25614-03-3

• 常用中文名：溴隐亭
• 常用英文名：Bromocriptine
• CAS号：25614-03-3
• 分子式：C₃₂H₄₀BrN₅O₅
• 分子量：654.59400
• 相关类别： 原料药 神经系统用药 抗震颤麻痹药
• 发布时间：2018-07-04 23:21:40
• 更新时间：2024-01-07 08:57:26
• 溴隐亭是一种有效的多巴胺D2/D3受体激动剂,可将多巴胺D2受体与8.05±0.2的pKi结合。

名称

• 中文名: 溴隐亭
• 英文名: bromocriptine
• 英文别名: Bromocryptine; MFCD00870213; Bromoergocryptine; Bromergocryptine; Bromoergocriptine; Bromocriptinum; Ergoset; EINECS 247-128-5; Bromocriptin

物化性质

• 密度: 1.52 g/cm3
• 沸点: 891.3ºC at 760 mmHg
• 分子式: C₃₂H₄₀BrN₅O₅
• 分子量: 654.59400
• 闪点: 492.8ºC
• 精确质量: 653.22100
• PSA: 118.21000
• LogP: 3.39740
• 外观性状: 白色结晶粉末
• 蒸汽压: 4.15E-34mmHg at 25°C
• 折射率: 1.696
• 储存条件: 库房通风干燥低温
• 分子结构:

  1、 摩尔折射率：165.35

  2、 摩尔体积（cm³/mol）：429.3

  3、 等张比容（90.2K）：1257.7

  4、 表面张力（dyne/cm）：73.6

  5、 极化率（10-24cm3）：65.55

• 计算化学:

  1.疏水参数计算参考值（XlogP）:3.8

  2.氢键供体数量:3

  3.氢键受体数量:6

  4.可旋转化学键数量:5

  5.互变异构体数量:8

  6.拓扑分子极性表面积118

  7.重原子数量:43

  8.表面电荷:0

  9.复杂度:1230

  10.同位素原子数量:0

  11.确定原子立构中心数量:6

  12.不确定原子立构中心数量:0

  13.确定化学键立构中心数量:0

  14.不确定化学键立构中心数量:0

  15.共价键单元数量:1

• 更多:

  1性状：白色结晶性粉末。

  2熔点：215-218℃(分解)。

生物活性

• 描述: 溴隐亭是一种有效的多巴胺D2/D3受体激动剂,可将多巴胺D2受体与8.05±0.2的pKi结合。
• 相关类别:
  信号通路 >> G 蛋白偶联受体/G 蛋白 >> 多巴胺受体
  信号通路 >> 神经信号通路 >> 多巴胺受体
  研究领域 >> 神经疾病
• 靶点:

  pKi: 8.05±0.2 (dopamine D2 receptor)[1]

