Research Applications
Sexual Function Enhancement and Arousal
PT-141 demonstrates significant efficacy in improving sexual desire and reducing distress in women with hypoactive sexual desire disorder. The pivotal RECONNECT Phase 3 trials, two identically designed randomized, double-blind, placebo-controlled studies involving 1,267 women, established the peptide's therapeutic benefit. Women receiving PT-141 1.75 mg subcutaneously showed statistically significant increases in sexual desire scores using the Female Sexual Function Index-desire domain (FSFI-D), with improvements of 0.30 points in study 301 and 0.42 points in study 302 compared to placebo. These changes were accompanied by significant reductions in distress related to low sexual desire, as measured by the Female Sexual Distress Scale-Desire/Arousal/Orgasm (FSDS-DAO), with improvements ranging from -11.6 to -15.4 points versus placebo.
The long-term safety and sustained efficacy of PT-141 was demonstrated in the 52-week open-label extension of the RECONNECT trials. Among 684 participants who elected to continue treatment, improvements in desire domain scores ranged from 1.25 to 1.30 points, and distress reduction scores ranged from -1.4 to -1.7 points for patients who received PT-141 during the core phase. The peptide's effects were maintained throughout extended treatment, with no new safety signals observed during long-term use. Integrated subgroup analyses confirmed PT-141's effectiveness across diverse patient populations, including women of varying ages, body mass indices, baseline testosterone levels, and hormonal contraceptive use status.
Clinical research demonstrates that PT-141 enhances both subjective and physiological measures of sexual response. In preclinical studies, the peptide activated melanocortin receptors in the medial preoptic area, leading to increased dopamine signaling and enhanced sexual motivation. This central mechanism of action distinguishes PT-141 from peripheral vasodilators, making it particularly valuable for addressing desire-related dysfunction rather than solely physical arousal deficits. The peptide increases vaginal pulse amplitude during exposure to erotic stimuli and improves subjective perceptions of physiological and sexual response within 24 hours of administration.
Male subjects receiving intranasal PT-141 at doses of 4 to 20 mg experienced significantly increased duration of rigid erections (140 minutes) compared to placebo (22 minutes) in early-phase clinical trials. The peptide demonstrated synergistic effects when co-administered with sildenafil in men with erectile dysfunction, suggesting complementary mechanisms of action. PT-141's ability to enhance both central desire pathways and peripheral erectile function positions it as a promising option for addressing multifactorial sexual dysfunction, particularly in cases with significant psychological or neurological components.
Sources:
- Kingsberg SA, et al. "Bremelanotide for the Treatment of Hypoactive Sexual Desire Disorder: Two Randomized Phase 3 Trials." Obstetrics & Gynecology. 2019;134(5):899-908. https://pubmed.ncbi.nlm.nih.gov/31599840/
- Simon JA, et al. "Long-Term Safety and Efficacy of Bremelanotide for Hypoactive Sexual Desire Disorder." Obstetrics & Gynecology. 2019;134(5):909-917. https://pubmed.ncbi.nlm.nih.gov/31599847/
- Simon JA, et al. "Prespecified and Integrated Subgroup Analyses from the RECONNECT Phase 3 Studies of Bremelanotide." Journal of Women's Health. 2022;31(3):391-400. https://pubmed.ncbi.nlm.nih.gov/35230162/
- Pfaus JG, et al. "The neurobiology of bremelanotide for the treatment of hypoactive sexual desire disorder in premenopausal women." CNS Spectrums. 2022;27(3):281-289. https://pubmed.ncbi.nlm.nih.gov/33455598/
- Diamond LE, et al. "An effect on the subjective sexual response in premenopausal women with sexual arousal disorder by bremelanotide (PT-141), a melanocortin receptor agonist." Journal of Sexual Medicine. 2006;3(4):628-638. https://pubmed.ncbi.nlm.nih.gov/16839319/
Metabolic Enhancement and Weight Loss
PT-141 demonstrates significant effects on appetite regulation and body weight through activation of melanocortin-4 receptors in the hypothalamus. Two Phase 1 randomized, double-blind, placebo-controlled trials in premenopausal women with obesity (BMI >30 kg/m²) established the peptide's metabolic benefits. In Study A, women receiving PT-141 three times daily for 15 days exhibited significantly greater body weight reduction compared to placebo (1.3 kg difference) with high statistical significance. Mean caloric intake decreased by approximately 400 kcal/day throughout the study period. Study B, employing a crossover design, demonstrated that twice-daily PT-141 administration resulted in greater mean body weight reduction (1.7 kg) versus placebo (0.9 kg). Total caloric intake reduction was consistently 398-469 kcal/day greater in PT-141 groups compared to placebo across all dosing regimens.
