甲芬太尼 | 42045-86-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 中文名称: 甲芬太尼
• 英文名称: 3-methylfentanyl
• 英文别名: Mefentanyl；N-[3-methyl-1-(2-phenylethyl)piperidin-4-yl]-N-phenylpropanamide
• CAS: 42045-86-3
• 化学式: C₂₃H₃₀N₂O
• 分子量: 350.504
• InChiKey: MLQRZXNZHAOCHQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.5
• 重原子数：
  26
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  23.6
• 氢给体数：
  0
• 氢受体数：
  2

ADMET

代谢

阿片类药物3-甲基芬太尼，是一种强力并具有滥用潜力的芬太尼类设计药物，因此被《管制物质法》列管。为了规避这一规定，另一种设计型芬太尼——异芬太尼，在秘密实验室中合成并被德国警方查获。本研究的目的在于识别在大鼠尿液中3-甲基芬太尼和异芬太尼的I相和II相代谢物，确定参与它们初步代谢步骤的细胞色素P450（CYP）同工酶，并最终测试它们在尿液中的可检测性。利用液相色谱（LC）-线性离子阱-质谱（MS(n)）技术，可以识别出3-甲基芬太尼的9个I相代谢物和5个II相代谢物，以及异芬太尼的11个I相代谢物和4个II相代谢物。可以假设两种药物都经历了以下代谢步骤：N-脱烷基化随后是烷基和芳基部分的羟基化，丙酰胺侧链的羟基化随后氧化为相应的羧酸，最后是苯甲基部分的羟基化随后甲基化。此外，还可以观察到异芬太尼的N-氧化。所有羟基代谢物部分以葡萄糖苷酸形式排出。使用重组人同工酶，发现CYP2C19、CYP2D6、CYP3A4和CYP3A5参与了初步代谢步骤。我们的LC-MS(n)筛查方法允许在掺有尿液中检测到0.01 mg/L的3-甲基芬太尼和异芬太尼。然而，在大鼠给予疑似娱乐剂量后，尿液中无法检测到母药，但可以检测到它们的共同代谢物，因此这应该是尿液筛查的目标。

The opioid 3-methylfentanyl, a designer drug of the fentanyl type, was scheduled by the Controlled Substance Act due to its high potency and abuse potential. To overcome this regulation, isofentanyl, another designer fentanyl, was synthesized in a clandestine laboratory and seized by the German police. The aims of the presented study were to identify the phase I and phase II metabolites of 3-methylfentanyl and isofentanyl in rat urine, to identify the cytochrome P450 (CYP) isoenzymes involved in their initial metabolic steps, and, finally, to test their detectability in urine. Using liquid chromatography (LC)-linear ion trap-mass spectrometry (MS(n)), nine phase I and five phase II metabolites of 3-methylfentanyl and 11 phase I and four phase II metabolites of isofentanyl could be identified. The following metabolic steps could be postulated for both drugs: N-dealkylation followed by hydroxylation of the alkyl and aryl moiety, hydroxylation of the propanamide side chain followed by oxidation to the corresponding carboxylic acid, and, finally, hydroxylation of the benzyl moiety followed by methylation. In addition, N-oxidation of isofentanyl could also be observed. All hydroxy metabolites were partly excreted as glucuronides. Using recombinant human isoenzymes, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 were found to be involved in the initial metabolic steps. Our LC-MS(n) screening approach allowed the detection of 0.01 mg/L of 3-methylfentanyl and isofentanyl in spiked urine. However, in urine of rats after the administration of suspected recreational doses, the parent drugs could not be detected, but their common nor metabolite, which should therefore be the target for urine screening.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 毒性总结

身份和使用：3-甲基芬太尼（TMF）是一类受控物质。这种阿片类药物TMF是一种高药效和滥用潜力的设计药物，属于芬太尼类型。人体研究：2005-2006年，通过对爱沙尼亚吸毒者的死后法医毒理学研究，揭示了一场由于TMF引起的特殊流行性中毒事件。TMF主要通过静脉注射使用。同时使用的其他药物包括酒精、安非他明、苯二氮卓类药物和大麻，但很少使用其他阿片类药物。最近，报告显示，在欧洲国家，芬太尼和TMF都被作为海洛因的替代品销售。动物研究：向大鼠静脉注射（+）-顺-TMF（50微克/千克）产生了明显的僵直状态。

IDENTIFICATION AND USE: 3-Methylfentanil (TMF) is a Schedule I controlled substance. The opioid TMF is a designer drug of the fentanyl type with high potency and abuse potential. HUMAN STUDIES: An exceptional epidemic of poisonings due to TMF was revealed among Estonian drug users in 2005-2006 by post-mortem forensic toxicology. TMF was used predominantly by intravenous injection. Concomitant use of other drugs involved alcohol, amphetamines, benzodiazepines, and cannabis, but very rarely other opioids. More recently, reports indicate that both fentanyl and TMF have been marketed as a replacement for heroin in European countries. ANIMAL STUDIES: Intravenous administration of (+)-cis-TMF (50 ug/kg) to rats produced a pronounced catalepsy.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

三起由于3-甲基芬太尼导致的致命中毒案例被描述。在每个案例中，死亡是意外的，发生在注射了与安非他明、海洛因或其他药物混合的阿片类药物之后。受害者的年龄从30岁到41岁，高于芬兰海洛因中毒案例中通常发现的年龄。通过一种特定的串联质谱法首次测量到的顺式-3-甲基芬太尼的血药浓度范围为0.3至0.9微克/升（平均值为0.5微克/升）。这些值显著低于在致命中毒案例中报告的α-甲基芬太尼和芬太尼的水平。在欧洲靠近俄罗斯边境的地区已经报告了多次查获芬太尼及其类似物的情况。

Three fatal poisoning cases due to 3-methylfentanyl are described. In each case, the death was accidental and occurred after injection of the opioid combined with amphetamine, heroin, or other drugs. The victims' ages, ranging from 30 to 41 years, were higher than those typically found in heroin poisonings in Finland. The blood concentrations of cis-3-methylfentanyl, measured here for the first time by a specific tandem mass spectrometric method, ranged from 0.3 to 0.9 ug/L (mean 0.5 ug/L). These values are significantly lower than the levels reported for alpha-methylfentanyl and fentanyl in fatal poisonings. Repeated seizures of fentanyl and its analogs have been reported in Europe close to the Russian border.

