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

Bremelanotide Acetate 能以浓度依赖的方式抑制放射性配体 [¹²⁵I]-NDP-α-MSH 与转染了人源 MC3R 和 MC4R 的 HEK-293 细胞膜的结合。[1]
在使用表达人源 MC4R 的 HEK-293 细胞进行的功能性实验中，Bremelanotide Acetate 刺激了细胞内 cAMP 的积累，证实了其在该受体上的激动剂活性。[1]

Bremelanotide Acetate（50-200 μg/kg；皮下注射；一次）显着增加在双层室中用苯甲酸雌二醇+黄体酮或单独苯甲酸雌二醇引发的雌性的性欲诱惑[2]。动物模型：去卵巢Long-Evans大鼠[2] 剂量：50、100、200 μg/kg 给药方式：皮下注射；结果：在双层室中使用苯甲酸雌二醇+黄体酮或单独使用苯甲酸雌二醇后，雌性的性欲诱惑显着增加。

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给雄性 Sprague-Dawley 大鼠鼻内注射 Bremelanotide Acetate (50 µg/kg)，显著增加了每只大鼠的平均阴茎勃起次数，以及在 30 分钟观察期内至少出现一次勃起的大鼠比例。[1]
给大鼠全身性给予有效剂量的 Bremelanotide Acetate (50 µg/kg，鼻内给药) 后，在下丘脑的室旁核和视上核诱导出 c-Fos 免疫反应性，表明在与性功能相关的大脑区域神经元被激活。[1]
侧脑室内注射 Bremelanotide Acetate 诱发勃起的剂量比全身给药剂量低 100 至 1000 倍。[1]
在一项安慰剂对照研究中，给健康男性志愿者鼻内给予 Bremelanotide Acetate (4-20 mg)，导致勃起活动呈剂量依赖性增加（以基础硬度 >60% 的勃起累计持续时间衡量）。[1]
在轻度至中度勃起功能障碍（ED）患者中，与安慰剂相比，鼻内给予 Bremelanotide Acetate（测试了两个剂量）显著增加了勃起活动的持续时间（基础硬度 >60% 和 >80%），首次勃起的平均起效时间约为 30 分钟。[1]

使用表达克隆人源黑皮质素受体的 HEK-293 细胞膜进行放射性配体结合实验。将不同浓度的 Bremelanotide Acetate 与细胞膜以及放射性配体 [¹²⁵I]-NDP-α-MSH 一起孵育。用于 MC3R 研究的配体浓度为 0.4 nM，用于 MC4R 研究的为 0.2 nM。结合率以总结合的百分比表示。[1]
在表达人源 MC4R 的 HEK-293 细胞中进行功能性 cAMP 积累实验。制备细胞裂解液，并使用酶免疫分析法（EIA）测量 cAMP 水平以评估激动剂活性。[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

416

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

注意： 请将本产品存放在密封且受保护的环境中（例如氮气保护），避免吸湿/受潮和光照。

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)

配方 1 中的溶解度: ≥ 2.08 mg/mL (1.92 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 20.8 mg/mL澄清DMSO储备液加入400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.08 mg/mL (1.92 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 20.8 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.08 mg/mL (1.92 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 20.8 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
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