(1R,15S)-17-ethyl-7-methoxy-3,13-diazapentacyclo[13.3.1.02,10.04,9.013,18]nonadeca-2(10),4(9),5,7-tetraene

• 分子结构分类: 有机化合物 - 生物碱及其衍生物 - 依波格型生物碱
• 英文名称: (1R,15S)-17-ethyl-7-methoxy-3,13-diazapentacyclo[13.3.1.02,10.04,9.013,18]nonadeca-2(10),4(9),5,7-tetraene
• 化学式: C₂₀H₂₆N₂O
• 分子量: 310.4
• InChiKey: HSIBGVUMFOSJPD-WBPAKMTCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  23
• 可旋转键数：
  2
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.6
• 拓扑面积：
  28.3
• 氢给体数：
  1
• 氢受体数：
  2

ADMET

代谢

伊博加因是一种具有潜在治疗鸦片和可卡因成瘾作用的活性生物碱。其主要代谢物通过在12位上进行O-脱甲基反应产生12-羟基伊博加胺。在本报告中，提出了证据表明在人类肝微粒体中观察到的伊博加因O-脱甲基反应主要由多态性表达的细胞色素P-4502D6（CYP2D6）催化。对来自人类混合肝微粒体的伊博加因O-脱甲基酶活性进行酶动力学检查，表明有两个（或更多）酶参与此反应：一个具有低KMapp（1.1 uM）的酶，另一个具有高KMapp（>200 uM）的酶。低KMapp活性占总内在清除率的>95%。来自三个个体捐赠者的肝微粒体显示出相似的酶动力学参数（低和高KM活性的平均KMapp分别为0.55 +/- 0.09 uM和310 +/- 10 microM）。然而，第四个看似CYP2D6表型不良代谢者的微粒体样本只具有高KMapp活性。在来自人类捐赠者的一组肝微粒体中，低KMapp伊博加因O-脱甲基酶活性与CYP2D6催化的布夫拉醇1'-羟基化酶活性相关，而与其他P450同种型特异性活性无关。奎尼丁，一种CYP2D6特异性抑制剂，抑制了伊博加因O-脱甲基酶（IC50 = 0.2 uM），而其他P450同种型特异性抑制剂并未抑制此活性。此外，在一组重组异源表达的人类P450同种型中，只有rCYP2D6具有显著的伊博加因O-脱甲基酶活性。因此，可以得出结论，伊博加因O-脱甲基酶由CYP2D6催化，且该同种型是人类伊博加因O-脱甲基化反应的主要酶。报告还讨论了这些发现的潜在药理影响。

Ibogaine is a psychoactive alkaloid that possesses potential as an agent to treat opiate and cocaine addiction. The primary metabolite arises via O-demethylation at the 12-position to yield 12-hydroxyibogamine. In this report, evidence is presented that the O-demethylation of ibogaine observed in human hepatic microsomes is catalyzed primarily by the polymorphically expressed cytochrome P-4502D6 (CYP2D6). An enzyme kinetic examination of ibogaine O-demethylase activity in pooled human liver microsomes suggested that two (or more) enzymes are involved in this reaction: one with a low KMapp (1.1 uM) and the other with a high KMapp (>200 uM). The low KMapp activity comprised >95% of total intrinsic clearance. Human liver microsomes from three individual donors demonstrated similar enzyme kinetic parameters (mean KMapp = 0.55 +/- 0.09 uM and 310 +/- 10 microM for low and high KM activities, respectively). However, a fourth human microsome sample that appeared to be a phenotypic CYP2D6 poor metabolizer possessed only the high KMapp activity. In hepatic microsomes from a panel of human donors, the low KMapp ibogaine O-demethylase activity correlated with CYP2D6-catalyzed bufuralol 1'-hydroxylase activity but not with other P450 isoform-specific activities. Quinidine, a CYP2D6-specific inhibitor, inhibited ibogaine O-demethylase (IC50 = 0.2 uM), whereas other P450 isoform-specific inhibitors did not inhibit this activity. Also, of a battery of recombinant heterologously expressed human P450 isoforms, only rCYP2D6 possessed significant ibogaine O-demethylase activity. Thus, it is concluded that ibogaine O-demethylase is catalyzed by CYP2D6 and that this isoform is the predominant enzyme of ibogaine O-demethylation in humans. The potential pharmacological implications of these findings are discussed.

