Melanocortin receptors: MC1R, MC4R, MC3R, MC5R, and MC2R

Bremelanotide Acetate inhibits the binding of radioligand [¹²⁵I]-NDP-α-MSH to human recombinant MC3R and MC4R expressed in transfected HEK-293 cell membranes in a concentration-dependent manner.[1]
In functional assays using HEK-293 cells expressing human MC4R, Bremelanotide Acetate stimulated intracellular cAMP accumulation, confirming its agonist activity at this receptor.[1]

Bremelanotide Acetate (50-200 μg/kg; s.c.; once) significantly increases proceptive solicitations in females primed with either estradiol benzoate alone or estradiol benzoate plus progesterone in bilevel chambers[2].

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Intranasal (IN) administration of Bremelanotide Acetate (50 µg/kg) to male Sprague-Dawley rats significantly increased the mean number of penile erections per rat and the percentage of rats showing at least one erection during a 30-minute observation period.[1]
Systemic administration of an efficacious dose of Bremelanotide Acetate (50 µg/kg, IN) to rats induced c-Fos immunoreactivity in the paraventricular nucleus and supraoptic nucleus of the hypothalamus, indicating neuronal activation in brain regions associated with sexual function.[1]
Intracerebroventricular injection of Bremelanotide Acetate induced erections at doses 100 to 1000-fold lower than systemic doses.[1]
Intranasal administration of Bremelanotide Acetate (4-20 mg) to healthy male volunteers in a placebo-controlled study resulted in a dose-dependent increase in erectile activity, measured as cumulative duration of erection with >60% base rigidity.[1]
In patients with mild-to-moderate erectile dysfunction (ED), intranasal Bremelanotide Acetate (two doses tested) significantly increased the duration of erectile activity (both >60% and >80% base rigidity) compared to placebo, with an average time to onset of the first erection of approximately 30 minutes.[1]

Radioligand binding assays were performed using membranes from HEK-293 cells expressing cloned human melanocortin receptors. Varying concentrations of Bremelanotide Acetate were incubated with the membranes and the radioligand [¹²⁵I]-NDP-α-MSH. The concentration of radioligand was 0.4 nM for MC3R studies and 0.2 nM for MC4R studies. Binding was expressed as a percentage of total binding.[1]
Functional cAMP accumulation assays were conducted in HEK-293 cells expressing human MC4R. Cell lysates were prepared, and cAMP levels were measured using an enzyme immunoassay (EIA) to evaluate agonist activity.[1]

Ovariectomized Long–Evans rats
50, 100, 200 μg/kg
s.c.; once

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Male Sprague-Dawley rats (200-250 g) were dosed with 50 µg/kg of Bremelanotide Acetate via intranasal administration. A micropipette was used to deliver 25 µL of the drug solution into one nostril. Immediately after dosing, rats were placed in individual cages for a 30-minute behavioral observation period during which penile erections were counted.[1]
For neuronal activation studies (c-Fos), rats were dosed intranasally with an efficacious dose (50 µg/kg) of Bremelanotide Acetate. Two hours later, they were perfusion-fixed, and brains were removed for immunohistochemical processing.[1]
For neuroanatomical tracing, pseudorabies virus (PRV) was injected directly into the corpus cavernosum of the rat penis. After 4-6 days, brains were harvested and processed with anti-PRV antiserum for immunohistochemistry to identify retrogradely labeled neurons.[1]

Absorption, Distribution and Excretion
The Tmax of bremelanotide is 1.0 h (0.5–1.0 h), with a bioavailability of 100%. The Cmax is 72.8 ng/mL, and the AUC is 276 h·ng/mL. 64.8% of the radiolabeled dose is excreted in the urine, and 22.8% is recovered in the feces. The mean volume of distribution of bremelanotide is 25.0 ± 5.8 L. The mean clearance of bremelanotide is 6.5 ± 1.0 L/hr. Metabolism/Metabolites Bremelanotide consists of 7 amino acids, therefore its metabolism involves multiple hydrolytic reactions. Biological Half-Life The half-life of bremelanotide is 2.7 h (1.9–4.0 h).
In healthy subjects, the mean time to reach maximum plasma concentration (Tmax) after intranasal administration of 20 mg bumeranopeptide acetate (10 mg per nostril) was approximately 30 minutes. [1]
Maximum plasma concentration (Cmax) increased in a dose-dependent manner. [1]
The mean terminal elimination half-life (t1/2) was approximately 2 hours (120 minutes). [1]
The relatively rapid decline in plasma concentration suggests a low risk of drug interaction. [1]