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 相互作用

2005-2006年间，爱沙尼亚药物使用者中爆发了一种由高活性阿片类药物设计药物3-甲基芬太尼（TMF）引起的异常中毒疫情，通过法医毒理学的尸检揭示。通过液相色谱-串联质谱法对顺式-TMF、反式-TMF和芬太尼进行了定量分析。使用多技术方法进行了全面的毒理学分析。2005年和2006年分别确认了46起和71起与TMF相关的致命意外中毒事件。男性受害者的比例为91.5%，所有受害者的平均死亡年龄为26岁。TMF主要通过静脉注射使用。在纯TMF中毒和混合TMF中毒之间，顺式-TMF和反式-TMF的血药浓度没有显著差异。纯TMF病例中TMF立体异构体的平均组合浓度（1.9微克/升）比与芬太尼相关的致命事故中芬太尼的平均浓度低十倍以上。同时使用其他药物涉及酒精、安非他明、苯二氮卓类药物和大麻，但很少涉及其他阿片类药物。

An exceptional epidemic of poisonings due to the highly potent opioid designer drug 3-methylfentanyl (TMF) was revealed among Estonian drug users in 2005-2006 by post-mortem forensic toxicology. Quantitative analysis of cis-TMF, trans-TMF, and fentanyl was performed by liquid chromatography-tandem mass spectrometry. Comprehensive toxicological analysis was performed using a multi-technique approach. The number of TMF-related fatal accidental poisonings identified was 46 and 71 for 2005 and 2006, respectively. The proportion of male victims was 91.5% and the mean age of all victims was 26 years at death. TMF was used predominantly by intravenous injection. There was no significant difference in the blood concentrations of cis-TMF and trans-TMF between pure TMF poisonings and mixed TMF poisonings. The mean combined concentration of TMF stereoisomers among pure TMF cases (1.9 ug/L) was more than ten times lower than the mean fentanyl concentration in fentanyl-related fatalities. Concomitant use of other drugs involved alcohol, amphetamines, benzodiazepines, and cannabis, but very rarely other opioids.

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，让患者向前倾或将其置于左侧（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，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……。预见并处理癫痫发作，如有必要……。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，则用水冲洗口腔，并给予5毫升/千克，最多200毫升的水进行稀释……。/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 ... . /Poisons A and B/

来源:Hazardous Substances Data Bank (HSDB)

文献信息

• NOVEL OPIATE COMPOUNDS, METHODS OF MAKING AND METHODS OF USE
  申请人：Research Triangle Institute

  公开号：US20020165396A1

  公开（公告）日：2002-11-07

  The present application relates to novel opioid receptor antagonists and agonists, methods of making these compounds, and methods of use thereof.

  本申请涉及新型阿片受体拮抗剂和激动剂，制备这些化合物的方法以及它们的使用方法。
• [EN] NOVEL OPIATE COMPOUNDS, METHODS OF MAKING AND METHODS OF USE<br/>[FR] NOUVEAUX COMPOSES OPIACES ET LEURS PROCEDES DE PREPARATION ET D'UTILISATION
  申请人：RESEARCH TRIANGLE INSTITUTE

  公开号：WO1999045925A1

  公开（公告）日：1999-09-16

  (EN) The present invention relates to a class of nitrogen-containing heterocyclic compounds which bind to opioid receptors. The inventive compounds can be used to treat a variety of disease states which involve the opioid receptors.(FR) L'invention porte sur une classe de composés hétérocycliques azotés se fixant au récepteurs opioïdes et pouvant servir à traiter différentes maladies impliquant lesdits récepteurs.

  (中) 本发明涉及一类与阿片受体结合的含氮杂环化合物。这些创新化合物可用于治疗涉及阿片受体的各种疾病状态。(法) 本发明涉及一类与阿片受体结合的含氮杂环化合物，可用于治疗涉及阿片受体的各种疾病状态。
• Novel opiate compounds, methods of making and methods of use
  申请人：Research Triangle Institute

  公开号：US20020193602A1

  公开（公告）日：2002-12-19

  The present application relates to novel opioid receptor antagonists and agonists, methods of making these compounds, and methods of use thereof.

  本申请涉及新型阿片受体拮抗剂和激动剂，制备这些化合物的方法以及使用它们的方法。
• EP1061919A4
  申请人：——

  公开号：EP1061919A4

  公开（公告）日：2002-09-04
• NASAL DRUG PRODUCTS AND METHODS OF THEIR USE
  申请人：Adapt Pharma Limited

  公开号：US20170071851A1

  公开（公告）日：2017-03-16

  Drug products adapted for nasal delivery, comprising a pre-primed device filled with a pharmaceutical composition comprising an opioid receptor antagonist, are provided. Methods of treating opioid overdose or its symptoms with the inventive drug products are also provided.

表征谱图