and direct introduction into the lateral ventricles or the medial preoptic area (mPOA) but not the ventromedial hypothalamus. The mPOA has been implicated in modulating the drive toward mating behaviors across various species, though its precise role remains under investigation. Bremelanotide’s interaction with this region, as well as other hypothalamic and limbic structures, suggests potential involvement in neural pathways associated with behavioral modulation. It has been hypothesized that Bremelanotide may exert its impacts through the activation of dopamine terminals within the mPOA, though further research is required to validate this hypothesis.^[5]

To further elucidate these mechanisms, a randomized, double-blinded, placebo-controlled crossover study^[6] incorporated psychometric assessments, functional neuroimaging, and hormonal analyses to examine the impact of MC4R agonism on neural processing. Results suggested that MC4R agonists, including Bremelanotide, might support an increase in copulatory motivation for up to 24 hours relative to placebo controls. Functional neuroimaging analyses suggested increased activation in the cerebellar and supplementary motor regions, alongside possible deactivation of the secondary somatosensory cortex when exposed to erotic stimuli. Additionally, MC4R agonism was associated with heightened functional connectivity between the amygdala and insular cortex under similar conditions. These findings suggest a potential role of melanocortin receptor modulation in neural circuits governing behavioral and neuroendocrine responses. Further studies are warranted to delineate the precise neurophysiological mechanisms underlying these observations.

 

Melanocortin Receptor Activation and Cavernosal Response

Bremelanotide has been hypothesized to activate melanocortin 4 receptors (MC4R) and modulate vasodilatory pathways, potentially influencing erectile function in male animal models.

Research^[7] suggests that this activation may upregulate the production of nitric oxide (NO) within penile tissues, which may ultimately contribute to increased cavernosal pressure. Bremelanotide, a synthetic derivative of Melanotan-II (MT-II), shares a similar receptor affinity profile, with both peptides exhibiting agonistic properties toward melanocortin receptors.

Experimental findings suggest that melanocortin agonists might induce dose-dependent elevations in cavernosal pressure. The non-selective MC3R and MC4R antagonist SHU 9119 did not appear to directly impact systemic or cavernosal blood pressure; however, it seemingly inhibited the cavernosal pressure increases induced by melanocortin agonists. Additionally, SHU 9119 was reported to suppress the depressor response potentially associated with melanocortin activation.

Further studies investigated the role of the NO-cyclic GMP-dependent pathway in melanocortin-mediated cavernosal responses. When a pharmacological combination of phentolamine mesylate, papaverine, and prostaglandin E1 (PGE1) was locally introduced to cavernosal tissue, cavernosal pressure reportedly increased fourfold. The involvement of neuronal NO release was examined through bilateral pudendal nerve transection and inhibition of NO synthase via L-NAME. These interventions appeared to negate the cavernosal pressure increases observed with melanocortin agonists, suggesting that central melanocortin receptor activation might influence penile tissue responses through NO-mediated neural pathways.

These findings provide preliminary insights into the potential physiological interactions between melanocortin receptor activation and neurovascular regulation, though further research is necessary to elucidate the precise mechanisms involved.

 

Bremelanotide Peptide and Hemorrhagic Shock

In 2009, a modified form of Bremelanotide was explored for its potential role in mitigating hemorrhagic shock. As an agonist of both melanocortin 1 receptor (MC1R) and melanocortin 4 receptor (MC4R), the peptide has been hypothesized to exert protective impacts against ischemic injury by supporting tissue resilience under conditions of reduced blood perfusion.

Preclinical investigations suggest that its receptor interactions may contribute to vascular stability and modulate systemic responses to hypovolemia. To further assess its viability in this context, a structurally altered analog, PL-6983, was developed and advanced to Phase IIb clinical trials.

 

Bremelanotide Peptide and Infectious Disease

Research on melanocortin receptors (MC1R) suggests that they may modulate immune responses, particularly in fungal infections. In experimental murine models, MC1R activation has been associated with antifungal and anti-inflammatory properties^[9], suggesting a possible role in host defense mechanisms. Given the limitations of conventional antifungal research tools, many of which exhibit restrictive mechanisms of action and significant adverse impacts, MC1R-targeting compounds may offer an alternative strategy for infection management. This might prove particularly relevant for immunocompromised individuals, where fungal infections pose substantial morbidity and mortality risks.