Hepatotoxicity
In pre-registration clinical trials, a small number of patients treated with bumeranolide reported elevated serum enzymes, a similar proportion of which occurred in the placebo group. One patient who received 10 bumeranolide injections within one year developed acute hepatitis, characterized by significantly elevated serum transaminase levels, mildly elevated alkaline phosphatase, and mild jaundice; symptoms resolved upon discontinuation of the drug. There are currently no reported cases of bumeranolide causing acute liver failure or chronic liver injury, but overall clinical experience with this drug is limited. Therefore, bumeranolide may cause acute liver injury, but this is rare. Probability Score: D (May cause clinically significant liver injury, but this is rare). Pregnancy and Lactation Effects ◉ Overview of Use During Lactation There is currently no information on the clinical use of bumeranolide during lactation. Because bumelanotide is a cyclic peptide molecule with a molecular weight of 1025, its content in breast milk may be very low, and it is unlikely to be absorbed because it may be destroyed in the infant's gastrointestinal tract. Until more data are available, breastfeeding women should use bumelanotide with caution, especially when breastfeeding newborns or premature infants.
◉ Effects on breastfed infants
No relevant published information was found as of the revision date.
◉ Effects on lactation and breast milk
No relevant published information was found as of the revision date.

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In clinical studies in healthy volunteers and patients with erectile dysfunction, all doses of intranasal bumelanotide acetate (4–20 mg) were well tolerated. [1]
No significant changes in blood pressure, heart rate, or ECG parameters were observed. [1]
No treatment-related serious adverse events were observed. [1]
No priapism occurred in any subjects. [1]

[1]. PT-141: a melanocortin agonist for the treatment of sexual dysfunction. Ann N Y Acad Sci. 2003 Jun;994:96-102.

[2]. Selective facilitation of sexual solicitation in the female rat by a melanocortin receptor agonist. Proc Natl Acad Sci U S A. 2004 Jul 6;101(27):10201-4.

Bumelanotide is an oligopeptide. It is a 7-amino acid peptide used to treat hypoactive sexual desire disorder in premenopausal women. Bumelanotide does not interact with alcohol. The mechanism by which bumelanotide acts on receptors to produce clinical efficacy is not fully understood. Bumelanotide was first reported in the literature in 2003 under the research code PT-141. Since then, its use in treating male and female sexual dysfunction has been investigated, but it is currently only approved for use in women. Other medications used to treat female sexual dysfunction include flubanoxetine, estrogen, opemifene, and prastorhinone. Bumelanotide received approval from the U.S. Food and Drug Administration (FDA) on June 21, 2019. Bumelanotide is a melanocortin receptor agonist. Its mechanism of action is as a melanocortin receptor agonist. Bumelanotide is a parenteral melanocortin receptor agonist used to treat hypoactive sexual desire disorder in women. Bumeranolide has been reported to cause mild elevation of serum enzymes during treatment and has been associated with rare cases of clinically significant acute liver injury. See also: Bumeranolide acetate (active ingredient). Drug Indications Bumeranolide is indicated for the treatment of hypoactive sexual desire disorder in premenopausal women not caused by medical or psychiatric illness, partner problems, or drug side effects. Mechanism of Action Bumeranolide is an agonist of multiple melanocortin receptors, in order of potency: MC1R, MC4R, MC3R, MC5R, and MC2R. It is currently unclear how these receptor agonists improve hypoactive sexual desire disorder, but the MC4R receptor is present in many areas of the central nervous system. MC3R and MC4R are present in the hypothalamus and are involved in food intake and energy homeostasis. One theory suggests that bumeranolide stimulates the release of dopamine in the medial preoptic area, which is involved in sexual behavior in various organisms.

