methyl 2-[(2R,3S,12bR)-3-ethyl-8-methoxy-1,2,3,4,6,7,12,12b-octahydroindolo[2,3-a]quinolizin-2-yl]-3-methoxyprop-2-enoate

• 分子结构分类: 有机化合物 - 生物碱及其衍生物 - 柯楠因类生物碱
• 英文名称: methyl 2-[(2R,3S,12bR)-3-ethyl-8-methoxy-1,2,3,4,6,7,12,12b-octahydroindolo[2,3-a]quinolizin-2-yl]-3-methoxyprop-2-enoate
• 化学式: C₂₃H₃₀N₂O₄
• 分子量: 398.5
• InChiKey: LELBFTMXCIIKKX-IDHHARJASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  29
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  63.8
• 氢给体数：
  1
• 氢受体数：
  5

ADMET

代谢

Mitragyna speciosa（Kratom）是一种滥用药物。在监测尿液中其滥用情况时，必须考虑几种生物碱及其代谢物。在以前的研究中，可以使用液相色谱-串联质谱法（LC-MS(n)）在大鼠和人类尿液中鉴定出Mitragynine（MG）、其对映异构体Speciogynine（SG）、Paynantheine及其代谢物。在Kratom使用者的尿液中，除了MG和SG外，还检测到进一步的同分异构化合物。为了阐明MG和SG对映异构体Speciociliatine（SC）及其代谢物是否代表进一步的化合物，首先在大鼠给药纯生物碱后在大鼠尿液中鉴定了SC的I相和II相代谢物。然后，使用上述LC-MS(n)程序在Kratom使用者的尿液中筛选出已鉴定的大鼠代谢物。考虑到质量光谱和保留时间，可以确认SC及其代谢物迄今为止是人类尿液中未识别的同分异构体。总之，SC及其代谢物可以作为Kratom使用的进一步标志物，特别是通过摄入含有高量马来西亚植物M.speciosa果实的原材料或产品。

Mitragyna speciosa (Kratom) is ... a drug of abuse. When monitoring its abuse in urine, several alkaloids and their metabolites must be considered. In former studies, mitragynine (MG), its diastereomer speciogynine (SG), and paynantheine and their metabolites could be identified in rat and human urine using /Liquid Chromatography - Tandem Mass Spectometry/ (LC-MS(n)). In Kratom users' urines, besides MG and SG, further isomeric compounds were detected. To elucidate whether the MG and SG diastereomer speciociliatine (SC) and its metabolites represent further compounds, the phase I and II metabolites of SC were identified first in rat urine after the administration of the pure alkaloid. Then, the identified rat metabolites were screened for in the urine of Kratom users using the above-mentioned LC-MS(n) procedure. Considering the mass spectra and retention times, it could be confirmed that SC and its metabolites are so far the unidentified isomers in human urine. In conclusion, SC and its metabolites can be used as further markers for Kratom use, especially by consumption of raw material or products that contain a high amount of fruits of the Malaysian plant M. speciosa.

来源:Hazardous Substances Data Bank (HSDB)

代谢

这项研究的目标是使用液相色谱-线性离子阱质谱（liquid chromatography-linear ion trap mass SPectrometry）在固体相萃取（solid-phase extraction, SPE）后，识别大鼠和人体尿液中Mitragynine（MG）的一相和二相代谢物，特别是在高分辨率下，通过MSn模式提供详细的结构信息。识别出的七个一相代谢物表明MG通过在16位点的甲基酯水解、9-甲氧基和17-甲氧基的O-去甲基化，随后通过中间体醛，被氧化成羧酸或还原成醇，以及这些步骤的组合来进行代谢。在大鼠中，有四个代谢物额外与葡萄糖苷酸结合，一个与硫酸盐结合；而在人类中，有三个代谢物与葡萄糖苷酸结合，三个与硫酸盐结合。

... The aim of /this/ study is to identify the phase I and II metabolites of mitragynine (MG) in rat and human urine after solid-phase extraction (SPE) using liquid chromatography-linear ion trap mass spectrometry providing detailed structure information in the MSn mode particularly with high resolution. The seven identified phase I metabolites indicated that MG was metabolized by hydrolysis of the methylester in position 16, O-demethylation of the 9-methoxy group and of the 17-methoxy group, followed, via the intermediate aldehydes, by oxidation to carboxylic acids or reduction to alcohols and combinations of some steps. In rats, four metabolites were additionally conjugated to glucuronides and one to sulfate, but in humans, three metabolites to glucuronides and three to sulfates.

