61477-94-9

• 常用中文名：盐酸Pirmenol
• 常用英文名：Pirmenol hydrochloride
• CAS号：61477-94-9
• 分子式：C₂₂H₃₁ClN₂O
• 分子量：374.94700
• 相关类别： 信号通路 G 蛋白偶联受体/G 蛋白 由mAChR
• 发布时间：2018-12-08 11:30:07
• 更新时间：2024-01-03 17:01:55
• Pirmenol hydrochloride 通过阻断毒蕈碱性受体来抑制 IK.ACh。Pirmenol 抑制 Carbachol 诱导的 IK.ACh,IC50 值为 0.1 μM。

名称

• 中文名: 4-[(2R,6s)-2,6-二甲基-1-哌啶]-1-苯基-1-吡啶-2-丁烷-1-醇盐酸盐
• 英文名: 4-[(2S,6R)-2,6-dimethylpiperidin-1-yl]-1-phenyl-1-pyridin-2-ylbutan-1-ol,hydrochloride
• 英文别名: Pirmenol hydrochloride monohydrate; pirmenol hydrochloride; Pirmenol hydrochloride (USAN); Pirmenol HCl; CI 845; 4-[(2R,6S)-2,6-dimethylpiperidin-1-yl]-1-phenyl-1-pyridin-2-ylbutan-1-ol hydrochloride; Pirmenol (hydrochloride)

物化性质

• 沸点: 499.6ºC at 760 mmHg
• 分子式: C₂₂H₃₁ClN₂O
• 分子量: 374.94700
• 闪点: 256ºC
• 精确质量: 374.21200
• PSA: 36.36000
• LogP: 5.10050
• 储存条件: -20°C

生物活性

• 描述: Pirmenol hydrochloride 通过阻断毒蕈碱性受体来抑制 IK.ACh。Pirmenol 抑制 Carbachol 诱导的 IK.ACh,IC50 值为 0.1 μM。
• 相关类别:
  信号通路 >> G 蛋白偶联受体/G 蛋白 >> 由mAChR
  信号通路 >> 神经信号通路 >> mAChR
  信号通路 >> 跨膜转运 >> 钾通道
  天然产物 >> 生物碱
  研究领域 >> 心血管疾病
• 靶点:

  IC50: 0.1 μM (IK.ACh)[1]

• 体外研究: Pirmenol以浓度依赖性方式抑制卡巴胆碱诱导的IK.ACh。 Pirmenol也抑制GTPγS诱导的电流,尽管抑制GTPγS诱导电流所需的Pirmenol浓度远高于抑制卡巴胆碱诱导的IK.ACh的浓度。 Pirmenol抑制GTPγS诱导电流的IC50为30μM。 Pirmenol对这些IK.ACh的抑制作用几乎是完全可逆的,并且在Pirmenol冲洗后再次出现外向电流。 Pirmenol对心房细胞中毒蕈碱乙酰胆碱受体操纵的K +电流(IK.ACh)和离体豚鼠心脏的实验性心房颤动。在分离的心房肌细胞中,Pirmenol浓度依赖性地抑制由卡巴胆碱诱导的IK.ACh或GTPγS的细胞内负载。在Langendorff灌注的心脏中,Pirmenol逆转了卡巴胆碱诱导的有效不应期和心房颤动阈值的降低[1]。
• 体内研究: 吡啶-甲醇衍生物盐酸Pirmenol是一种新型抗心律失常药。啮齿动物的单剂量研究表明po和iv LD50值之间有10到15倍的差异。在大鼠中,po LD50为359.9mg/kg,静脉LD50为23.6mg/kg。对于po和iv途径,小鼠LD50值分别为215.5和20.8mg/kg。对大鼠(2.5,5.0和7.5mg/kg)和狗(2.5,5和10mg/kg)进行4周的短期亚急性静脉毒性研究引起最小反应。狗的心脏影响包括药物相关的心率增加,QRS持续时间的增加,ST间期的缩短,没有心脏组织损伤的迹象和注射部位的轻微局部反应。口服,Pirmenol在接受25,50和100 mg/kg /天的大鼠中耐受13周,而5,10和15 mg/kg /日的狗在高水平下表现出抗胆碱能作用(粘膜干燥,身体震颤) )。仅在研究开始时心率显着加快,并且QRS变化具有广泛的个体差异。在这些物种中没有引起与药物相关的组织变化。在大鼠(50,100和150mg/kg)和兔(10,25和50mg/kg)中进行的畸形学研究显示对器官发生没有明显影响,但在大鼠中观察到150mg/kg的胚胎毒性[2]。
• 动物实验: 小鼠和大鼠[2]这些研究中使用的物种和菌株是：雄性小鼠，21-29克;大鼠，116-261克;纯种比格犬，6.8-12.4千克;和兔子，平均2.9千克。对于急性口服和静脉内研究和亚急性口服研究，盐酸Pirmenol，以下称为Pirmenol，以大约89％纯度的本体白色结晶化合物的形式提供。剂量是根据基础内容计算的。在急性研究中，Pirmenol通过管饲法给予2（小鼠）或2.5％（大鼠）的水溶液;静脉内给药，0.5（小鼠）或1％（大鼠）水溶液。在狗的口服亚急性研究中，它在明胶胶囊中给予，并且在大鼠中，将其与饮食混合以产生预期的剂量浓度。兔子通过胃内插管在5％水溶液中接受药物。对于亚急性iv研究，Pirmenol以无菌小瓶的形式提供，为1％溶液。在大鼠中，iv注射接近0.6mL / min，并且在狗中，药物通过输注泵以1mg / kg / min的速率施用。
• 参考文献:

  [1]. Watanabe Y, et al. Pirmenol inhibits muscarinic acetylcholine receptor-operated K+ current in the guinea pig heart. Eur J Pharmacol. 1997 Oct 29;338(1):71-4.

