盐酸Pirmenol

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。

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

IC50: 0.1 μM (IK.ACh)[1]

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]。

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]。

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。

[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.

尼日利亚菌素钠 | 4-氟-A-(4-氟苯基)-A-苯基-苯甲酰胺 | N-[4-[[1-[2-(6-甲基-2-吡啶基)乙基]-4-哌啶基]羰基]苯基]甲磺酰胺二盐酸盐 | 4-氨基吡啶 | 卡巴胆碱 | 人参皂苷Rg3 | 1-[(2-氯苯基)二苯甲基]-1H-吡唑 | 多非利特 | 5-(4-苯氧基丁氧基)补骨脂素(PAP-1) | 米诺地尔 | 氢溴酸达非那新 | 氟芬那酸 | 氢溴酸槟榔碱 | 马来酸氟吡汀 | 1-(2-羟基-5-(三氟甲基)苯基)-5-(三氟甲基)-1H-苯并[d]咪唑-2(3h)-酮

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