 

Bremelanotide Peptide and Oncological Research

MC1R has been implicated in DNA repair mechanisms, suggesting its potential relevance in oncological studies. Genetic variants of MC1R have been linked to increased susceptibility to basal cell carcinoma and squamous cell carcinoma, suggesting a role in cutaneous oncogenesis. Investigations into melanocortin receptor modulation propose that alterations in Bremelanotide or its derivatives may influence cellular repair pathways, potentially contributing to strategies aimed at mitigating cancer risk or progression^[10]. However, further research is required to determine the mechanistic implications of MC1R modulation in cancer mitigation.

Disclaimer: The products mentioned are not intended for human or animal consumption. Research chemicals are intended solely for laboratory experimentation and/or in-vitro testing. Bodily introduction of any sort is strictly prohibited by law. All purchases are limited to licensed researchers and/or qualified professionals. All information shared in this article is for educational purposes only.

 

References:

1. Pfaus, J., Giuliano, F., & Gelez, H. (2007). Bremelanotide: an overview of preclinical CNS effects on female sexual function. The journal of sexual medicine, 4 Suppl 4, 269–279. https://doi.org/10.1111/j.1743-6109.2007.00610.x
2. National Center for Biotechnology Information (2023). PubChem Compound Summary for CID 9941379, Bremelanotide. Retrieved August 10, 2023 from Pubchem.
3. Renquist, B. J., Lippert, R. N., Sebag, J. A., Ellacott, K. L., & Cone, R. D. (2011). Physiological roles of the melanocortin MC₃ receptor. European journal of pharmacology, 660(1), 13–20. https://doi.org/10.1016/j.ejphar.2010.12.025
4. Renquist, B. J., Lippert, R. N., Sebag, J. A., Ellacott, K. L., & Cone, R. D. (2011). Physiological roles of the melanocortin MC₃ receptor. European journal of pharmacology, 660(1), 13–20. https://doi.org/10.1016/j.ejphar.2010.12.025
5. Vemulapalli, R., Kurowski, S., Salisbury, B., Parker, E., & Davis, H. (2001). Activation of central melanocortin receptors by MT-II increases cavernosal pressure in rabbits by the neuronal release of NO. British journal of pharmacology, 134(8), 1705–1710. https://doi.org/10.1038/sj.bjp.0704437
6. Thurston, L., Hunjan, T., Mills, E. G., Wall, M. B., Ertl, N., Phylactou, M., Muzi, B., Patel, B., Alexander, E. C., Suladze, S., Modi, M., Eng, P. C., Bassett, P. A., Abbara, A., Goldmeier, D., Comninos, A. N., & Dhillo, W. S. (2022). Melanocortin 4 receptor agonism enhances sexual brain processing in women with hypoactive sexual desire disorder. The Journal of Clinical Investigation, 132(19), e152341. https://doi.org/10.1172/JCI152341
7. Adan, R. A., Tiesjema, B., Hillebrand, J. J., la Fleur, S. E., Kas, M. J., & de Krom, M. (2006). The MC4 receptor and control of appetite. British journal of pharmacology, 149(7), 815–827. https://doi.org/10.1038/sj.bjp.0706929
8. Pfaus, J. G., Shadiack, A., Van Soest, T., Tse, M., & Molinoff, P. (2004). Selective facilitation of sexual solicitation in the female rat by a melanocortin receptor agonist. Proceedings of the National Academy of Sciences of the United States of America, 101(27), 10201–10204. https://doi.org/10.1073/pnas.0400491101
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 https://doi.org/10.1371/journal.pone.0056004
10. Maresca V, Flori E, Picardo M. Skin phototype: a new perspective. Pigment Cell Melanoma Res. 2015 Jul;28(4):378-89. doi: 10.1111/pcmr.12365. Epub 2015 Apr 11. PMID: 25786343. https://pubmed.ncbi.nlm.nih.gov/25786343/