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乌头碱

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乌头碱
IUPAC名
8-(acetyloxy)-20-ethyl-3α,13,15-trihydroxy-1α,6α,16β-trimethoxy-4-(methoxymethyl)aconitan-14α-yl benzoate
别名 Acetylbenzoylaconine
乙酰苯甲酰阿康碱
识别
CAS号 302-27-2  checkY
PubChem 245005
ChemSpider 214292
SMILES
 
  • COC[C@]12CN(C)[C@@H]3[C@H]4[C@H](OC)C1[C@@]3([C@H](C[C@H]2O)OC)[C@@H]5C[C@]6(O)[C@@H](OC)[C@H](O)[C@@]4(OC(C)=O)[C@H]5C6OC(=O)c7ccccc7
ChEBI 2430
KEGG C06091
IUPHAR配体 2617
性质
化学式 C34H47NO11
摩尔质量 645.74 g·mol−1
外观 固体
熔点 203 °C（476 K）
溶解性（水） H2O: 0.3 mg/mL

乙醇: 35 mg/mL

危险性
GHS危险性符号
《全球化学品统一分类和标签制度》（简称“GHS”）中有毒物质的标签图案
GHS提示词 Danger
H-术语 H300, H330
P-术语 P260, P264, P270, P271, P284, P301+310, P304+340, P310, P320, P321, P330, P403+233, P405, P501
性质
化学式 C34H47NO11
摩尔质量 645.73708 g·mol⁻¹
危险性
NFPA 704
0
4
0
 
若非注明，所有数据均出自标准状态（25 ℃，100 kPa）下。

乌头碱（英语：aconitine）是一种生物碱毒素。是常用中药乌头属中所含有的一种化学物质，具强烈毒性,口服0.2mg左右即能使人中毒，3-5mg即可致死。[1]民间常用草乌、川乌等植物来泡制药酒，但这种药酒可能是极端危险的，也经常因此出现中毒甚至死亡的情况。[2][3]

用途

乌头碱以前被用作解热药和镇痛药，但在草药中的应用仍然有限。狭窄的治疗指数使计算合适的剂量很困难。[4]

结构和反应性

附子属和翠雀属植物的生物活性分离物被归类为去甲二萜生物碱。[5]根据C18碳的存在与否进一步细分。[6]乌头碱是一种C19去甲二萜生物碱，因为它含有C18。乌头碱几乎不溶于水，但极易溶于有机溶剂，例如氯仿或乙醚。[7][8]如果酒精浓度足够高，乌头碱也可溶于乙醇和水的混合物中。

像许多其他生物碱一样，乌头碱六元环的碱性氮很容易形成盐和离子，使其对极性和亲脂性结构过血脑屏障。[9]

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The acetoxyl group at the c8 position can readily be replaced by a methoxy group, by heating aconitine in methanol, to produce a 8-deacetyl-8-O-methyl derivatives.[10] If aconitine is heated in its dry state, it undergoes a pyrolysis to form pyroaconitine ((1α,3α,6α,14α,16β)-20-ethyl-3,13-dihydroxy-1,6,16-trimethoxy-4-(methoxymethyl)-15-oxoaconitan-14-yl benzoate) with the chemical formula C32H43NO9.[11][12]

作用

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Aconitine can interact with the voltage-dependent sodium-ion channels, which are proteins in the cell membranes of excitable tissues, such as cardiac and skeletal muscles and neurons. These proteins are highly selective for sodium ions. They open very quickly to depolarize the cell membrane potential, causing the upstroke of an action potential. Normally, the sodium channels close very rapidly, but the depolarization of the membrane potential causes the opening (activation) of potassium channels and potassium efflux, which results in repolarization of the membrane potential.

Aconitine binds to the channel at the neurotoxin binding site 2 on the alpha subunit.[13] This binding results in a sodium-ion channel that stays open longer. Aconitine suppresses the conformational change in the sodium-ion channel from the active state to the inactive state. The membrane stays depolarized due to the constant sodium influx (which is 10–1000-fold greater than the potassium efflux). As a result, the membrane cannot be repolarized. The binding of aconitine to the channel also leads to the channel to change conformation from the inactive state to the active state at a more negative voltage.[14] In neurons, aconitine increases the permeability of the membrane for sodium ions, resulting in a huge sodium influx in the axon terminal. As a result, the membrane depolarizes rapidly. Due to the strong depolarization, the permeability of the membrane for potassium ions increases rapidly, resulting in a potassium reflux to release the positive charge out of the cell. Not only the permeability for potassium ions but also the permeability for calcium ions increases as a result of the depolarization of the membrane. A calcium influx takes place. The increase of the calcium concentration in the cell stimulates the release of the neurotransmitter acetylcholine into the synaptic cleft. Acetylcholine binds to acetylcholine receptors at the postsynaptic membrane to open the sodium-channels there, generating a new action potential.