The melanocortin-4 receptor plays a central role in the leptin-melanocortin pathway, serving as a key regulator of energy homeostasis. Genetic mutations that inhibit MC4R signaling cause hyperphagia, decreased energy expenditure, and early-onset severe obesity, demonstrating the receptor's fundamental importance in weight regulation. PT-141's agonist activity at MC4R promotes satiety by mimicking the effects of endogenous melanocortin hormones, particularly alpha-melanocyte stimulating hormone. The peptide counteracts the appetite-stimulating effects of agouti-related peptide (AgRP), an endogenous MC4R antagonist that works with neuropeptide Y to stimulate food intake.
Recent Phase 2 clinical data from the BMT-801 study demonstrated that PT-141 co-administered with the GLP-1/GIP agonist tirzepatide produces synergistic effects on weight loss. Patients receiving combination therapy showed greater weight reduction compared to either agent alone. Importantly, low-dose PT-141 effectively prevented weight regain after discontinuation of tirzepatide therapy, a major challenge in obesity management with GLP-1/GIP medications. Patients transitioning to low-dose PT-141 after initial weight loss maintained their reduced body weight without significant regain, while those switching to placebo experienced rapid weight rebound. The combination therapy showed no increase in gastrointestinal side effects compared to tirzepatide alone, demonstrating favorable tolerability.
Appetite suppression measurements using validated daily questionnaires revealed that patients receiving PT-141 experienced significant improvements in fullness, satiety, and reduced hunger compared to placebo. These subjective measures correlated with objective reductions in caloric intake and body weight. The peptide's effects on appetite control were maintained throughout treatment periods, with no evidence of tolerance development. PT-141's mechanism of central appetite suppression through melanocortin receptor activation represents a complementary approach to incretin-based therapies, providing an alternative pathway for addressing obesity through neurohormonal regulation of energy balance.
Sources:
- Spana C, et al. "Effect of bremelanotide on body weight of obese women: Data from two phase 1 randomized controlled trials." Diabetes, Obesity and Metabolism. 2022;24(6):1084-1092. https://pubmed.ncbi.nlm.nih.gov/35170192/
- Clayton AH, et al. "Bremelanotide for female sexual dysfunctions in premenopausal women: a randomized, placebo-controlled dose-finding trial." Women's Health. 2016;12(3):325-337. https://pubmed.ncbi.nlm.nih.gov/27287503/
Anticancer Properties and Cell Death Induction
PT-141 demonstrates potent anticancer activity against glioblastoma cells through selective inhibition of survivin expression. Research published in Anticancer Research demonstrates that PT-141 reduces survivin levels and induces cell death in human glioblastoma cell lines at concentrations that are non-toxic to normal human cells. Survivin is an inhibitor of apoptosis protein that is overexpressed in glioblastoma and many other cancers, promoting tumor cell survival and resistance to therapy. PT-141's ability to suppress survivin expression provides a novel mechanism for sensitizing glioblastoma cells to programmed cell death.
The anticancer effects of PT-141 are specifically mediated through melanocortin receptors 3 and 4. Treatment with an MC3R/MC4R antagonist completely abolished PT-141's cytotoxic effects, confirming receptor-specific activity. Forced overexpression of survivin in glioblastoma cells prevented PT-141-induced cell death, establishing that survivin suppression is the primary mechanism underlying the peptide's anticancer activity. This receptor-mediated mechanism suggests potential for targeted therapy with minimal effects on normal tissues that do not express high levels of MC3R and MC4R.
PT-141 enhances the efficacy of standard chemotherapeutic agents used in glioblastoma treatment. The peptide significantly promoted cell death induced by temozolomide, the first-line chemotherapy for glioblastoma, and osimertinib, a targeted tyrosine kinase inhibitor. This synergistic effect suggests PT-141 could serve as a chemosensitizing agent, potentially allowing dose reduction of cytotoxic drugs while maintaining or improving therapeutic efficacy. The combination approach addresses the challenge of chemotherapy resistance in glioblastoma, a major factor contributing to treatment failure and tumor recurrence.