  [2]. Schardein JL, et al. Preclinical toxicology studies with a new antiarrhythmic agent: Pirmenol hydrochloride (CI-845). Toxicol Appl Pharmacol. 1980 Nov;56(2):294-301.

毒性和生态

CHEMICAL IDENTIFICATION RTECS NUMBER : UT4810000 CHEMICAL NAME : 2-Pyridinemethanol, alpha-(3-(2,6-dimethyl-1-piperidinyl)propyl)-alpha-ph enyl-, monohydrochloride, Z-(+-)- CAS REGISTRY NUMBER : 61477-94-9 LAST UPDATED : 199612 DATA ITEMS CITED : 12 MOLECULAR FORMULA : C22-H30-N2-O.Cl-H MOLECULAR WEIGHT : 375.00 WISWESSER LINE NOTATION : T6NTJ B1 F1 A3XQR&- BT6NJ &GH HEALTH HAZARD DATA ACUTE TOXICITY DATA TYPE OF TEST : LD50 - Lethal dose, 50 percent kill ROUTE OF EXPOSURE : Oral SPECIES OBSERVED : Rodent - rat DOSE/DURATION : 251 mg/kg TOXIC EFFECTS : Behavioral - convulsions or effect on seizure threshold Behavioral - changes in motor activity (specific assay) Lungs, Thorax, or Respiration - dyspnea TYPE OF TEST : LD50 - Lethal dose, 50 percent kill ROUTE OF EXPOSURE : Intravenous SPECIES OBSERVED : Rodent - rat DOSE/DURATION : 7900 ug/kg TOXIC EFFECTS : Behavioral - changes in motor activity (specific assay) Lungs, Thorax, or Respiration - dyspnea Lungs, Thorax, or Respiration - cyanosis TYPE OF TEST : LD50 - Lethal dose, 50 percent kill ROUTE OF EXPOSURE : Oral SPECIES OBSERVED : Rodent - mouse DOSE/DURATION : 159 mg/kg TOXIC EFFECTS : Behavioral - convulsions or effect on seizure threshold Behavioral - changes in motor activity (specific assay) Lungs, Thorax, or Respiration - dyspnea TYPE OF TEST : LD50 - Lethal dose, 50 percent kill ROUTE OF EXPOSURE : Intravenous SPECIES OBSERVED : Rodent - mouse DOSE/DURATION : 16 mg/kg TOXIC EFFECTS : Behavioral - changes in motor activity (specific assay) Lungs, Thorax, or Respiration - dyspnea Lungs, Thorax, or Respiration - cyanosis TYPE OF TEST : LDLo - Lowest published lethal dose ROUTE OF EXPOSURE : Oral SPECIES OBSERVED : Mammal - dog DOSE/DURATION : 120 mg/kg TOXIC EFFECTS : Behavioral - altered sleep time (including change in righting reflex) Behavioral - ataxia Gastrointestinal - nausea or vomiting TYPE OF TEST : LD - Lethal dose ROUTE OF EXPOSURE : Intravenous SPECIES OBSERVED : Mammal - dog DOSE/DURATION : >20 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 : 18200 mg/kg/1Y-C TOXIC EFFECTS : Behavioral - food intake (animal) Blood - changes in serum composition (e.g. TP, bilirubin, cholesterol) Nutritional and Gross Metabolic - weight loss or decreased weight gain TYPE OF TEST : TDLo - Lowest published toxic dose ROUTE OF EXPOSURE : Oral DOSE : 5800 mg/kg SEX/DURATION : female 15 day(s) pre-mating - 21 day(s) post-birth TOXIC EFFECTS : Reproductive - Effects on Newborn - growth statistics (e.g.%, reduced weight gain) TYPE OF TEST : TDLo - Lowest published toxic dose ROUTE OF EXPOSURE : Oral DOSE : 13 gm/kg SEX/DURATION : male 9 week(s) pre-mating female 2 week(s) pre-mating - 3 week(s) post-birth TOXIC EFFECTS : Reproductive - Maternal Effects - parturition Reproductive - Fertility - pre-implantation mortality (e.g. reduction in number of implants per female; total number of implants per corpora lutea) Reproductive - Effects on Newborn - growth statistics (e.g.%, reduced weight gain) TYPE OF TEST : TDLo - Lowest published toxic dose ROUTE OF EXPOSURE : Oral DOSE : 2800 mg/kg SEX/DURATION : female 15-21 day(s) after conception lactating female 21 day(s) post-birth TOXIC EFFECTS : Reproductive - Maternal Effects - other 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 : Oral DOSE : 650 mg/kg SEX/DURATION : female 6-18 day(s) after conception TOXIC EFFECTS : Reproductive - Maternal Effects - other effects MUTATION DATA TYPE OF TEST : Cytogenetic analysis TEST SYSTEM : Rodent - hamster Lung DOSE/DURATION : 1500 mg/L REFERENCE : MUREAV Mutation Research. (Elsevier Science Pub. B.V., POB 211, 1000 AE Amsterdam, Netherlands) V.1- 1964- Volume(issue)/page/year: 280,205,1992