PT-141

PT-141, also known by its generic name bremelanotide, is a synthetic cyclic heptapeptide derived from the naturally occurring melanocortin peptide alpha-MSH. Structurally, it is a metabolite of the earlier investigational tanning peptide melanotan II, with specific modifications that confer selectivity for central melanocortin receptor pathways involved in sexual arousal. PT-141 was developed by Palatin Technologies and received FDA approval in June 2019 under the brand name Vyleesi for treatment of acquired, generalized hypoactive sexual desire disorder (HSDD) in premenopausal women. What distinguishes PT-141 from other sexual function agents is its unique mechanism of action. Unlike phosphodiesterase type 5 (PDE5) inhibitors such as sildenafil, which act peripherally on vascular smooth muscle to enhance blood flow, PT-141 acts centrally in the nervous system on melanocortin-3 and melanocortin-4 receptors (MC3R/MC4R). These receptors are expressed in hypothalamic and limbic brain regions that govern sexual motivation and arousal. This central mechanism means PT-141 addresses the motivational and desire components of sexual function rather than the downstream physiological response. The development of PT-141 also represents a significant milestone in melanocortin receptor pharmacology. The melanocortin system is involved in a remarkably diverse array of physiological processes including pigmentation, appetite regulation, adrenal function, and inflammation. PT-141's specificity for the sexual function aspects of this system required careful medicinal chemistry optimization. Its approval validated the melanocortin pathway as a druggable target for CNS-mediated sexual dysfunction, opening avenues for further research in this receptor family. All information presented here is for educational and research purposes only.

PT-141 activates central melanocortin pathways to modulate sexual desire and arousal: **MC3R/MC4R Agonism**: PT-141 is a non-selective agonist at melanocortin-3 (MC3R) and melanocortin-4 (MC4R) receptors. These G-protein-coupled receptors are highly expressed in hypothalamic nuclei (particularly the paraventricular nucleus and medial preoptic area) and limbic structures involved in sexual behavior. Receptor activation stimulates adenylyl cyclase, increasing intracellular cAMP and triggering downstream signaling cascades that influence neural circuits governing arousal and motivation. **Central Nervous System Action**: Unlike peripheral vasodilators, PT-141 crosses into CNS compartments where it modulates dopaminergic and oxytocinergic pathways in brain regions associated with sexual desire. Functional MRI studies have demonstrated that PT-141 increases activation in brain areas associated with sexual arousal processing, including the entorhinal cortex, cingulate, and insular regions. **Downstream Neurotransmitter Modulation**: MC4R activation by PT-141 enhances release of oxytocin and dopamine in key hypothalamic and mesolimbic circuits. These neurotransmitters are well-established mediators of sexual motivation, pair bonding, and reward signaling, providing a neurochemical basis for PT-141's pro-sexual effects. **Distinction from PDE5 Mechanism**: PDE5 inhibitors prevent cGMP degradation in penile vascular smooth muscle, producing a localized hemodynamic effect. PT-141 instead acts upstream at the level of central motivation and desire. This mechanistic distinction explains why PT-141 is effective in conditions where peripheral hemodynamic function is intact but central desire is impaired. **Melanocortin System Context**: The melanocortin system integrates diverse physiological signals including energy status, stress, and social cues. PT-141's engagement with this system means its effects on sexual function may be influenced by broader physiological and psychological context, consistent with the complexity of human sexual desire regulation.

Clinical development of PT-141 involved extensive Phase II and Phase III trials: **RECONNECT Phase III Trials**: The pivotal Phase III RECONNECT program consisted of two replicate, randomized, double-blind, placebo-controlled, multicenter trials in premenopausal women with HSDD. PT-141 (1.75 mg subcutaneous) demonstrated statistically significant increases in the number of satisfying sexual events and significant decreases in distress associated with low sexual desire compared to placebo over 24 weeks. These results formed the basis for FDA approval. **Male Sexual Dysfunction Studies**: Earlier Phase II studies evaluated PT-141 in men with erectile dysfunction, including those who had failed PDE5 inhibitor therapy. Intranasal PT-141 demonstrated pro-erectile effects in men with both organic and psychogenic ED, confirming the peptide's activity across both sexes. However, development in men was not pursued to approval due to bioavailability and nausea concerns with the intranasal formulation. **Functional Neuroimaging Research**: fMRI studies in healthy volunteers demonstrated that PT-141 increases blood-oxygen-level-dependent (BOLD) signal in brain regions associated with sexual arousal processing during exposure to visual sexual stimuli. These findings provided neurobiological evidence supporting the central mechanism of action. **Melanocortin Receptor Pharmacology**: Structure-activity relationship studies have characterized PT-141's binding affinity across the melanocortin receptor family. The peptide shows highest affinity for MC4R (Ki ~2.9 nM) and MC3R (Ki ~12 nM), with lower but measurable affinity for MC1R and MC5R. This receptor profile explains both its efficacy and its side effect pattern. **Cardiovascular Safety**: Dedicated QTc studies and extensive cardiovascular monitoring across clinical trials demonstrated no clinically significant effects on cardiac conduction or blood pressure at therapeutic doses. Transient increases in blood pressure (mean ~3 mmHg systolic) were observed but were not clinically concerning.

PT-141 dosing is based on the FDA-approved label and clinical trial data: **Approved Dose (Vyleesi)**: 1.75 mg administered subcutaneously in the abdomen at least 45 minutes before anticipated sexual activity. This dose was selected based on Phase II dose-ranging studies that evaluated 0.75, 1.25, and 1.75 mg doses. **Dosing Frequency**: On-demand use as needed. The FDA label recommends no more than one dose per 24-hour period and no more than 8 doses per month. **Onset and Duration**: Peak plasma concentrations occur approximately 1 hour after subcutaneous injection. Clinical effects have been reported as early as 45 minutes post-dose, with duration of several hours consistent with the ~2.7-hour elimination half-life. **Special Populations**: No dose adjustment is recommended for hepatic or renal impairment based on pharmacokinetic studies. The medication is specifically indicated for premenopausal women. **Note**: The above reflects the FDA-approved indication and dosing for Vyleesi. Research applications in other populations or indications should be designed based on published clinical trial protocols. All dosing information is provided for educational and research reference only and does not constitute medical advice.

The safety profile of PT-141 is well characterized from Phase III clinical trials and post-marketing experience: **Nausea**: The most common adverse effect, occurring in approximately 40% of subjects in clinical trials. Nausea is typically mild to moderate, self-limiting (resolving within hours), and decreases with repeated use. It is mediated by melanocortin receptor activation in brainstem emetic centers. **Other Common Effects**: - Flushing (20%) — related to melanocortin effects on vascular tone - Headache (11%) — typically mild and transient - Injection site reactions (5.4%) — pain, erythema, or bruising at the subcutaneous injection site **Cardiovascular Effects**: Transient, small increases in blood pressure (mean ~3 mmHg systolic, ~1.5 mmHg diastolic) have been documented. The FDA label includes a recommendation to monitor blood pressure in patients with cardiovascular risk factors. **Skin Hyperpigmentation**: Due to residual MC1R activity, focal areas of hyperpigmentation (darkening) may occur, particularly in the face and gingiva. This effect is generally reversible upon discontinuation. The FDA label warns about this possibility with repeated use. **Contraindications**: PT-141 is contraindicated in patients with uncontrolled hypertension or known cardiovascular disease. It should not be used with naltrexone due to potential interaction. **Research Context**: The side effect profile reflects on-demand use at the approved 1.75 mg dose. Effects at other doses or with chronic administration require further characterization.