阿布查米卡代谢物M4 | 1271630-11-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并吡唑类
• 中文名称: 阿布查米卡代谢物M4
• 英文名称: 1-(cyclohexylmethyl)-1H-indazole-3-carboxylic acid
• 英文别名: Ab-chminaca metabolite M4；1-(cyclohexylmethyl)indazole-3-carboxylic acid
• CAS: 1271630-11-5
• 化学式: C₁₅H₁₈N₂O₂
• 分子量: 258.32
• InChiKey: DVXHKIOGZJHOPD-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  19
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  55.1
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  金刚烷胺 、 阿布查米卡代谢物M4 在 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 以82%的产率得到N-(adamantan-1-yl)-1-(cyclohexylmethyl)-1H-indazole-3-carboxamide
  参考文献：
  名称：

  Synthesis and in Vitro Cannabinoid Receptor 1 Activity of Recently Detected Synthetic Cannabinoids 4F-MDMB-BICA, 5F-MPP-PICA, MMB-4en-PICA, CUMYL-CBMICA, ADB-BINACA, APP-BINACA, 4F-MDMB-BINACA, MDMB-4en-PINACA, A-CHMINACA, 5F-AB-P7AICA, 5F-MDMB-P7AICA, and 5F-AP7AICA

  摘要：

  Synthetic cannabinoid receptor agonists (SCRAs) are an evolving class of new psychoactive substances (NPS) with structurally diverse compounds emerging each year. Due to the rapid pace at which these drugs enter the market, there is often little or nil information regarding the pharmacology of these substances despite widespread human use. In this study, 12 recently emerged SCRAs (reported between 2018 and 2020) were synthesized, analytically characterized, and pharmacologically evaluated using a live cell-based nanoluciferase complementation reporter assay that monitors in vitro cannabinoid receptor type 1 (CB1) activation via its interaction with β-arrestin 2 (βarr2). All synthesized SCRAs acted as agonists of CB1, although differences in potency (EC50 = 2.33-5475 nM) and efficacy (Emax = 37-378%) were noted, and several structure-activity relationships were identified. SCRAs featuring indazole cores (EC50 = 2.33-159 nM) were generally of equal or greater potency than indole analogues (EC50 = 32.9-330 nM) or 7-azaindole derivatives (EC50 = 64.0-5475 nM). Interestingly, with the exception of APP-BINACA (Emax = 75.7%) and 5F-A-P7AICA (Emax = 37.4%), all SCRAs showed greater efficacy than the historical SCRA JWH-018 to which responses were normalized (Emax = 142-378%). The most potent CB1 agonists in the study were ADB-BINACA (EC50 = 6.36 nM), 4F-MDMB-BINACA (EC50 = 7.39 nM), and MDMB-4en-PINACA (EC50 = 2.33 nM). Notably, all of these SCRAs featured an indazole core as well as a "bulky" tert-butyl moiety in the pendant amino acid side chain. This study confirms that recently detected SCRAs 4F-MDMB-BICA, 5F-MPP-PICA, MMB-4en-PICA, CUMYL-CBMICA, ADB-BINACA, APP-BINACA, 4F-MDMB-BINACA, MDMB-4en-PINACA, A-CHMINACA, 5F-AB-P7AICA, 5F-MDMB-P7AICA, and 5F-AP7AICA were all able to activate the CB1 receptor in vitro, albeit to different extents, and are potentially psychoactive in vivo. These results indicate that further evaluation of these widely used NPS is warranted to better understand the risks associated with human consumption of these drugs.

  DOI：

  10.1021/acschemneuro.0c00644
• 作为产物：
  描述：

  吲哚-3-甲酸甲酯 在 potassium tert-butylate 、 水 、 sodium hydroxide 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 反应 67.0h， 生成 阿布查米卡代谢物M4
  参考文献：
  名称：