来源:Hazardous Substances Data Bank (HSDB)

代谢

在针对大鼠和人类研究主要卡痛生物碱Mitragynine（MG）时，在大鼠尿液和人类尿液中发现了几个去氢类似物，但在纯MG给药后的大鼠尿液中并未发现这些物质。问题是，这些化合物是否仅由人类从MG形成，还是由第二种丰富的卡痛生物碱Paynantheine（PAY）的MG去氢类似物形成的代谢物。因此，本研究旨在识别在大鼠尿液中对纯生物碱给药后PAY的I相和II相代谢物。这首先从卡痛叶中分离出来。液相色谱-线性离子阱质谱在MS(n)模式下提供了代谢物的高分辨率详细结构信息。除了PAY，还可以识别以下I相代谢物：9-O-去甲基PAY，16-羧基PAY，9-O-去甲基-16-羧基PAY，17-O-去甲基PAY，17-O-去甲基-16,17-二氢PAY，9,17-O-双去甲基PAY，9,17-O-双去甲基-16,17-二氢PAY，17-羧基-16,17-二氢PAY和9-O-去甲基-17-羧基-16,17-二氢PAY。这些代谢物表明，PAY通过与MG相同的途径被代谢。几种代谢物以葡萄糖苷酸或硫酸盐形式排出。在大鼠中的代谢研究表明，PAY及其代谢物与卡痛使用者尿液中检测到的与MG相关的去氢化合物相对应。总之，除了MG及其代谢物之外，PAY及其代谢物可能是卡痛滥用的进一步标志。

During studies on the main Kratom alkaloid mitragynine (MG) in rats and humans, several dehydro analogs could be detected in urine of Kratom users, which were not found in rat urine after administration of pure MG. Questions arose as to whether these compounds are formed from MG only by humans or whether they are metabolites formed from the second abundant Kratom alkaloid paynantheine (PAY), the dehydro analog of MG. Therefore, the aim of /this/ study was to identify the phase I and II metabolites of PAY in rat urine after administration of the pure alkaloid. This was first isolated from Kratom leaves. Liquid chromatography-linear ion trap mass spectrometry provided detailed structure information of the metabolites in the MS(n) mode particularly with high resolution. Besides PAY, the following phase I metabolites could be identified: 9-O-demethyl PAY, 16-carboxy PAY, 9-O-demethyl-16-carboxy PAY, 17-O-demethyl PAY, 17-O-demethyl-16,17-dihydro PAY, 9,17-O-bisdemethyl PAY, 9,17-O-bisdemethyl-16,17-dihydro PAY, 17-carboxy-16,17-dihydro PAY, and 9-O-demethyl-17-carboxy-16,17-dihydro PAY. These metabolites indicated that PAY was metabolized via the same pathways as MG. Several metabolites were excreted as glucuronides or sulfates. The metabolism studies in rats showed that PAY and its metabolites corresponded to the MG-related dehydro compounds detected in urine of the Kratom users. In conclusion, PAY and its metabolites may be further markers for a Kratom abuse in addition of MG and its metabolites.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

米特拉琴碱（MG）是从植物Mitragyna speciosa Korth中提取的主要生物碱成分，已知具有类似阿片样的活性。... 之前的研究表明阿片系统参与了MG在小鼠尾尖测试和热板测试中的镇痛活性。在这项研究中，为了澄清MG镇痛作用中涉及的阿片受体亚型，... 调查了选择性的mu-、delta-和kappa-阿片受体拮抗剂对MG通过脑室内注射（i.c.v.）引起的镇痛效果的影响。在小鼠的尾尖测试和热板测试中，选择性mu-阿片受体拮抗剂赛普迪明（1-10微克，i.c.v.）的联合给药和选择性mu1-阿片受体拮抗剂纳洛酮唑（1-3微克，i.c.v.）的预处理显著拮抗了MG（10微克，i.c.v.）和吗啡（MOR，3微克，i.c.v.）的镇痛活性。选择性delta-阿片受体拮抗剂纳曲吲哚（1-5纳克，i.c.v.）也阻断了MG（10微克，i.c.v.）的效果，而不影响MOR（3微克，i.c.v.）的镇痛作用。Nor-binaltorphimine，一种选择性kappa-阿片受体拮抗剂，在尾尖测试中显著减弱了MG（10微克，i.c.v.）的镇痛作用，但在热板测试中则没有，在拮抗选择性kappa-阿片受体激动剂U50,488H在两个测试中的镇痛效果的剂量（1微克，i.c.v.）下，而对MOR在任一测试中的镇痛作用没有影响。这些结果表明，脑室内注射MG引起的镇痛作用主要由mu-和delta-阿片受体亚型介导，且MG对小鼠脊髓上阿片受体亚型的选择性不同于MOR。