• 体外研究: 溴隐亭刺激pEC50为8.15±0.05的CHO细胞中表达的D2多巴胺受体[35S]-GTPγS结合[1]。溴隐亭也是脑一氧化氮合酶的强抑制剂。麦角生物碱溴隐亭(BKT)被发现是纯化神经型一氧化氮合酶(NOS)的强抑制剂(IC50=10±2μM),而它对诱导巨噬细胞NOS(IC50>100μM)的活性较差[2]。溴隐亭被发现可以抑制至少一种人类细胞色素P450酶的活性。溴隐亭是CYP3A4的有效抑制剂,其相互作用的IC50值为1.69μM[3]。
• 体内研究: 与对照组相比,溴隐亭(多巴胺激动剂)治疗组(2 mg/kg,i.p.)显示出显著的抗静止作用。当溴隐亭在最后一次7天MPE治疗30分钟后给药并接受FST时,与单独MPE治疗相比,该多巴胺能激动剂产生了显著的剂量依赖性增强MPE抗静止作用(200 mg/kg,p.o.)。溴隐亭(多巴胺激动剂)治疗组(2 mg/kg,i.p.)与对照组相比,不动时间显著减少。与单独使用MPE治疗相比,使用MPE(100和200 mg/kg,p.o.)预处理7天后服用溴隐亭显示出MPE抗静止作用的显著和剂量依赖性增强[4]。与假手术组相比,腹腔内注射溴隐亭可使CCI-IoN组的疼痛评分显著降低,且呈剂量依赖性(0.1 mg和1 mg/Kg),且持续6小时。最高剂量的溴隐亭导致最高评分降低(P<0.01)。作为阳性对照,使用SKF8129(DR1激动剂)。与假手术(注射生理盐水)相比,腹腔内给药导致SMA评分无显著增加。与假手术(注射生理盐水)相比,脑池内注射溴隐亭可显著降低SMA评分。溴隐亭作用持续20分钟。腹腔注射溴隐亭可导致CCI IoN？+？的SMA评分显著降低,且呈剂量依赖性？6-OHDA损伤组与假手术组比较。其作用持续6小时。服用SKF81297可增加痛觉超敏评分。与假手术组(生理盐水注射大鼠)相比,脑池内注射溴隐亭可显著降低SMA评分,其作用持续30分钟[5]。
• 激酶实验: 进行[35S]-GTPγS结合分析。细胞膜（25±75 ug）在30°C下，在含有0.1 mM二硫苏糖醇（DTT）和1 uM GDP以及体积为0.9 mL的药物的缓冲液B中培养30分钟。当添加[35S]-GTPγS（50±150 pM，最终浓度）（在100 uL缓冲液B中）以启动反应时，该预培养确保受试激动剂处于平衡状态。除非另有说明，否则将分析混合物再培养20分钟。通过快速过滤和结合放射性测定终止分析，如上述放射性配体结合分析所述。[35S]-GTPγS的总结合量小于添加量的20%[1]。
• 动物实验: 小鼠[4]选用瑞士小鼠（20-25克），雌雄各半（共150只）。甲磺酸溴隐亭被用作多巴胺受体（D2）激动剂。氟哌啶醇用蒸馏水稀释，蒸馏水用于注射载体。甲磺酸溴隐亭溶于一滴冰醋酸中，并在蒸馏水中定容。Imipramine溶于0.9%生理盐水中。在强迫游泳试验（FST）和尾部悬吊试验（TST）中，给小鼠组服用氟哌啶醇（0.1 mg/kg，i.p.）和甲磺酸溴隐亭（2 mg/kg，i.p.），持续7天。阳性对照组给予伊米帕明（10 mg/kg，p.o.）作为标准，持续7天。大鼠[5]使用成年雄性Sprague-Dawley大鼠（N=112275-325 g）。6-OHDA注射两周后，使用面罩用2%氟烷对动物进行短暂麻醉（<3分钟），并接受池内给药溴隐亭（7μg/kg溶于5μL溶媒中）或单独给药溶媒（5μL 0.9%生理盐水）。对于腹腔注射，我们使用溴隐亭（1 mg/kg）和SKF81297（3 mg/kg溶于0.9%生理盐水）浓度。恢复期（<2分钟）后，将大鼠置于观察区，由一名盲实验人员进行40分钟的周期测试。
• 参考文献:

  [1]. Gardner B, et al. Agonist action at D2(long) dopamine receptors: ligand binding and functional assays. Br J Pharmacol. 1998 Jul;124(5):978-84.

  [2]. Renodon A, et al. Bromocriptine is a strong inhibitor of brain nitric oxide synthase: possible consequences for the origin of its therapeutic effects.FEBS Lett. 1997 Apr 7;406(1-2):33-6.

  [3]. Wynalda MA, et al. Assessment of potential interactions between dopamine receptor agonists and various human cytochrome P450 enzymes using a simple in vitro inhibition screen. Drug Metab Dispos. 1997 Oct;25(10):1211-4.

  [4]. Rana DG, et al. Dopamine mediated antidepressant effect of Mucuna pruriens seeds in various experimental models of depression. Ayu. 2014 Jan;35(1):90-7.

  [5]. Dieb W, et al. Nigrostriatal dopaminergic depletion increases static orofacial allodynia. J Headache Pain. 2016;17:11.

