1-戊基-3-(1-萘甲酰基)吲哚 | 209414-07-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 中文名称: 1-戊基-3-(1-萘甲酰基)吲哚
• 中文别名: 萘-1-基(1-戊基-1H-吲哚-3-基)甲酮；1-萘基-(1-戊基吲哚-3-基)甲酮
• 英文名称: 1-pentyl-3-(1-naphthoyl)indole
• 英文别名: JWH-018；1-naphthalenyl(1-pentyl-1H-indol-3-yl)methanone；naphthalen-1-yl-(1-pentylindol-3-yl)methanone；(1-pentyl-1H-indol-3-yl)-1-naphthalenylmethanone；naphthalen-1-yl(1-pentyl-1H-indol-3-yl)methanone；3-(naphthalene-1-carbonyl)-1-pentyl-1H-indole
• CAS: 209414-07-3
• 化学式: C₂₄H₂₃NO
• 分子量: 341.453
• InChiKey: JDNLPKCAXICMBW-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.3
• 重原子数：
  26
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  22
• 氢给体数：
  0
• 氢受体数：
  1

ADMET

代谢

JWH-018的高药理活性和成瘾性突显了解析JWH-018代谢的重要性，否则无法对其药代动力学和毒性有深入的了解。在本研究中，通过将药物与人肝微粒体共同孵化并进行液相色谱-串联质谱分析，研究了JWH-018的细胞色素P450 I相代谢物。这揭示了萘环系统、吲哚部分和烷基侧链的单羟基化。此外，还观察到萘环系统和吲哚部分的双羟基化，或者是因为萘环系统和吲哚部分或烷基侧链的单羟基化组合，或者是因为吲哚环系统和烷基侧链的单羟基化组合。还有证据表明，分子中不同位置的羟基团发生了三羟基化。此外，还发现了烷基侧链的脱水，与单羟基化和双羟基化以及萘环系统的芳香族氧化相结合，以及在氧化不同位点上的单羟基化和双羟基化组合。还检测到了N-脱烷基化，与单羟基化和N-脱烷基化代谢物的双羟基形成相结合。最后，在烷基侧链发现了一种被羧化的代谢物。

... The high pharmacological and addictive potency of JWH-018 highlights the importance of elucidating the metabolism of JWH-018, without which a meaningful insight into its pharmacokinetics and its toxicity would not be possible. In the present study, the cytochrome P450 phase I metabolites of JWH-018 were investigated, after in vitro incubation of the drug with human liver microsomes, followed by liquid chromatography-tandem mass spectrometry analysis. This revealed monohydroxylation of the naphthalene ring system, the indole moiety, and the alkyl side chain. In addition, observations were made of dihydroxylation of the naphthalene ring system, and the indole moiety, or as result of a combination of monohydroxylations of both the naphthalene ring system and the indole moiety or the alkyl side chain, or a combination of monohydroxylations of both the indole ring system and the alkyl side chain. There is also evidence of trihydroxylation at different locations of the hydroxyl groups in the molecule. Furthermore, dehydration of the alkyl side chain, in combination with both monohydroxylation and dihydroxylation as well as arene oxidation of the naphthalene ring system, combined with both monohydroxylation and dihydroxylation at different sites of oxidation were found. N-dealkylation also in combination with both monohydroxylation and dihydrodiol formation of the N-dealkylated metabolite was detected. Finally, a metabolite was found carboxylated at the alkyl side chain.

来源:Hazardous Substances Data Bank (HSDB)

代谢

本研究评估了九种人类重组尿苷二磷酸葡萄糖醛酸基转移酶（UGT）同种物以及人类肝脏和肠道微粒体的能力，以葡萄糖醛酸化1-萘基-1-(1-戊基-1H-吲哚-3-基)-甲酮（JWH-018）和(1-丁基-1H-吲哚-3-基)-1-萘基-甲酮（JWH-073）的羟基代谢物，这两种物质是K2产品中最常见的合成大麻素。使用液相色谱/串联质谱识别和表征了结合物，而使用高效液相色谱-紫外可见方法量化了动力学参数。UGT1A1、UGT1A3、UGT1A9、UGT1A10和UGT2B7被证明是主要涉及的酶，对某些羟基化K2表现出相对较高的亲和力，K(m)值范围从12到18微摩尔。这些UGT还对这些化合物表现出高代谢能力，这表明K2代谢物可能被迅速葡萄糖醛酸化并从体内消除。

