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title: PT-141 / Bremelanotide: A Cyclic Peptide Melanocortin Receptor Agonist description: "PT-141 (bremelanotide) is a synthetic cyclic heptapeptide derived from the endogenous melanocortin peptide α-melanocyte-"

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PT-141 / Bremelanotide: A Cyclic Peptide Melanocortin Receptor Agonist

Quick Facts

Full Name	Bremelanotide (USAN); PT-141 (developmental code)
Class	Synthetic cyclic heptapeptide melanocortin receptor agonist
Molecular Formula	C₅₀H₆₈N₁₄O₁₀
Molecular Weight	~1,025 Da
Amino Acid Sequence	Ac–Nle–cyclo[Asp–His–d-Phe–Arg–Trp–Lys]–NH₂ (cyclic lactam bridge)
Target Receptors	MC1R, MC3R, MC4R, MC5R (broad-spectrum melanocortin receptor agonist)
Primary Receptor Affinity	MC4R (Ki ~2.2 nM) and MC1R (Ki ~3.6 nM)
Modification	Derived from α-melanocyte-stimulating hormone (α-MSH) via cyclization and norleucine substitution
Route of Administration	Subcutaneous injection (autoinjector)
Regulatory Status	FDA-approved (Vyleesi) for hypoactive sexual desire disorder in premenopausal women (2019)
PubChem CID	11979310
CAS Number	1031870-02-2

Executive Summary

PT-141 (bremelanotide) is a synthetic cyclic heptapeptide derived from the endogenous melanocortin peptide α-melanocyte-stimulating hormone (α-MSH). It functions as a broad-spectrum melanocortin receptor agonist with highest affinity for the MC4R and MC1R subtypes.

Bremelanotide was originally investigated for the treatment of erectile dysfunction before its effects on female sexual desire were characterized. In June 2019, it received FDA approval under the brand name Vyleesi for the treatment of hypoactive sexual desire disorder (HSDD) in premenopausal women.

Beyond its approved indication, PT-141 remains an active subject of research in neuroendocrinology, behavioral neuroscience, and melanocortin biology.

Introduction

The melanocortin system comprises five G-protein-coupled receptors (MC1R through MC5R) activated by the proopiomelanocortin (POMC)-derived peptides: α-MSH, β-MSH, γ-MSH, and ACTH. In the early 2000s, researchers at Palatin Technologies developed PT-141 as a synthetic analog of α-MSH with enhanced metabolic stability and receptor potency.

The key innovation was cyclization through an aspartate-lysine lactam bridge, which constrained the peptide into a bioactive conformation that mimics the natural "His-Phe-Arg-Trp" melanocortin core motif.

This structural optimization reduced the peptide's susceptibility to proteolytic degradation while maintaining potent agonism at melanocortin receptors, particularly MC4R, which is centrally involved in the regulation of sexual behavior.

Molecular Characteristics

Bremelanotide has the sequence Ac–Nle–cyclo[Asp–His–d-Phe–Arg–Trp–Lys]–NH₂. The lactam bridge between the side chains of Asp (position 5) and Lys (position 10) creates a cyclic structure that is critical for receptor recognition and potency.

The d-Phe residue at position 7-rather than the natural l-Phe found in α-MSH-significantly enhances melanocortin receptor affinity. The N-terminal acetylation and C-terminal amidation protect against exopeptidase cleavage.

The substitution of norleucine (Nle) for methionine (Met) at position 4 prevents oxidative degradation, a common liability in methionine-containing peptides.

The cyclic scaffold also restricts conformational flexibility, which improves the entropy of receptor binding and confers greater selectivity for MC4R relative to MC3R compared with the linear α-MSH. Bremelanotide is supplied as a sterile solution in citrate-buffered saline, formulated for subcutaneous administration via autoinjector.