  枯基羧酰胺合成大麻新精神活性物质（NPS）CUMYL-BICA，CUMYL-PICA，CUMYL-5F-PICA，CUMYL-5F-PINACA的药理作用

  摘要：

  合成大麻素（SC）是新型精神活性物质（NPS）的最大类别，并且越来越多地与严重的不良反应联系在一起。SC NPS的大多数是1，3-二取代的吲哚和吲唑，在1和3位具有多种亚基。最近，执法机构和急诊部门发现了枯基衍生的吲哚和吲唑-3-羧酰胺。在本文中，我们描述了SCs CUMYL-BICA，CUMYL-PICA，CUMYL-5F-PICA，CUMYL-PINACA，CUMYL-5F-PINACA及其相关类似物的合成，表征和药理作用。所有枯基衍生的SC在CB 1（EC 50 = 0.43–12.3 nM）和CB 2（EC 50= 11.3–122 nM）受体在膜电位的荧光测定中，具有CB 1活化的选择性（是CB 2的3.1–53倍）。使用生物遥测法在大鼠中评估了CUMYL-PICA和CUMYL-5F-PICA，并以1 mg / kg的剂量诱发了体温过低和心动过缓。通过用CB 1而不是CB 2拮抗

  DOI：

  10.1021/acschemneuro.7b00267

文献信息

• Broadly Neutralizing Synthetic Cannabinoid Vaccines
  作者：Mingliang Lin、Jinny Claire Lee、Steven Blake、Beverly Ellis、Lisa M. Eubanks、Kim D. Janda

  DOI：10.1021/jacsau.0c00057

  日期：2021.1.25

  forming a major public health risk. Due to the wide variety of SCs, broadly neutralizing antibodies generated by active immunization present an intriguing pathway to combat cannabinoid use disorder. Here, we probed hapten design for antibody affinity and cross reactivity against two classes of SCs. Of the 10 haptens screened, 3 vaccine groups revealed submicromolar IC50, each targeting 5–6 compounds in

  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。
• Pharmacological insights emerging from the characterization of a large collection of synthetic cannabinoid receptor agonists designer drugs
  作者：Claudia Gioé-Gallo、Sandra Ortigueira、José Brea、Iu Raïch、Jhonny Azuaje、M. Rita Paleo、Maria Majellaro、María Isabel Loza、Cristian O. Salas、Xerardo García-Mera、Gemma Navarro、Eddy Sotelo

  DOI：10.1016/j.biopha.2023.114934

  日期：2023.8

  evaluation (binding and functional) of the largest and most diverse collection of enantiopure SCRAs published to date. Our results revealed novel SCRAs that could be (or may currently be) used as illegal psychoactive substances. We also report, for the first time, the cannabimimetic data of 32 novel SCRAs containing an (R) configuration at the stereogenic center. The systematic pharmacological profiling

  合成大麻素受体激动剂（SCRA）是最大且最具挑战性的滥用设计药物。这些新型精神活性物质 (NPS) 是作为不受管制的大麻替代品而开发的，具有强大的拟大麻作用，其使用通常与精神病、癫痫发作、依赖性、器官毒性和死亡有关。由于它们的结构不断变化，科学界和执法部门可以获得的结构、药理学和毒理学信息非常有限或为零。在这里，我们报告了迄今为止发布的最大和最多样化的对映体纯 SCRA 集合的合成和药理学评估（结合和功能）。我们的结果揭示了新型 SCRA 可能（或目前可能）被用作非法精神活性物质。我们还报道，R ) 立体中心的构型。该库的系统药理学分析能够识别新兴的结构-活性关系 (SAR) 和结构-选择性关系 (SSR) 趋势，检测显示出早期大麻素受体 2 型 (CB 2) 的配体R) 亚型选择性，并强调了代表性 SCRA 对小鼠原代神经元细胞的显着神经毒性。目前预计几种新出现的 SCRA 的潜在危害相
• Comprehensive Characterization of a Systematic Library of Alkyl and Alicyclic Synthetic Cannabinoids Related to CUMYL-PICA, CUMYL-BUTICA, CUMYL-CBMICA, and CUMYL-PINACA
  作者：Liesl K. Janssens、Adam Ametovski、Eric Sparkes、Rochelle Boyd、Felcia Lai、Callan J. Maloney、Dane Rhook、Roy R. Gerona、Matthew Connolly、Huiling Liu、David E. Hibbs、Elizabeth A. Cairns、Samuel D. Banister、Christophe P. Stove