... This study evaluates nine human recombinant uridine diphosphate-glucuronosyltransferase (UGT) isoforms and human liver and intestinal microsomes for their ability to glucuronidate hydroxylated metabolites of 1-naphthalenyl-1(1-pentyl-1H-indol-3-yl)-methanone (JWH-018) and (1-butyl-1H-indol-3-yl)-1-naphthalenyl-methanone (JWH-073), the two most common synthetic cannabinoids found in K2 products. Conjugates were identified and characterized using liquid chromatography/tandem mass spectrometry, whereas kinetic parameters were quantified using high-performance liquid chromatography-UV-visible methods. UGT1A1, UGT1A3, UGT1A9, UGT1A10, and UGT2B7 were shown to be the major enzymes involved, showing relatively high affinity with K(m) ranging from 12 to 18 uM for some hydroxylated K2s. These UGTs also exhibited a high metabolic capacity for these compounds, which indicates that K2 metabolites may be rapidly glucuronidated and eliminated from the body. ...

来源:Hazardous Substances Data Bank (HSDB)

代谢

这项研究旨在阐明JWH-018的代谢过程。从含有大量JWH-018的香炉中制备了乙醇提取物。去除乙醇后，将残留物通过胃插管给予Wistar大鼠，并在24小时内收集尿液。为了鉴定，通过液-液萃取（LLE）或固相萃取（C18）以及随后的乙酰化切割酶解或酸性切割的结合物来分离代谢物。通过气相色谱和质谱的电子电离（EI）模式分离和鉴定代谢物。在尿液提取物中只能检测到少量的母化合物JWH-018。除了母化合物外，还可以在尿液中检测到少量的N-脱烷基代谢物。羟基化的N-脱烷基代谢物的信号最强。羟基化可以发生在两个芳香系统中，即萘和吲哚部分，这可以通过相应片段的质量位移来证明。JWH-018在大鼠体内广泛代谢。根据我们的经验，可以预期人类会有类似的代谢模式。...

The aim of this study was to elucidate the metabolism of JWH-018. An ethanolic extract was prepared from an incense containing large amounts of JWH-018. After removal of the ethanol, the residue was given to Wistar rats by gastric intubation and urine was collected over 24 hours. For identification, the metabolites were isolated after enzymatic or acidic cleavage of conjugates by liquid-liquid extraction (LLE) or solid-phase extraction (C18) followed by acetylation. The metabolites were separated and identified by GC and MS in the electron ionization (EI) mode. The parent compound JWH-018 could be found in the urine extracts only in small amounts. Besides the parent compound, the N-dealkylated metabolite could be detected in urine in small amounts. The highest signals could be observed for the hydroxylated N-dealkyl metabolites. Hydroxylation can take place in both aromatic systems, the naphthalene and the indole part, which could be shown by mass shift of the corresponding fragments. JWH-018 is extensively metabolized in rats. According to our experience similar metabolic patterns can be expected in humans. ...

来源:Hazardous Substances Data Bank (HSDB)

代谢

...值得注意的是，与大多数合成大麻素代谢物不同，JWH-018的羟基化代谢物在体外和体内对CB1受体的活性得以保持...

... It is worth nothing that unlike metabolites of most synthetic cannabinoids, JWH-018 hydroxylated metabolites retain in vitro and in vivo activity at CB1 receptors...

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

大多数心理障碍可以通过简单的安慰来处理，可能需要辅助使用劳拉西泮、地西泮或咪达唑仑。窦性心动过速通常不需要治疗，但如果必要，可以使用β-受体阻滞剂进行控制。直立性低血压可以通过低头位和静脉输液来处理。没有特定的解毒剂。/大麻/

Most psychological disturbances may be managed by simple reassurance, possibly with adjunctive use of lorazepam, diazepam, or midazolam. Sinus tachycardia usually does not require treatment but if necessary may be controlled with beta-blockers. Orthostatic hypotension responds to head down position and IV fluids. There is no specific antidote. /Marijuana/

来源:Hazardous Substances Data Bank (HSDB)

毒理性

• 解毒与急救

摄入后进行解毒。院前急救。如果有的话，给予活性炭。医院。给予活性炭。如果可以迅速给予活性炭，则不需要进行胃排空。加强消除。由于大麻素分布体积大，这些程序无效。/大麻/