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Pharmacodynamics
Bumelanotide is a melanocortin receptor agonist, administered 45 minutes before the expected sexual activity. Agonism of the melanocortin receptor MC1R also leads to increased melanin expression. Nausea, headache, and vomiting may also occur in patients taking bumelanotide.

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Bumelanotide acetate is a synthetic cyclic heptapeptide and an analog of α-melanocyte-stimulating hormone (α-MSH). [1]
Its mechanism of action in treating erectile dysfunction is thought to be the activation of melanocortin receptors (MC3R and MC4R) in the hypothalamus, a brain region associated with sexual function. [1]
Neuroanatomical tracing experiments using pseudorabies virus injected into the penis of rats showed that neurons in the paraventricular nucleus of the hypothalamus project to the penis and that these neurons are activated by Bumelanotide acetate. [1]
Its pharmacokinetic characteristics (short time to peak concentration, short half-life) support its development as a drug for on-demand treatment of erectile dysfunction. [1]
Clinical efficacy was assessed using the RigiScan Plus system to evaluate penile rigidity and erectile function. [1]

C₅₂H₇₂N₁₄O₁₂

1085.22

1084.545

C, 57.55; H, 6.69; N, 18.07; O, 17.69

1607799-13-2

Bremelanotide; 189691-06-3

91971505

Ac-Nle-Asp(1)-His-D-Phe-Arg-Trp-Lys(1)-OH.CH3CO2H; Ac-[Nle}-Asp-His-{d-Phe}-Arg-Trp-Lys (Lactam bridge: Asp4-Lys7)

XDHFRWK; Ac-[Nle}-DHFRWK (Lactam bridge: Asp4-Lys7)

White to off-white solid powder

14

14

17

78

1980

7

O=C1[C@]([H])(C([H])([H])C([H])([H])C([H])([H])/N=C(\N([H])[H])/N([H])[H])N([H])C([C@@]([H])(C([H])([H])C2C([H])=C([H])C([H])=C([H])C=2[H])N([H])C([C@]([H])(C([H])([H])C2=C([H])N=C([H])N2[H])N([H])C([C@]([H])(C([H])([H])C(N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[C@@]([H])(C(=O)O[H])N([H])C([C@]([H])(C([H])([H])C2=C([H])N([H])C3=C([H])C([H])=C([H])C([H])=C23)N1[H])=O)=O)N([H])C([C@]([H])(C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H])N([H])C(C([H])([H])[H])=O)=O)=O)=O)=O.O([H])C(C([H])([H])[H])=O

MAYUSRUHXFWITM-GBRHMYBBSA-N

InChI=1S/C50H68N14O10.C2H4O2/c1-3-4-16-35(58-29(2)65)43(67)64-41-25-42(66)54-20-11-10-18-37(49(73)74)60-46(70)39(23-31-26-56-34-17-9-8-15-33(31)34)62-44(68)36(19-12-21-55-50(51)52)59-45(69)38(22-30-13-6-5-7-14-30)61-47(71)40(63-48(41)72)24-32-27-53-28-57-32;1-2(3)4/h5-9,13-15,17,26-28,35-41,56H,3-4,10-12,16,18-25H2,1-2H3,(H,53,57)(H,54,66)(H,58,65)(H,59,69)(H,60,70)(H,61,71)(H,62,68)(H,63,72)(H,64,67)(H,73,74)(H4,51,52,55);1H3,(H,3,4)/t35-,36-,37-,38+,39-,40-,41-;/m0./s1

(3S,6S,9R,12S,15S,23S)-15-[[(2S)-2-acetamidohexanoyl]amino]-9-benzyl-6-[3-(diaminomethylideneamino)propyl]-12-(1H-imidazol-5-ylmethyl)-3-(1H-indol-3-ylmethyl)-2,5,8,11,14,17-hexaoxo-1,4,7,10,13,18-hexazacyclotricosane-23-carboxylic acid;acetic acid

PT141 acetate; PT 141 acetate; PT-141 Acetate; PT-141; PT141; PT 141; Vyleesi; Bremelanotide acetate; Bremelanotide

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture and light.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

H2O: ≥ 50 mg/mL (~46.1 mM)
DMSO: ≥ 36 mg/mL (~33.2 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (1.92 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.08 mg/mL (1.92 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.08 mg/mL (1.92 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)