来源:Hazardous Substances Data Bank (HSDB)

代谢

作者报告了在一例48岁的白人男性体内，主要代谢物为诺伊波加因的伊波加因的组织分布情况。该男性有药物滥用史，因摄入自毒藤Tabernanthe iboga根皮的毒物而在家中被发现死亡。使用完全验证的液相色谱-电喷雾质谱法对组织和液体中的伊波加因和诺伊波加因进行了量化。除了心脏组织外，所有被调查的基质中均发现了伊波加因和诺伊波加因。在脾脏、肝脏、大脑和肺中发现了最高的浓度。组织和锁骨下血液的浓度比分别为：伊波加因在脾脏、肝脏、大脑和肺中分别为1.78、3.75、1.16和4.64，诺伊波加因在脾脏、肝脏、大脑和肺中分别为0.83、2.43、0.90和2.69。在前列腺组织中发现了这两种药物非常低的浓度。伊波加因和诺伊波加因都分泌入胆汁并穿越血脑屏障。在大多数被研究的基质中检测到了另外四种化合物。其中一种被确认为伊波加胺。不幸的是，由于缺乏参考物质，作者无法确定另外三种化合物。其中两种可能归因于以下氧化产物：伊波特因和去甲氧基伊波特因。第三种化合物可能是伊波加林。

/The authors/ report ... the tissue distribution of ibogaine and noribogaine, the main metabolite of ibogaine, in a 48-year-old Caucasian male, with a history of drug abuse, found dead at his home after a poisoning involving the ingestion of root bark from the shrub Tabernanthe iboga. Ibogaine and noribogaine were quantified in tissues and fluids using a fully validated liquid chromatography-electrospray mass spectrometry method. Apart from cardiac tissue, ibogaine and noribogaine were identified in all matrices investigated. The highest concentrations were found in spleen, liver, brain, and lung. The tissue/subclavian blood concentration ratios averaged 1.78, 3.75, 1.16, and 4.64 for ibogaine and 0.83, 2.43, 0.90, and 2.69 for noribogaine for spleen, liver, brain, and lung, respectively. Very low concentrations of the two drugs were found in the prostatic tissue. Both ibogaine and noribogaine are secreted in the bile and cross the blood-brain barrier. Four other compounds were detected in most of the studied matrices. One of them was identified as ibogamine. Unfortunately, /the authors/ were not able to positively identify the other three compounds because of the unavailability of reference substances. Two of them could possibly be attributed to the following oxidation products: iboluteine and desmethoxyiboluteine. The third compound could be ibogaline.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

/SRP:/ 立即急救：确保已经进行了充分的中毒物清除。如果患者停止呼吸，开始人工呼吸，最好使用需求阀复苏器、袋阀面罩装置或口袋面罩，按训练操作。如有必要，执行心肺复苏。立即用缓慢流动的水冲洗受污染的眼睛。不要催吐。如果发生呕吐，让患者前倾或置于左侧（如果可能的话，头部向下）以保持呼吸道畅通，防止吸入。保持患者安静，维持正常体温。寻求医疗帮助。 /毒物A和B/

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

/SRP:/ 基本治疗：建立专利气道（如有需要，使用口咽或鼻咽气道）。如有必要，进行吸痰。观察呼吸不足的迹象，如有需要，辅助通气。通过非循环呼吸面罩以10至15升/分钟的速度给予氧气。监测肺水肿，如有必要，进行治疗……。监测休克，如有必要，进行治疗……。预防癫痫发作，如有必要，进行治疗……。对于眼睛污染，立即用水冲洗眼睛。在运输过程中，用0.9%的生理盐水（NS）持续冲洗每只眼睛……。不要使用催吐剂。对于摄入，如果患者能吞咽、有强烈的干呕反射且不流口水，则用温水冲洗口腔，并给予5毫升/千克，最多200毫升的水进行稀释……。在去污后，用干燥的无菌敷料覆盖皮肤烧伤……。/毒物A和B/