Decontamination after ingestion. Prehospital. Administer activated charcoal if available. Hospital. Administer activated charcoal. Gastric emptying is not necessary if activated charcoal can be given promptly. Enhanced elimination. These procedures are not effective owing to the large volume of distribution of cannabinoids. /Marijuana/

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，按培训操作。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……。/毒药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"，最低流量/。如果出现低血容量的迹象，使用0.9%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

JWH-018（1-2小时）对人类的影响持续时间似乎比THC短，而CP 47,497-C8（5-6小时）的影响持续时间则要长得多，这一点在一份自我实验报告中有所提及。

The duration of effects in humans compared to THC seems to be shorter for JWH-018 (1-2 hours) and considerably longer for CP 47,497-C8 (5-6 hours), as reported in a self-experiment.

来源:Hazardous Substances Data Bank (HSDB)

反应信息

• 作为反应物：
  描述：

  1-戊基-3-(1-萘甲酰基)吲哚 在 lithium aluminium tetrahydride 、 三氯化铝 作用下， 以 乙醚 为溶剂， 反应 48.0h， 以40%的产率得到3-(naphth-1'-ylmethyl)-1-pentyl-1H-indole
  参考文献：
  名称：

  3-Indolyl-1-naphthylmethanes: new cannabimimetic indoles provide evidence for aromatic stacking interactions with the CB1 cannabinoid receptor

  摘要：

  A series of 1-pentyl-1H-indol-3-yl-(1-naphthyl)methanes (9 11) and 2-methyl-1-pentyl-1H-indol-3-yl-(1-naphthyl)methanes (12-14) have been synthesized to investigate the hypothesis that cannabimimetic 3-(1-naphthoyl)indoles interact with the CB I receptor by hydrogen bonding to the carbonyl group. Indoles 9-11 have significant (K-i 17-23 nM) receptor affinity, somewhat less than that of the corresponding naphthoylindoles (5, 15, 16). 2-Methyl-1-indoles 12-14 have little affinity for the CB1 receptor, in contrast to 2-methyl-3-(1-naphthoyl)indoles 17-19, which have affinities comparable to those of 5, 15, 16. A cannabimimetic indene hydrocarbon (26) was synthesized and found to have K-i = 26 +/- 4 nM. Molecular modeling and receptor docking studies of naphthoylindole 16, its 2-methyl congener (19) and indolyl-1-naphthylmethanes 11 and 14, combined with the receptor affinities of these cannabimimetic indoles, strongly suggest that these cannabinoid receptor ligands bind primarily by aromatic stacking interactions in the transmembrane helix 3-4-5-6 region of the CB1 receptor. (C) 2002 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(02)00451-0
• 作为产物：
  描述：

  1-萘甲酰氯 在 二甲基氯化铝 、 sodium hydride 作用下， 以 正己烷 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 32.5h， 生成 1-戊基-3-(1-萘甲酰基)吲哚
  参考文献：
  名称：

  广泛中和合成大麻素疫苗

  摘要：

  合成大麻素 (SC) 是构成主要公共卫生风险的精神活性物质的重要组成部分。由于 SCs 种类繁多，主动免疫产生的广泛中和抗体提供了一种有趣的途径来对抗大麻素使用障碍。在这里，我们探讨了针对两类 SCs 的抗体亲和力和交叉反应性的半抗原设计。在筛选的 10 个半抗原中，3 个疫苗组显示亚微摩尔 IC 50，每个针对我们的 22 种药物中的 5-6 种化合物。此外，当通过电子烟或腹腔注射给药时，SCs 被成功隔离，这在动物模型中通过观察运动、体温和药代动力学得到证实。我们还发现了通过混合疫苗方法同时减弱两种药物类别的协同效应。总的来说，我们的研究为开发针对 SCs 的疫苗提供了全面的基础。

  DOI：

  10.1021/jacsau.0c00057

文献信息

• A novel microwave-irradiated solvent-free 3-acylation of indoles on alumina
  作者：Qiu Yu Lai、Rong Su Liao、Shao Yong Wu、Jia Xin Zhang、Xin Hong Duan

  DOI：10.1039/c3nj00854a

  日期：——

  A simple and efficient 3-acylation of indoles under microwave-heated and solvent-free conditions is developed. This general procedure uses neutral Al2O3 as a new, green and reusable catalyst giving good to high yields within short reaction times. Utilizing such an environmentally-benign methodology, a variety of indoles bearing electron-releasing or electron-withdrawing groups were conveniently acylated.