Research with mouse nerve-hemidiaphragm muscle preparation indicate that at low concentrations (<0.1 μM) aconitine increases the electrically evoked acetylcholine release causing an induced muscle tension.[15] Action potentials are generated more often at this concentration. At higher concentration (0.3–3 μM) aconitine decreases the electrically evoked acetylcholine release, resulting in a decrease in muscle tension. At high concentration (0.3–3 μM), the sodium-ion channels are constantly activated, transmission of action potentials is suppressed, leading to non-excitable target cells or paralysis.

合成

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Aconitine is biosynthesized by the monkshood plant via the terpenoid biosynthesis pathway (MEP chloroplast pathway).[16] Approximately 700 naturally occurring C19-diterpenoid alkaloids have been isolated and identified, but the biosynthesis of only a few of these alkaloids are well understood.[17]

Likewise, only a few alkaloids of the aconitine family have been synthesized in the laboratory. In particular, despite over one hundred years having elapsed since its isolation, the prototypical member of its family of norditerpenoid alkaloids, aconitine itself, represents a rare example of a well-known natural product that has yet to succumb to efforts towards its total synthesis. The challenge that aconitine poses to synthetic organic chemists is due to both the intricate interlocking hexacyclic ring system that make up its core and the elaborate collection of oxygenated functional groups at its periphery. A handful of simpler members of the aconitine alkaloids, however, have been prepared synthetically. In 1971, the Weisner group discovered the total synthesis of talatisamine (a C19-norditerpenoid).[18] In the subsequent years, they also discovered the total syntheses of other C19-norditerpenoids, such as chasmanine,[19] and 13-deoxydelphonine.[20]

Schematic for the syntheses of Napelline Deoxydelphonine, and Talatisamine Wiesner Syntheses of Napelline Deoxydelphonine, and Talatisamine

The total synthesis of napelline (Scheme a) begins with aldehyde 100.[18] In a 7 step process, the A-ring of napelline is formed (104). It takes another 10 steps to form the lactone ring in the pentacyclic structure of napelline (106). An additional 9 steps creates the enone-aldehyde 107. Heating in methanol with potassium hydroxide causes an aldol condensation to close the sixth and final ring in napelline (14). Oxidation then gives rise to diketone 108 which was converted to (±)-napelline (14) in 10 steps.

A similar process is demonstrated in Wiesner's synthesis of 13-desoxydelphinone (Scheme c).[19] The first step of this synthesis is the generation of a conjugated dienone 112 from 111 in 4 steps. This is followed by the addition of a benzyl vinyl ether to produce 113. In 11 steps, this compound is converted to ketal 114. The addition of heat, DMSO and o-xylene rearranges this ketol (115), and after 5 more steps (±)-13-desoxydelphinone (15) is formed.

Lastly, talatisamine (Scheme d) is synthesized from diene 116 and nitrile 117.[20] The first step is to form tricycle 118 in 16 steps. After another 6 steps, this compound is converted to enone 120. Subsequently, this allene is added to produce photoadduct 121. This adduct group is cleaved and rearrangement gives rise to the compound 122. In 7 steps, this compound forms 123, which is then rearranged, in a similar manner to compound 114, to form the aconitine-like skeleton in 124. A racemic relay synthesis is completed to produce talatisamine (13).

More recently, the laboratory of the late David Y. Gin completed the total syntheses of the aconitine alkaloids nominine[21] and neofinaconitine.[22]

代谢

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Aconine: an amorphous, bitter, non-poisonous alkaloid, derived from the decomposition of aconitine

Aconitine is metabolized by cytochrome P450 isozymes (CYPs). There has been research in 2011 in China to investigate in-depth the CYPs involved in aconitine metabolism in human liver microsomes.[23] It has been estimated that more than 90 percent of currently available human drug metabolism can be attributed to eight main enzymes (CYP 1A2, 2C9, 2C8, 2C19, 2D6, 2E1, 3A4, 3A5).[24] The researchers used recombinants of these eight different CYPs and incubated it with aconitine. To initiate the metabolism pathway the presence of NADPH was needed. Six CYP-mediated metabolites (M1–M6) were found by liquid chromatography, these six metabolites were characterized by mass-spectrometry. The six metabolites and the involved enzymes are summarized in the following table:

Metabolite Name Involved CYPs
M1 O-Demethyl-aconitine CYP3A4, CYP3A5, CYP2D6, CYP2C8
M2 16-O-Demethyl-aconitine CYP3A4, CYP3A5, CYP2D6, CYP2C9
M3 N-deethyl-aconitine CYP3A4, CYP3A5, CYP2D6, CYP2C9
M4 O-didemethyl-aconitine CYP3A5, CYP2D6
M5 3-Dehydrogen-aconitine CYP3A4, CYP3A5
M6 Hydroxyl-aconitine CYP3A5, CYP2D6

Selective inhibitors were used to determine the involved CYPs in the aconitine metabolism. The results indicate that aconitine was mainly metabolized by CYP3A4, 3A5 and 2D6. CYP2C8 and 2C9 had a minor role to the aconitine metabolism, whereas CYP1A2, 2E1 and 2C19 did not produce any aconitine metabolites at all. The proposed metabolic pathways of aconitine in human liver microsomes and the CYPs involved to it are summarized in the table above.

诊断和治疗

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For the analysis of the Aconitum alkaloids in biological specimens such as blood, serum and urine, several GC-MS methods have been described. These employ a variety of extraction procedures followed by derivatisation to their trimethylsilyl derivatives. New sensitive HPLC-MS methods have been developed as well, usually preceded by SPE purification of the sample.[25] The antiarrhythmic drug lidocaine has been reported to be an effective treatment of aconitine poisoning of a patient. Considering the fact that aconitine acts as an agonist of the sodium channel receptor, antiarrhythmic agents which block the sodium channel (Vaughan-Williams' classification I) might be the first choice for the therapy of aconitine induced arrhythmias.[26] Animal experiments have shown that the mortality of aconitine is lowered by tetrodotoxin. The toxic effects of aconitine were attenuated by tetrodotoxin, probably due to their mutual antagonistic effect on excitable membranes.[27] Also paeoniflorin seems to have a detoxifying effect on the acute toxicity of aconitine in test animals. This may result from alternations of pharmacokinetic behavior of aconitine in the animals due to the pharmacokinetic interaction between aconitine and paeoniflorin.[28] In addition, in emergencies, one can wash the stomach using either tannic acid or powdered charcoal. Heart stimulants such as strong coffee or caffeine may also help until professional help is available.[29]

著名中毒事件

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During the Indian Rebellion of 1857, a British detachment was the target of attempted poisoning with aconitine by the Indian regimental cooks. The plot was thwarted by John Nicholson who, having detected the plot, interrupted the British officers just as they were about to consume the poisoned meal. The chefs refused to taste their own preparation, whereupon it was force-fed to a monkey who "expired on the spot". The cooks were hanged.

Aconitine was the poison used by George Henry Lamson in 1881 to murder his brother-in-law in order to secure an inheritance. Lamson had learned about aconitine as a medical student from professor Robert Christison, who had taught that it was undetectable—but forensic science had improved since Lamson's student days.[30][31][32]

Rufus T. Bush, American industrialist and yachtsman, died on September 15, 1890, after accidentally taking a fatal dose of aconite.

In 1953 aconitine was used by a Soviet biochemist and poison developer, Grigory Mairanovsky, in experiments with prisoners in the secret NKVD laboratory in Moscow. He admitted killing around 10 people using the poison.[33]

In 2004 Canadian actor Andre Noble died from aconitine poisoning. He accidentally ate some monkshood while he was on a hike with his aunt in Newfoundland.

In 2009 Lakhvir Singh of Feltham, west London, used aconitine to poison the food of her ex-lover Lakhvinder Cheema (who died as a result of the poisoning) and his current fiancée Aunkar Singh. Singh received a life sentence with a 23-year minimum for the murder on February 10, 2010.[34]

流行文化

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乌头碱是古代世界最受欢迎的毒药。普布利乌斯·奥维修斯·纳索提到了众所周知的继母不喜欢继子的问题，他写道：

Lurida terribiles miscent aconita novercae.[35]

Fearsome stepmothers mix lurid aconites.

Aconitine was also made famous by its use in Oscar Wilde's 1891 story "Lord Arthur Savile's Crime". Aconite also plays a prominent role in James Joyce's Ulysses, in which the father to protagonist Leopold Bloom used pastilles of the chemical to commit suicide. Aconitine poisoning plays a key role in the murder mystery Breakdown by Jonathan Kellerman (2016). In Twin Peaks (season 3) Part 13, aconitine is suggested to poison the main character.[36]

Monk's Hood is the name of the third Cadfael Novel written in 1980 by Ellis Peters. The novel was made into an episode of the well known television series Cadfael starring Derek Jacobi.