毒性和生态

CHEMICAL IDENTIFICATION RTECS NUMBER : KE7625000 CHEMICAL NAME : Ergotaman-3',6',18-trione, 2-bromo-12'-hydroxy-2'-(1-methylethyl)-5'-(2-methylpr opyl)-, (5'-alpha)- CAS REGISTRY NUMBER : 25614-03-3 LAST UPDATED : 199703 DATA ITEMS CITED : 38 MOLECULAR FORMULA : C32-H40-Br-N5-O5 MOLECULAR WEIGHT : 654.68 HEALTH HAZARD DATA ACUTE TOXICITY DATA TYPE OF TEST : TDLo - Lowest published toxic dose ROUTE OF EXPOSURE : Oral SPECIES OBSERVED : Human - woman DOSE/DURATION : 6 mg/kg/60D-I TOXIC EFFECTS : Sense Organs and Special Senses (Olfaction) - effect, not otherwise specified TYPE OF TEST : LD50 - Lethal dose, 50 percent kill ROUTE OF EXPOSURE : Intravenous SPECIES OBSERVED : Rodent - rat DOSE/DURATION : 72 mg/kg TOXIC EFFECTS : Details of toxic effects not reported other than lethal dose value TYPE OF TEST : LD50 - Lethal dose, 50 percent kill ROUTE OF EXPOSURE : Oral SPECIES OBSERVED : Rodent - mouse DOSE/DURATION : >800 mg/kg TOXIC EFFECTS : Details of toxic effects not reported other than lethal dose value TYPE OF TEST : LD50 - Lethal dose, 50 percent kill ROUTE OF EXPOSURE : Unreported SPECIES OBSERVED : Rodent - mouse DOSE/DURATION : 200 mg/kg TOXIC EFFECTS : Details of toxic effects not reported other than lethal dose value TYPE OF TEST : LD50 - Lethal dose, 50 percent kill ROUTE OF EXPOSURE : Oral SPECIES OBSERVED : Rodent - rabbit DOSE/DURATION : >1 gm/kg TOXIC EFFECTS : Details of toxic effects not reported other than lethal dose value TYPE OF TEST : LD50 - Lethal dose, 50 percent kill ROUTE OF EXPOSURE : Intravenous SPECIES OBSERVED : Rodent - rabbit DOSE/DURATION : 12 mg/kg TOXIC EFFECTS : Details of toxic effects not reported other than lethal dose value TYPE OF TEST : TDLo - Lowest published toxic dose ROUTE OF EXPOSURE : Oral SPECIES OBSERVED : Rodent - rat DOSE/DURATION : 7 gm/kg/2Y-C TOXIC EFFECTS : Tumorigenic - Carcinogenic by RTECS criteria Reproductive - Tumorigenic effects - uterine tumors TYPE OF TEST : TDLo - Lowest published toxic dose ROUTE OF EXPOSURE : Oral DOSE : 2423 ug/kg SEX/DURATION : lactating female 3 week(s) post-birth TOXIC EFFECTS : Reproductive - Maternal Effects - other effects TYPE OF TEST : TDLo - Lowest published toxic dose ROUTE OF EXPOSURE : Oral DOSE : 1500 ug/kg SEX/DURATION : lactating female 9 day(s) post-birth TOXIC EFFECTS : Reproductive - Maternal Effects - postpartum TYPE OF TEST : TDLo - Lowest published toxic dose ROUTE OF EXPOSURE : Oral DOSE : 1500 ug/kg SEX/DURATION : lactating female 15 day(s) post-birth TOXIC EFFECTS : Reproductive - Maternal Effects - postpartum TYPE OF TEST : TDLo - Lowest published toxic dose ROUTE OF EXPOSURE : Oral DOSE : 1750 ug/kg SEX/DURATION : lactating female 21 day(s) post-birth TOXIC EFFECTS : Reproductive - Maternal Effects - postpartum TYPE OF TEST : TDLo - Lowest published toxic dose ROUTE OF EXPOSURE : Unreported DOSE : 21700 ug/kg SEX/DURATION : female 28 week(s) pre-mating female 1-21 day(s) after conception TOXIC EFFECTS : Reproductive - Specific Developmental Abnormalities - respiratory system TYPE OF TEST : TDLo - Lowest published toxic dose ROUTE OF EXPOSURE : Unreported DOSE : 3500 ug/kg SEX/DURATION : female 14 day(s) pre-mating female 1-21 day(s) after conception TOXIC EFFECTS : Reproductive - Specific Developmental Abnormalities - musculoskeletal system TYPE OF TEST : TDLo - Lowest published toxic dose ROUTE OF EXPOSURE : Unreported DOSE : 11900 ug/kg SEX/DURATION : female 77 day(s) pre-mating female 1-42 day(s) after conception TOXIC EFFECTS : Reproductive - Specific Developmental Abnormalities - urogenital system TYPE OF TEST : TDLo - Lowest published toxic dose ROUTE OF EXPOSURE : Unreported DOSE : 11200 ug/kg SEX/DURATION : female 44 day(s) pre-mating female 1-12 day(s) after conception TOXIC EFFECTS : Reproductive - Specific Developmental Abnormalities - craniofacial (including nose and tongue) TYPE OF TEST : TDLo - Lowest published toxic dose ROUTE OF EXPOSURE : Unreported DOSE : 2800 ug/kg SEX/DURATION : female 24-52 day(s) after conception TOXIC EFFECTS : Reproductive - Specific Developmental Abnormalities - body wall TYPE OF TEST : TDLo - Lowest published toxic dose ROUTE OF EXPOSURE : Subcutaneous DOSE : 70 mg/kg SEX/DURATION : female 13-19 day(s) after conception TOXIC EFFECTS : Reproductive - Effects on Newborn - behavioral TYPE OF TEST : TDLo - Lowest published toxic dose ROUTE OF EXPOSURE : Subcutaneous DOSE : 1950 ug/kg SEX/DURATION : female 5-15 day(s) after conception TOXIC EFFECTS : Reproductive - Fertility - other measures of fertility TYPE OF TEST : TDLo - Lowest published toxic dose ROUTE OF EXPOSURE : Subcutaneous DOSE : 5100 ug/kg SEX/DURATION : lactating female 3 day(s) post-birth TOXIC EFFECTS : Reproductive - Maternal Effects - postpartum TYPE OF TEST : TDLo - Lowest published toxic dose ROUTE OF EXPOSURE : Subcutaneous DOSE : 17500 ug/kg SEX/DURATION : male 35 day(s) pre-mating TOXIC EFFECTS : Reproductive - Paternal Effects - spermatogenesis (incl. genetic material, sperm morphology, motility, and count) Reproductive - Paternal Effects - testes, epididymis, sperm duct TYPE OF TEST : TDLo - Lowest published toxic dose ROUTE OF EXPOSURE : Subcutaneous DOSE : 88 mg/kg SEX/DURATION : female 1-22 day(s) after conception TOXIC EFFECTS : Reproductive - Fertility - pre-implantation mortality (e.g. reduction in number of implants per female; total number of implants per corpora lutea) Reproductive - Fertility - other measures of fertility TYPE OF TEST : TDLo - Lowest published toxic dose ROUTE OF EXPOSURE : Intramuscular DOSE : 8125 ug/kg SEX/DURATION : female 6-18 day(s) after conception TOXIC EFFECTS : Reproductive - Effects on Embryo or Fetus - extra-embryonic structures (e.g., placenta, umbilical cord) Reproductive - Effects on Embryo or Fetus - fetotoxicity (except death, e.g., stunted fetus) TYPE OF TEST : TDLo - Lowest published toxic dose ROUTE OF EXPOSURE : Subcutaneous DOSE : 84 mg/kg SEX/DURATION : lactating female 21 day(s) post-birth TOXIC EFFECTS : Reproductive - Effects on Newborn - weaning or lactation index (e.g., # alive at weaning per # alive at day 4) Reproductive - Effects on Newborn - growth statistics (e.g.