Biological Research Background

Melanocortin Receptor Pharmacology

Bremelanotide acts as a non-selective melanocortin receptor agonist, with the following reported binding affinities (Ki): MC1R ~3.6 nM, MC3R ~25 nM, MC4R ~2.2 nM, MC5R ~14 nM. The MC4 receptor is the primary mediator of the peptide's effects on sexual behavior, as demonstrated by knockout mouse studies and site-specific antagonist experiments. MC4R is expressed in the paraventricular nucleus of the hypothalamus, the medial preoptic area, and limbic structures-brain regions known to regulate appetitive and consummatory aspects of sexual behavior.

Mechanism in Sexual Behavior

Activation of central MC4R by bremelanotide modulates the activity of-inter alia-dopaminergic and oxytocinergic pathways. In the medial preoptic area, melanocortinergic signaling increases dopamine release, which is associated with heightened sexual motivation and arousal.

Oxytocin release from the paraventricular nucleus also contributes to the downstream behavioral response. In male animal models, MC4R agonism facilitates penile erection independent of nitric oxide synthase pathways, distinguishing this mechanism from PDE5-dependent erectogenic agents.

In female models, bremelanotide facilitates sexual solicitations and receptivity behaviors through a mechanism involving dopaminergic and oxytocinergic transmission.

Clinical Studies

The pivotal phase III clinical program for bremelanotide-the RECONNECT study-enrolled over 1,200 premenopausal women with HSDD across two 24-week randomized, double-blind, placebo-controlled trials.

Results demonstrated statistically significant improvements in the Female Sexual Function Index (FSFI) desire domain and a reduction in distress associated with low sexual desire, as measured by the Female Sexual Distress Scale-Desire/Arousal/Orgasm (FSDS-DAO).

Treatment-emergent adverse events included nausea (~40%), flushing (~20%), headache (~11%), and injection-site reactions (~6%). The nausea was typically mild to moderate and dose-limiting in a subset of patients.

Current Research Landscape

Bremelanotide research extends beyond sexual dysfunction into several novel areas:

• Neuropsychiatric disorders: The melanocortinergic system is implicated in stress responses, anxiety, and social behavior.

Preclinical studies are exploring MC4R agonists for conditions such as social anxiety disorder and autism-spectrum behavioral phenotypes. - Energy homeostasis and body weight: MC4R is a well-established regulator of appetite and energy expenditure.

Although bremelanotide is not optimized for this indication, its MC4R agonism produces modest effects on food intake and thermogenesis, offering a scaffold for developing melanocortin-based therapeutics for metabolic disorders. - Pain and inflammation: MC1R is expressed on peripheral macrophages and microglia, and its activation produces anti-inflammatory and analgesic effects in animal models.

Bremelanotide has been investigated for pain associated with endometriosis, leveraging its MC1R agonist activity. - Opioid use disorder: Melanocortin receptor modulation may reduce opioid reward and withdrawal symptoms.

Early preclinical data suggest that MC4R antagonists, rather than agonists, attenuate opioid self-administration, but the reciprocal relationship continues to be investigated. - Pigmentation research: As an MC1R agonist, bremelanotide can stimulate melanogenesis, and its effects on skin pigmentation are being studied in contexts where increased melanin production is desired (e.g., erythropoietic protoporphyria).

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Frequently Asked Questions

+ **What is the difference between PT-141 and bremelanotide?**

PT-141 is the developmental code name for the compound that was later assigned the USAN (United States Adopted Name) bremelanotide. Both names refer to the same synthetic cyclic heptapeptide. The FDA-approved product is marketed as Vyleesi.

+ **What is the mechanism of bremelanotide?**

Bremelanotide is a melanocortin receptor agonist that primarily activates MC4R in the hypothalamus and limbic brain regions. This activation modulates dopaminergic and oxytocinergic pathways involved in sexual desire and arousal, independent of sex hormone levels or the nitric oxide–cGMP pathway targeted by PDE5 inhibitors.

+ **Is bremelanotide a hormone?**

Bremelanotide is a synthetic analog of α-melanocyte-stimulating hormone (α-MSH), which is an endogenous peptide hormone derived from the proopiomelanocortin (POMC) precursor. While bremelanotide mimics the action of a natural hormone, it is a synthetic construct with enhanced stability and receptor-binding properties.