  开发出一种简单高效的3-位吲哚酰化反应方法，该方法在无溶剂条件下采用微波加热，使用中性Al2O3作为新型、绿色且可重复使用的催化剂，在短时间内获得良好至高产率的产物。运用这种环保的方法，多种带有供电子或吸电子基团的吲哚化合物得以方便地进行酰化反应。
• [EN] PERIPHERALLY-ACTING CANNABINOID RECEPTOR AGONISTS FOR CHRONIC PAIN<br/>[FR] AGONISTES DE RÉCEPTEURS CANNABINOÏDES À ACTION PÉRIPHÉRIQUE CONTRE LA DOULEUR CHRONIQUE
  申请人：UNIV CALIFORNIA

  公开号：WO2014015298A1

  公开（公告）日：2014-01-23

  Peripherally acting cannabinoid agonist compounds, pharmaceutical compositions, and methods of using them are presented.

  外周作用的大麻素激动剂化合物、药物组合物以及使用它们的方法被提出。
• CB2-selective cannabinoid analogues
  申请人：Martin R. Billy

  公开号：US20050009903A1

  公开（公告）日：2005-01-13

  Cannabinoid analogues that exhibit specificity for the CB 2 cannabinoid receptor are provided. The analogues are 1-methoxy-, 1-deoxy-11-hydroxy- and 11-hydroxy-1-methoxy-Δ 8 -tetrahydrocannabinols and 1-alkyl-3(1-naphthoyl)indoles. The compounds are useful for the treatment of pain (especially pain resulting from inflammation) and cancer (especially glioma tumors).

  提供了对CB2大麻素受体具有特异性的大麻素类似物。这些类似物是1-甲氧基-、1-去氧-11-羟基-和11-羟基-1-甲氧基-Δ8-四氢大麻酚以及1-烷基-3(1-萘酰)吲哚。这些化合物对于治疗疼痛（尤其是由炎症引起的疼痛）和癌症（尤其是胶质瘤）具有用途。
• One-Pot Desulfonylative Alkylation of N-Sulfonyl Azacycles Using Alkoxides Generated by Phase-Transfer Catalysis
  作者：Justin Denton

  DOI：10.1055/s-0029-1218627

  日期：2010.3

  Sulfonamide heterocycles, specifically 3-acylindoles, undergo a deprotection/alkylation sequence in the presence of an appropriate alcohol when cesium carbonate or potassium carbonate and a phase-transfer catalyst are utilized. The outcome of the one-pot protocol was found to be significantly dependent on both the alcohol and sulfonamide heterocycle employed. Strictly anhydrous conditions are not necessary

  当使用碳酸铯或碳酸钾和相转移催化剂时，在合适的醇存在下，磺酰胺杂环，特别是3-酰基环，经历脱保护/烷基化序列。发现一锅法的结果很大程度上取决于所用的醇和磺酰胺杂环。严格的无水条件对于该方案不是必需的。 相转移催化-磺酰胺-杂环-裂解-烷基化
• Visible-Light Photocatalytic Aerobic Benzylic C(sp³ )−H Oxygenations with the ³ DDQ*/<i>tert</i> -Butyl Nitrite Co-catalytic System
  作者：Fabian Rusch、Jan-Christian Schober、Malte Brasholz

  DOI：10.1002/cctc.201600704

  日期：2016.9.21

  aerobic benzylic C(sp3)−H oxygenations of aromatic hydrocarbons and C3‐substituted indoles were studied by employing a co‐catalytic system of 3DDQ* (DDQ=2,3‐dichloro‐5,6‐dicyano‐1,4‐benzoquinone) and tert‐butyl nitrite. The superior efficiency of these reaction conditions was demonstrated by comparison with the analogous thermal protocol, and a range of substrates could be oxidized catalytically and selectively

  通过使用3 DDQ *（DDQ = 2,3-dichloro-5,6-dicyanoano，1,4的共催化系统）研究了芳烃和C3取代的吲哚的光催化好氧苄基C（sp 3）-H氧化苯醌）和亚硝酸叔丁酯。通过与类似的热方案进行比较，证明了这些反应条件的优异效率，并且可以以良好的收率催化和选择性地氧化多种底物。