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

Bremelanotide is an agonist of many melanocortin receptors which in order of potency are MC1R, MC4R, MC3R, MC5R, and MC2R. The mechanism by which agonism of these receptors translates to an improvement in hypoactive sexual desire disorder is currently unknown, however MC4R receptors are present in many areas of the central nervous system. MC3R and MC4R are found in the hypothalamus and are involved in food intake and energy homeostasis. One theory is that bremelanotide stimulates dopamine in the medial preoptic area, which is involved in the sexual behaviour of a number of organisms.Bremelanotide is a melanocortin receptor agonist injected 45 minutes before anticipated sexual activity. Agonism of the melanocortin receptor MC1R also leads to increased melanin expression.

Bremelanotide is a 7 amino acid peptide used to treat hypoactive sexual desire disorder in premenopausal women. Bremelanotide does not interact with alcohol. The mechanism by which bremelanotide's action on receptors translates to a clinical effect is still unknown. Bremelanotide was first described in the literature in 2003 when it was known by the investigational code PT-141. Since then it was investigated for its place in treating sexual dysfunction in men and women but is now only indicated for women. Other drugs used to treat female sexual dysfunction include [flibanserin], [estrogen], [ospemifene], and [prasterone]. Bremelanotide was granted FDA approval on 21 June 2019. Bremelanotide is a Melanocortin Receptor Agonist. The mechanism of action of bremelanotide is as a Melanocortin Receptor Agonist. Bremelanotide is a parenterally administered melanocortin receptor agonist that is used to treat female hypoactive sexual desire disorder. Bremelanotide has been reported to cause mild serum enzyme elevations during therapy and has been implicated in rare instances of clinically apparent acute liver injury. BREMELANOTIDE is a Protein drug with a maximum clinical trial phase of IV (across all indications) that was first approved in 2019 and has 3 approved and 3 investigational indications.

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 hng/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/h. 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).

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 (likely a rare cause of clinically significant liver injury). Pregnancy and Lactation Effects ◉ Overview of Use During Lactation There is currently no information on the clinical use of bumeranolide during lactation. Because bumelanopeptide is a cyclic peptide molecule with a molecular weight of 1025, its content in breast milk is likely to 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 bumelanopeptide with caution, especially when breastfeeding newborns or premature infants.
◉ Effects on breastfed infants
No published information found as of the revision date.
◉ Effects on lactation and breast milk
No published information found as of the revision date.

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Protein binding
Bumelanopeptide has a protein binding rate of 21% in serum.

[1]. Bremelanotide: an overview of preclinical CNS effects on female sexual function. J Sex Med. 2007 Nov;4 Suppl 4:269-79.

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

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 anticipated 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.

C50H68N14O10

1025.18

1024.524

C, 58.58; H, 6.69; N, 19.13; O, 15.61

189691-06-3

Bremelanotide Acetate; 1607799-13-2

9941379

Nle-D(1)HFRWK(1); Ac-Nle-Asp(1)-His-D-Phe-Arg-Trp-Lys(1)-OH

XDHFRWK

Solid powder

1.4±0.1 g/cm3

1.679

-1.21

13

12

17

74

1950

7

CCCC[C@H](NC(C)=O)C(N[C@H]1CC(NCCCC[C@H](NC([C@@H](NC([C@@H](NC([C@H](NC([C@@H](NC1=O)CC2=CN=CN2)=O)CC3=CC=CC=C3)=O)CCCNC(N)=N)=O)CC4=CNC5=CC=CC=C45)=O)C(O)=O)=O)=O

FFHBJDQSGDNCIV-MFVUMRCOSA-N

InChI=1S/C50H68N14O10/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/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)/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

PT-141; PT141; 189691-06-3; Bremelanotida; 6Y24O4F92S; PT-141 FREE BASE; Bremelanotide; PT 141

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

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

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*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.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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