+ **What are the melanocortin receptors?**

The melanocortin system consists of five GPCR subtypes (MC1R–MC5R). MC1R regulates pigmentation and inflammation; MC2R binds ACTH exclusively and controls adrenal steroidogenesis; MC3R and MC4R are centrally expressed and regulate energy homeostasis, feeding behavior, and sexual function; MC5R is involved in exocrine gland function. Bremelanotide is an agonist at MC1R, MC3R, MC4R, and MC5R.

+ **Does bremelanotide affect blood pressure?**

In clinical studies, bremelanotide was associated with a small, transient increase in blood pressure (~2–4 mmHg systolic) following administration. Patients with uncontrolled hypertension or cardiovascular disease were excluded from pivotal trials, and blood pressure monitoring is recommended during clinical use.

+ **Can bremelanotide cause skin darkening?**

Yes. As an MC1R agonist, bremelanotide can stimulate melanogenesis, leading to increased skin pigmentation and darkening of existing nevi. This effect is dose- and duration-dependent and was observed in some patients during clinical trials. Patients are advised to monitor for changes in moles or skin coloration.

+ **How is bremelanotide administered?**

Bremelanotide is administered as a subcutaneous injection using a single-use autoinjector. The recommended dose is 1.75 mg administered at least 45 minutes before anticipated sexual activity. The maximum frequency is one dose per 24 hours and no more than 8 doses per month.

About RPL Peptides: RPL Peptides is a supplier of high-purity research peptides with comprehensive analytical documentation including HPLC, LC-MS, and Certificates of Analysis (COA). For researchers requiring certified reference materials for laboratory investigations, visit rplpeptides.com or explore detailed molecular data at the RPL Peptides Data Center.

References

- Diamond LE, Earle DC, Rosen RC, et al. Double-blind, placebo-controlled evaluation of the safety, pharmacokinetic properties and pharmacodynamic effects of PT-141, a melanocortin receptor agonist, in healthy males. J Sex Med. 2006;3(1):93-104. doi:10.1111/j.1743-6109.2005.00184.x - Diamond LE, Earle DC, Heiman JR, 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 Sex Med. 2006;3(4):628-638. doi:10.1111/j.1743-6109.2006.00267.x - Kingsberg SA, Clayton AH, Portman D, et al. Bremelanotide for the treatment of hypoactive sexual desire disorder in premenopausal women. JAMA Netw Open. 2019;2(11):e1916018. doi:10.1001/jamanetworkopen.2019.16018 - Clayton AH, Kingsberg SA, Goldstein I, et al. Baseline characteristics and treatment response in the RECONNECT study of bremelanotide. J Womens Health (Larchmt). 2020;29(8):1051-1059. doi:10.1089/jwh.2019.8088 - Shadiack AM, Sharma SD, Earle DC, et al. Melanocortins in the treatment of male and female sexual dysfunction. Curr Opin Investig Drugs. 2007;8(9):751-755. - Pfaus JG, Shadiack A, Van Soest T, et al. Selective facilitation of sexual solicitation in the female rat by a melanocortin receptor agonist. Proc Natl Acad Sci USA. 2004;101(27):10201-10204. doi:10.1073/pnas.0402036101 - Hadley ME. Discovery that a melanocortin regulates sexual functions in male and female humans. Peptides. 2005;26(10):1687-1689. doi:10.1016/j.peptides.2005.03.012 - Wessells H, Gralnek D, Dorr R, et al. Effect of MC4-R agonist bremelanotide on erectile dysfunction in men with type 2 diabetes. BJU Int. 2008;101(6):689-694. doi:10.1111/j.1464-410X.2007.07336.x - Rosen RC, Diamond LE, Earle DC, et al. Evaluation of the safety, pharmacokinetics and pharmacodynamic effects of subcutaneously administered PT-141, a melanocortin receptor agonist, in healthy male subjects. Clin Pharmacol Ther. 2004;75(2):P85.