Glioblastoma is the most aggressive primary brain tumor with extremely poor prognosis despite multimodal treatment including surgery, radiation, and chemotherapy. Current standard-of-care therapies provide median survival of only 14-15 months, highlighting the urgent need for novel therapeutic approaches. PT-141's ability to target melanocortin receptors represents a new strategy for modulating glioblastoma biology through neurotransmitter pathways. The peptide's documented safety profile in clinical trials for sexual dysfunction, combined with its blood-brain barrier penetration capability, positions it as a promising candidate for drug repurposing in neuro-oncology applications.
Sources:
- Suzuki S, et al. "Melanocortin Receptor Agonist Bremelanotide Induces Cell Death and Growth Inhibition in Glioblastoma Cells via Suppression of Survivin Expression." Anticancer Research. 2024;44(9):3875-3883. https://pubmed.ncbi.nlm.nih.gov/39197897/
Neurobiological Mechanisms and Central Nervous System Effects
PT-141 exerts its primary therapeutic effects through modulation of central nervous system pathways, particularly in the hypothalamus. The peptide nonselectively activates multiple melanocortin receptor subtypes, with MC4R being most relevant at therapeutic doses. MC4R is predominantly expressed in the medial preoptic area of the hypothalamus, a brain region critical for integrating hormonal, sensory, and motivational signals related to sexual behavior and appetite regulation. Activation of presynaptic MC4Rs on neurons in this region increases the release of dopamine, an excitatory neurotransmitter that enhances sexual desire and motivation.
The melanocortin system serves as a critical regulator at the intersection of multiple physiological processes including energy homeostasis, inflammation, immune responses, and behavioral functions. PT-141's activation of MC4R modulates the balance between excitatory and inhibitory neurotransmitters in brain regions controlling sexual response. The peptide enhances dopaminergic and noradrenergic signaling while potentially modulating GABAergic and serotonergic inhibitory pathways. This multi-neurotransmitter effect produces complex neuromodulation that addresses both the motivational and arousal components of sexual response, as well as homeostatic regulation of energy balance.
PT-141 demonstrates dose-dependent effects on cardiovascular parameters through MC4R activation. Clinical trials employing ambulatory blood pressure monitoring documented small, transient increases in systolic blood pressure (2-3 mmHg) and reductions in heart rate occurring 0-4 hours post-dose. These hemodynamic effects are mediated through melanocortin receptor activation in cardiovascular control centers and are generally mild and self-limiting. The transient nature of blood pressure changes, combined with the on-demand dosing strategy, mitigates concerns about sustained cardiovascular effects during long-term use.
Pharmacokinetic studies demonstrate that subcutaneous administration provides 100% bioavailability with predictable absorption profiles. Peak plasma concentrations occur at approximately 1 hour post-injection, with therapeutic effects manifesting within 45-90 minutes and persisting for 6-8 hours in most individuals. The peptide undergoes metabolism through hydrolysis of amide bonds, with metabolites excreted predominantly through renal pathways. PT-141 does not interact significantly with cytochrome P450 enzymes, minimizing potential for drug-drug interactions compared to oral medications metabolized through hepatic pathways.
Sources:
- Pfaus JG, et al. "The neurobiology of bremelanotide for the treatment of hypoactive sexual desire disorder in premenopausal women." CNS Spectrums. 2022;27(3):281-289. https://pubmed.ncbi.nlm.nih.gov/33455598/
- Jordan R, et al. "Usefulness of ambulatory blood pressure monitoring to assess the melanocortin receptor agonist bremelanotide." Journal of Hypertension. 2017;35(4):761-768. https://pubmed.ncbi.nlm.nih.gov/27977473/
- Clayton AH, et al. "Phase I Randomized Placebo-controlled, Double-blind Study of the Safety and Tolerability of Bremelanotide Coadministered With Ethanol in Healthy Male and Female Participants." Clinical Therapeutics. 2017;39(3):514-526. https://pubmed.ncbi.nlm.nih.gov/28189361/