%, reduced weight gain) TYPE OF TEST : TDLo - Lowest published toxic dose ROUTE OF EXPOSURE : Subcutaneous DOSE : 200 mg/kg SEX/DURATION : female 50 day(s) pre-mating TOXIC EFFECTS : Reproductive - Fertility - female fertility index (e.g. # females pregnant per # sperm positive females; # females pregnant per # females mated) TYPE OF TEST : TDLo - Lowest published toxic dose ROUTE OF EXPOSURE : Subcutaneous DOSE : 212 mg/kg SEX/DURATION : female 32 day(s) pre-mating female 21 day(s) after conception TOXIC EFFECTS : Reproductive - Maternal Effects - parturition TYPE OF TEST : TDLo - Lowest published toxic dose ROUTE OF EXPOSURE : Subcutaneous DOSE : 4 mg/kg SEX/DURATION : male 10 day(s) pre-mating TOXIC EFFECTS : Reproductive - Paternal Effects - prostate, seminal vesicle, Cowper's gland, accessory glands TYPE OF TEST : TDLo - Lowest published toxic dose ROUTE OF EXPOSURE : Oral DOSE : 750 ug/kg SEX/DURATION : female 43-48 day(s) after conception TOXIC EFFECTS : Reproductive - Fertility - abortion TYPE OF TEST : TDLo - Lowest published toxic dose ROUTE OF EXPOSURE : Intramuscular DOSE : 600 ug/kg SEX/DURATION : female 42-47 day(s) after conception TOXIC EFFECTS : Reproductive - Fertility - abortion TYPE OF TEST : TDLo - Lowest published toxic dose ROUTE OF EXPOSURE : Subcutaneous DOSE : 8 mg/kg SEX/DURATION : female 27-30 day(s) after conception TOXIC EFFECTS : Reproductive - Effects on Embryo or Fetus - fetotoxicity (except death, e.g., stunted fetus) Reproductive - Effects on Embryo or Fetus - other effects to embryo TYPE OF TEST : TDLo - Lowest published toxic dose ROUTE OF EXPOSURE : Subcutaneous DOSE : 400 ug/kg SEX/DURATION : male 50 day(s) pre-mating TOXIC EFFECTS : Reproductive - Paternal Effects - testes, epididymis, sperm duct TYPE OF TEST : TDLo - Lowest published toxic dose ROUTE OF EXPOSURE : Subcutaneous DOSE : 3 mg/kg SEX/DURATION : male 84 day(s) pre-mating TOXIC EFFECTS : Reproductive - Paternal Effects - prostate, seminal vesicle, Cowper's gland, accessory glands Reproductive - Paternal Effects - other effects on male TYPE OF TEST : TDLo - Lowest published toxic dose ROUTE OF EXPOSURE : Intramuscular DOSE : 75200 ug/kg SEX/DURATION : female 42-49 week(s) after conception TOXIC EFFECTS : Reproductive - Maternal Effects - parturition Reproductive - Maternal Effects - postpartum TYPE OF TEST : TDLo - Lowest published toxic dose ROUTE OF EXPOSURE : Intramuscular DOSE : 22400 ug/kg SEX/DURATION : female 42-44 week(s) after conception TOXIC EFFECTS : Reproductive - Maternal Effects - other effects Endocrine - estrogenic TYPE OF TEST : TDLo - Lowest published toxic dose ROUTE OF EXPOSURE : Intramuscular DOSE : 1 mg/kg SEX/DURATION : female 23 day(s) after conception TOXIC EFFECTS : Reproductive - Maternal Effects - parturition Reproductive - Effects on Newborn - viability index (e.g., # alive at day 4 per # born alive) MUTATION DATA TEST SYSTEM : Rodent - rat DOSE/DURATION : 4 mg/kg REFERENCE : CNREA8 Cancer Research. (Public Ledger Building, Suit 816, 6th & Chestnut Sts., Philadelphia, PA 19106) V.1- 1941- Volume(issue)/page/year: 36,2223,1976 *** NIOSH STANDARDS DEVELOPMENT AND SURVEILLANCE DATA *** NIOSH OCCUPATIONAL EXPOSURE SURVEY DATA : NOES - National Occupational Exposure Survey (1983) NOES Hazard Code - X6252 No. of Facilities: 9 (estimated) No. of Industries: 1 No. of Occupations: 1 No. of Employees: 339 (estimated) No. of Female Employees: 170 (estimated)

安全

• 危害码 (欧洲): Xn,Xi
• 风险声明 (欧洲): R20/21/22:Harmful by inhalation, in contact with skin and if swallowed .
• 安全声明 (欧洲): S45

合成路线

511-09-1 ~91% 25614-03-3

文献：Megyeri, Gabor; Keve, Tibor Synthetic Communications, 1989 , vol. 19, # 20 p. 3415 - 3430

2857-97-8 511-09-1 ~% 25614-03-3

文献：US4816587 A1, ;

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制备

由麦角隐亭和N-溴丁二酸亚胺反应得到。