/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

/SRP:/ 高级治疗：对于无意识、严重肺水肿或严重呼吸困难的病人，考虑进行口咽或鼻咽气管插管以控制气道。使用气囊面罩装置的正压通气技术可能有益。考虑使用药物治疗肺水肿……。对于严重的支气管痉挛，考虑给予β激动剂，如沙丁胺醇……。监测心率和必要时治疗心律失常……。开始静脉输注D5W /SRP: "保持开放"，最小流量/。如果出现低血容量的迹象，使用0.9%的生理盐水（NS）或乳酸林格氏液。对于伴有低血容量迹象的低血压，谨慎给予液体。注意液体过载的迹象……。使用地西泮或劳拉西泮治疗癫痫……。使用丙美卡因氢氯化物协助眼部冲洗……。/毒物A和B/

/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 人类毒性摘录

/CASE REPORTS/ /The authors/报告了一名男子在摄入粉状伊博加根12小时后死亡的案例，通常人们因其兴奋和致幻特性而服用它。通过液-液提取后的GC-MS/MS方法，在摄入的粉末和受害者的体液中定量了伊博加因和伊博加胺。在现场取得的血样和尸检过程中取得的末梢血、尿液和胃液样本中测得的伊博加因浓度分别为0.65、1.27、1.7和53.5微克/毫升，而粉末中的伊博加含量为7.2%。此外，对生物样本的系统毒理分析显示，存在治疗浓度的地西泮和美沙酮。死亡归因于在同时摄入美沙酮和地西泮的情况下，摄入了大量伊博加。

/CASE REPORTS/ /The authors/ report the case of a man who died twelve hours after ingesting powdered iboga root, commonly taken for its stimulant and hallucinogenic properties. Ibogaine and ibogamine were quantified in the powder ingested and the victim's body fluids by GC-MS/MS after liquid-liquid extraction. The concentrations of ibogaine measured in the blood samples taken at the scene and in the peripheral blood, urine, and gastric fluid samples taken during the autopsy were 0.65, 1.27, 1.7, and 53.5 ug/mL, while the iboga content in the powder was 7.2%. Moreover, systematic toxicological analyses of biological samples showed the presence of diazepam and methadone in therapeutic concentrations. Death was attributed to the ingestion of a substantial quantity of iboga in the context of simultaneous methadone and diazepam consumption.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 人类毒性摘录

/病例报告/ 伊博格碱是一种天然生物碱，来源于雨林灌木Tabernanthe iboga的根部。已有暂时与伊博格碱使用相关的死亡案例。然而，尽管伊博格碱没有被批准作为治疗药物，且有证据表明它可能会干扰心脏节律，这种生物碱目前在替代医学中作为抗成瘾药物用于戒毒目的。我们报告了一个男性使用伊博格碱进行酒精戒毒治疗12-24小时后突然死亡的案例。尸检发现了肝硬化和重度脂肪浸润。伊博格碱的浓度是2 mg/L。讨论了伊博格碱使用的潜在风险，尤其是对于有病理医学背景的人。

/CASE REPORTS/ Ibogaine is a naturally occurring alkaloid derived from the roots of the rain forest shrub Tabernanthe iboga. Deaths have occurred temporarily related to the use of ibogaine. However, although not licensed as therapeutic drug, and despite evidence that ibogaine may disturb the rhythm of the heart, this alkaloid is currently used as an anti-addiction drug in alternative medicine for detoxification purposes. We report the case of a man who died suddenly 12-24 hr after ibogaine use for alcohol detoxification treatment. In the autopsy liver cirrhosis and heavy fatty infiltration was found. The concentration of ibogaine was 2 mg/L. The potential risks of ibogaine use, especially for persons with pathological medical background, are discussed.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