毒性

乌头碱的毒性作用已在多种动物身上进行了测试有效，包括哺乳动物（狗、猫、豚鼠、小鼠、大鼠和兔子）、鸽、青蛙。观察到的毒性作用有：局部麻醉、腹泻、抽搐、心律失常、死亡。[37][38]

根据对人类附子中毒的不同报导的回顾，观察到以下临床特征：[4]

乌头碱中毒的最初症状出现在口服后约20分钟至2小时，包括感觉异常、出汗、恶心。这会导致严重的呕吐、绞痛性腹泻、剧烈疼痛，然后骨骼肌麻痹。威胁生命的心律失常，包括室性心动过速、心室颤动，会因呼吸麻痹或心脏骤停而死亡。[25]

小鼠的LD50值为口服 1 mg/kg、静脉 0.100 mg/kg、腹膜 0.270 mg/kg 和皮下 0.270 mg/kg。小鼠的最低致死量（LDLo）为口服 1 mg/kg 和腹腔 0.100 mg/kg。小鼠的最低中毒量（TDLo）为 0.0549 mg/kg 皮下注射。大鼠静脉注射的LD50值为 0.064 mg/kg。大鼠的LDLo为静脉注射 0.040 mg/kg和腹腔 0.250 mg/kg。大鼠的肠胃TDLo为 0.040 mg/kg。有关更多参见下表：LD50表示平均致死量；LDLo是指最低致死量；TDLo表示最低中毒量。[38]

物种 测试 路线 剂量（mg/kg） 毒性
人类 LDLo 口服 0.028 行为：兴奋

胃肠道：运动亢进、腹泻、其他变化

人类 LDLo 口服 0.029 除致死剂量值外未报告详情毒性作用
猫 LD50 静脉 0.080 行为：抽搐或对癫痫发作阈值的影响
猫 LDLo 皮下 0.100 除致死剂量值外未报告详情毒性作用
豚鼠 LD50 静脉 0.060 行为：抽搐或对癫痫发作阈值的影响
豚鼠 LDLo 皮下 0.050 除致死剂量值外未报告详情毒性作用
豚鼠 LDLo 静脉 0.025 心脏：心律失常（包括传导改变）
小鼠 LD50 腹腔 0.270 除致死剂量值外未报告详情毒性作用
小鼠 LD50 静脉 0.100 感觉器官和特殊感觉（眼睛）：流泪

行为：抽搐或对癫痫发作阈值的影响
肺、胸：呼吸困难

小鼠 LD50 口服 1 除致死剂量值外未报告详情毒性作用
小鼠 LD50 皮下 0.270 除致死剂量值外未报告详情毒性作用
小鼠 LDLo 腹腔 0.100 除致死剂量值外未报告详情毒性作用
小鼠 LDLo 口服 1 行为：抽搐或对癫痫发作阈值的影响

心脏：心律失常（包括传导改变）
胃肠道：运动亢进、腹泻

小鼠 TDLo 皮下 0.0549 周围神经和感觉：局部麻醉

行为：镇痛

兔子 LDLo 皮下 0.131 除致死剂量值外未报告详情毒性作用
大鼠 LD50 静脉 0.080 行为：抽搐或对癫痫发作阈值的影响
大鼠 LD50 静脉 0.064 除致死剂量值外未报告详情毒性作用
大鼠 LDLo 腹腔 0.250 心脏：其他变化

肺、胸：呼吸困难

大鼠 LDLo 静脉 0.040 心脏：心律失常（包括传导改变）
大鼠 TDLo 肠外 0.040 心脏：心律失常（包括传导改变）
青蛙 LDLo 皮下 0.586 除致死剂量值外未报告详情毒性作用
鸽子 LDLo 皮下 0.066 除致死剂量值外未报告详情毒性作用

对于人类，1969 年报导的最低口服致死剂量为 28 μg/kg。

乌头碱（草乌、川乌）中毒在急诊及内科中常见，多因服用自制中药及自制药膳不当所致。[39]

它主要使迷走神经兴奋，对周围神经损害临床主要表现为口舌及四肢麻木，全身紧束感等，通过兴奋迷走神经而降低窦房结的自律性，引起异位起搏点的自律性增高而引起各心律失常，损害心肌。

临床作用

本品具有镇痛作用，临床上用于缓解癌痛，尤其适用于消化系统癌痛；外用时能麻痹周围神经末梢，产生局部麻醉和镇痛作用；有消炎作用，本品毒性极大，能兴奋麻痹感觉神经和中枢神经，兴奋心脏迷走神经，直接毒害心肌细胞。还有发汗作用。[来源请求]

参考文献

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外部链接

吲哚：
苯乙胺：
嘌呤：
哌啶：
吡咯：
喹啉：
异喹啉：
莨菪烷：
萜类：
甜菜碱：
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