Mitragynine (MG), a major alkaloidal constituent extracted from the plant Mitragyna speciosa Korth, is known to exert an opioid-like activity. ... Previous study showed the involvement of opioid systems in the antinociceptive activity of MG in the tail-pinch and hot-plate tests in mice. In /this/ study, to clarify the opioid receptor subtypes involved in the antinociceptive action of MG, ... the effects of selective antagonists for mu-, delta- and kappa- opioid receptors on antinociception caused by the intracerebroventricular (i.c.v.) injection of MG in the tail-pinch and hot-plate tests in mice /were investigated/. The coadministration of a selective mu-opioid antagonist, cyprodime (1-10 ug, i.c.v.) and the pretreatment with a selective mu1-opioid antagonist naloxonazine (1-3 ug, i.c.v.) significantly antagonized the antinociceptive activities of MG (10 ug, i.c.v.) and morphine (MOR, 3 ug, i.c.v.) in the tail-pinch and hot-plate tests. Naltrindole (1-5 ng, i.c.v.), a selective delta-opioid antagonist, also blocked the effects of MG (10 ug, i.c.v.) without affecting MOR (3 ug, i.c.v.) antinociception. Nor-binaltorphimine, a selective kappa-opioid antagonist, significantly attenuated MG (10 ug, i.c.v.) antinociception in the tail-pinch test but not in the hot-plate test at the dose (1 ug, i.c.v.) that antagonized the antinociceptive effects of the selective kappa-opioid agonist U50,488H in both tests, while it had no effect on MOR antinociception in either tests. These results suggest that antinociception caused by i.c.v. MG is dominantly mediated by mu- and delta-opioid receptor subtypes, and that the selectivity of MG for the supraspinal opioid receptor subtypes differs from that of MOR in mice.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

...一名44岁男性，有酒精依赖和焦虑症病史，表现出对卡痛（kratom）的依赖，并出现了包括焦虑、不安、震颤、出汗和对该物质的渴望在内的戒断症状。通过逐步减少剂量的二氢可待因（dihydrocodeine）和洛非西定（lofexidine）的治疗方案，有效地治疗了主观和客观上的类阿片戒断现象，戒断过程相对短暂且温和。文献中关于监督下卡痛依赖的解毒和药物治疗的报告很少。...本案例的观察支持了卡痛依赖综合症是由于短效阿片受体激动剂活动的观点，并表明二氢可待因和洛非西定在支持解毒方面是有效的。/卡痛/

... A case of kratom dependence /is described/ in a 44-year-old man with a history of alcohol dependence and anxiety disorder. He demonstrated dependence on kratom with withdrawal symptoms consisting of anxiety, restlessness, tremor, sweating and cravings for the substance. A reducing regime of dihydrocodeine and lofexidine proved effective in treating subjective and objective measures of opioid-like withdrawal phenomena, and withdrawal was relatively short and benign. There are only few reports in the literature of supervised detoxification and drug treatment for kratom dependence. ... Observations /in this case/ support the idea that kratom dependence syndrome is due to short-acting opioid receptor agonist activity, and suggest that dihydrocodeine and lofexidine are effective in supporting detoxification. /Kratom/

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和。如果患者停止呼吸，请开始人工呼吸，最好使用需求阀复苏器、球囊阀面罩设备或口袋面罩，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。如果患者呕吐，让患者身体前倾或将其置于左侧（如果可能，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。寻求医疗救助。 /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，协助通气。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，并在必要时进行治疗……。监测休克，并在必要时进行治疗……。预期可能出现癫痫，并在必要时进行治疗……。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，如果患者能够吞咽、有强烈的呕吐反射且不流口水，则用水冲洗口腔，并给予5毫升/千克，最多200毫升的水进行稀释……。在去污染后，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……。 /Poisons A and 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)

吸收、分配和排泄

LC-MS/MS分析...被应用于量化在大鼠（每次采样时间点n=8）单次口服20 mg/kg剂量后血浆样本中的 mitragynine。得到了以下药代动力学参数（平均值）：最大血浆浓度：424 ng/mL；达到最大血浆浓度的时间：1.26小时；消除半衰期：3.85小时，表观总清除率：6.35 L/hr/kg，以及表观分布容积：37.90 L/kg。

... LC-MS/MS analysis... was applied to quantify mitragynine in plasma samples of rats (n=8 per sampling time) treated with a single oral dose of 20 mg/kg. The following pharmacokinetic parameters were obtained (mean): maximum plasma concentration: 424 ng/mL; time to reach maximum plasma concentration: 1.26 hr; elimination half-life: 3.85 hr, apparent total clearance: 6.35 L/hr/kg, and apparent volume of distribution: 37.90 L/kg.

来源:Hazardous Substances Data Bank (HSDB)