为了研究伊博格因这种潜在的抗成瘾生物碱的药代动力学特性，在大鼠静脉输注后长达3小时的时间内，对这种药物在血浆和组织中的水平进行了量化。在31-35分钟输注（20 mg/kg）后立即，平均血浆伊博格因水平为373 ng/mL；此后这些值迅速以双指数方式下降。7只动物中有5只的血浆时间过程与双室药代动力学模型非常吻合，α和β半衰期分别为7.3分钟和3.3小时。药物清除率估计为5.9 L/hr（n = 7）。输注结束时3小时后大脑、肝脏和肾脏中的伊博格因水平为143-170 ng/g，接近于模拟的外周药代动力学室值。然而，3小时后脂肪组织中的药物水平要高得多（3,328 ng/g），这意味着需要更复杂的药代动力学模型。血浆中伊博格因最初快速消失的机制可能包括代谢去甲基化以及重新分布到身体储存。脂肪组织对伊博格因的隔离可能是药物在体内持久存在的原因。这种持久性可能被本研究报告的β半衰期所低估。

To investigate the pharmacokinetic properties of ibogaine, a putatively anti-addictive alkaloid, levels of this drug were quantified in plasma and tissues for up to 3 hr following i.v. infusion in rats. Immediately following a 31-35 min infusion (20 mg/kg), mean plasma ibogaine levels were 373 ng/mL; these values declined rapidly thereafter in a biexponential manner. The plasma time course in 5 of 7 animals demonstrated an excellent fit to a two-compartment pharmacokinetic model, with alpha and beta half-lives of 7.3 min and 3.3 hr, respectively. Drug clearance was estimated to be 5.9 L/hr (n = 7). Ibogaine levels in brain, liver and kidney 3 hr after the end of drug infusion were 143-170 ng/g, close to simulated values for the peripheral pharmacokinetic compartment. However, 3-hr drug levels in adipose tissue were much higher (3,328 ng/g), implying the need for a more complex pharmacokinetic model. Mechanisms for the initial, rapid disappearance of plasma ibogaine are thought to include metabolic demethylation as well as redistribution to body stores. The sequestration of ibogaine by adipose tissue probably contributes to a protracted persistence of drug in the body. This persistence may be underestimated by the beta half-life reported in the present study.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

疑似具有抗成瘾作用的物质伊波加因在大鼠经腹腔（ip）和皮下（sc）给药后的血浆、大脑、肾脏、肝脏和脂肪中的分布进行了测量。腹腔给药一小时后（剂量为40 mg/kg），药物水平从106 ng/ml（血浆）到11,308 ng/g（脂肪）不等，皮下给药同一剂量后药物水平显著更高。给药12小时后，药物水平降低了10到20倍。这些结果提示：1）伊波加因在腹腔给药后受到显著的“首过效应”影响，表现为皮下给药后药物水平更高；2）伊波加因在脂肪组织中大量积累，与其亲脂性性质一致；3）药物在脂肪中的持久性可能是其作用持续时间长的原因。

The distribution of the putative anti-addictive substance ibogaine was measured in plasma, brain, kidney, liver and fat after ip and sc administration in rats. One hr after ip dosing (40 mg/kg), drug levels ranged from 106 ng/ml (plasma) to 11,308 ng/g (fat), with significantly higher values after sc administration of the same dose. Drug levels were 10-20 fold lower 12 hr after the same dose. These results suggest that: 1) ibogaine is subject to a substantial "first pass" effect after ip dosing, demonstrated by higher drug levels following the sc route, 2) ibogaine shows a large accumulation in adipose tissue, consistent with its lipophilic nature, and 3) persistence of the drug in fat may contribute to a long duration of action.

来源:Hazardous Substances Data Bank (HSDB)

吸收、分配和排泄

作者报告了在一例48岁的白人男性体内，主要代谢物为诺伊波加因的伊波加因的组织分布情况。该男性有药物滥用史，因摄入来自Tabernanthe iboga灌木的根皮而导致中毒，死在家中。使用完全验证的液相色谱-电喷雾质谱法对组织和液体中的伊波加因和诺伊波加因进行了量化。除了心脏组织外，所有被调查的基质中均发现了伊波加因和诺伊波加因。在脾脏、肝脏、大脑和肺中发现了最高浓度的药物。组织和锁骨下血液中药物浓度比值分别为：伊波加因在脾脏、肝脏、大脑和肺中分别为1.78、3.75、1.16和4.64；诺伊波加因在脾脏、肝脏、大脑和肺中分别为0.83、2.43、0.90和2.69。在前列腺组织中发现了两种药物的非常低浓度。伊波加因和诺伊波加因都分泌到胆汁中，并穿过血脑屏障。在大多数被研究的基质中检测到了另外四种化合物。其中一种被确认为伊波胺。不幸的是，由于缺乏参考物质，作者无法确定另外三种化合物。其中两种可能归因于以下氧化产物：伊波替宁和去甲氧基伊波替宁。第三种化合物可能是伊波加林。

/The authors/ report ... the tissue distribution of ibogaine and noribogaine, the main metabolite of ibogaine, in a 48-year-old Caucasian male, with a history of drug abuse, found dead at his home after a poisoning involving the ingestion of root bark from the shrub Tabernanthe iboga. Ibogaine and noribogaine were quantified in tissues and fluids using a fully validated liquid chromatography-electrospray mass spectrometry method. Apart from cardiac tissue, ibogaine and noribogaine were identified in all matrices investigated. The highest concentrations were found in spleen, liver, brain, and lung. The tissue/subclavian blood concentration ratios averaged 1.78, 3.75, 1.16, and 4.64 for ibogaine and 0.83, 2.43, 0.90, and 2.69 for noribogaine for spleen, liver, brain, and lung, respectively. Very low concentrations of the two drugs were found in the prostatic tissue. Both ibogaine and noribogaine are secreted in the bile and cross the blood-brain barrier. Four other compounds were detected in most of the studied matrices. One of them was identified as ibogamine. Unfortunately, /the authors/ were not able to positively identify the other three compounds because of the unavailability of reference substances. Two of them could possibly be attributed to the following oxidation products: iboluteine and desmethoxyiboluteine. The third compound could be ibogaline.

来源:Hazardous Substances Data Bank (HSDB)

文献信息

• NORIBOGAINE COMPOSITIONS
  申请人：Moriarty Robert M.

  公开号：US20130131046A1

  公开（公告）日：2013-05-23

  Disclosed are noribogaine compositions comprising a very high level of the 2(R), 4(S), 5(S), 6(S) and 18(R) enantiomer and not more than 0.5 wt % of ibogaine relative to the total amount of noribogaine.

  本发明涉及一种诺利波甘组合物，其包含非常高水平的2(R)，4(S)，5(S)，6(S)和18(R)对映体，相对于诺利波甘的总量，伊博甘的含量不超过0.5重量%。
• METHODS AND COMPOSITIONS FOR POTENTIATING THE ACTION OF OPIOID ANALGESICS USING IBOGA ALKALOIDS
  申请人：DemeRx, Inc.

  公开号：EP3845275A1

  公开（公告）日：2021-07-07

  Methods and compositions for potentiating the effect of an opioid analgesic in a patient undergoing or planning to undergo opioid analgesic therapy using a potentiating amount of iboga alkaloid or pharmaceutically acceptable salt and/or solvate thereof that does not prolong the patient's QT interval by more than about 50 milliseconds.

  用于增强正在或计划接受阿片类镇痛剂治疗的患者的阿片类镇痛剂效果的方法和组合物，使用的伊博格生物碱或其药学上可接受的盐和/或溶液的增效量不会使患者的QT间期延长约50毫秒以上。
• METHODS AND COMPOSITIONS FOR PREPARING AND PURIFYING NORIBOGAINE
  申请人：Mash Deborah C.

  公开号：US20140187655A1

  公开（公告）日：2014-07-03

  Disclosed are methods and compositions for purifying the non-addictive alkaloid noribogaine.
• METHODS FOR ACUTE AND LONG-TERM TREATMENT OF DRUG ADDICTION
  申请人：DemeRx, Inc.

  公开号：US20150231145A1

  公开（公告）日：2015-08-20

  This invention is directed to a method of treating opioid or opioid-like drug addiction, including acute and post-acute withdrawal symptoms, comprising treating an addicted patient with noribogaine at a dosage that provides an average serum concentration of about 50 ng/mL to about 850 ng/mL (AUC/24 h) under conditions where the QT interval prolongation does not exceed about 50 milliseconds.
• US8765737B1
  申请人：——

  公开号：US8765737B1

  公开（公告）日：2014-07-01