  DOI：10.1021/acschemneuro.2c00408

  日期：2023.1.4
• Synthesis and <i>in Vitro</i> Cannabinoid Receptor 1 Activity of Recently Detected Synthetic Cannabinoids 4F-MDMB-BICA, 5F-MPP-PICA, MMB-4en-PICA, CUMYL-CBMICA, ADB-BINACA, APP-BINACA, 4F-MDMB-BINACA, MDMB-4en-PINACA, A-CHMINACA, 5F-AB-P7AICA, 5F-MDMB-P7AICA, and 5F-AP7AICA
  作者：Annelies Cannaert、Eric Sparkes、Edward Pike、Jia Lin Luo、Ada Fang、Richard C. Kevin、Ross Ellison、Roy Gerona、Samuel D. Banister、Christophe P. Stove

  DOI：10.1021/acschemneuro.0c00644

  日期：2020.12.16

  Synthetic cannabinoid receptor agonists (SCRAs) are an evolving class of new psychoactive substances (NPS) with structurally diverse compounds emerging each year. Due to the rapid pace at which these drugs enter the market, there is often little or nil information regarding the pharmacology of these substances despite widespread human use. In this study, 12 recently emerged SCRAs (reported between 2018 and 2020) were synthesized, analytically characterized, and pharmacologically evaluated using a live cell-based nanoluciferase complementation reporter assay that monitors in vitro cannabinoid receptor type 1 (CB1) activation via its interaction with β-arrestin 2 (βarr2). All synthesized SCRAs acted as agonists of CB1, although differences in potency (EC50 = 2.33-5475 nM) and efficacy (Emax = 37-378%) were noted, and several structure-activity relationships were identified. SCRAs featuring indazole cores (EC50 = 2.33-159 nM) were generally of equal or greater potency than indole analogues (EC50 = 32.9-330 nM) or 7-azaindole derivatives (EC50 = 64.0-5475 nM). Interestingly, with the exception of APP-BINACA (Emax = 75.7%) and 5F-A-P7AICA (Emax = 37.4%), all SCRAs showed greater efficacy than the historical SCRA JWH-018 to which responses were normalized (Emax = 142-378%). The most potent CB1 agonists in the study were ADB-BINACA (EC50 = 6.36 nM), 4F-MDMB-BINACA (EC50 = 7.39 nM), and MDMB-4en-PINACA (EC50 = 2.33 nM). Notably, all of these SCRAs featured an indazole core as well as a "bulky" tert-butyl moiety in the pendant amino acid side chain. This study confirms that recently detected SCRAs 4F-MDMB-BICA, 5F-MPP-PICA, MMB-4en-PICA, CUMYL-CBMICA, ADB-BINACA, APP-BINACA, 4F-MDMB-BINACA, MDMB-4en-PINACA, A-CHMINACA, 5F-AB-P7AICA, 5F-MDMB-P7AICA, and 5F-AP7AICA were all able to activate the CB1 receptor in vitro, albeit to different extents, and are potentially psychoactive in vivo. These results indicate that further evaluation of these widely used NPS is warranted to better understand the risks associated with human consumption of these drugs.
• Pharmacology of Cumyl-Carboxamide Synthetic Cannabinoid New Psychoactive Substances (NPS) CUMYL-BICA, CUMYL-PICA, CUMYL-5F-PICA, CUMYL-5F-PINACA, and Their Analogues
  作者：Mitchell Longworth、Samuel D. Banister、Rochelle Boyd、Richard C. Kevin、Mark Connor、Iain S. McGregor、Michael Kassiou

  DOI：10.1021/acschemneuro.7b00267

  日期：2017.10.18

  3-disubstituted indoles and indazoles featuring a diversity of subunits at the 1- and 3-positions. Most recently, cumyl-derived indole- and indazole-3-carboxamides have been detected by law enforcement agencies and by emergency departments. Herein we describe the synthesis, characterization, and pharmacology of SCs CUMYL-BICA, CUMYL-PICA, CUMYL-5F-PICA, CUMYL-PINACA, CUMYL-5F-PINACA, and related analogues

  合成大麻素（SC）是新型精神活性物质（NPS）的最大类别，并且越来越多地与严重的不良反应联系在一起。SC NPS的大多数是1，3-二取代的吲哚和吲唑，在1和3位具有多种亚基。最近，执法机构和急诊部门发现了枯基衍生的吲哚和吲唑-3-羧酰胺。在本文中，我们描述了SCs CUMYL-BICA，CUMYL-PICA，CUMYL-5F-PICA，CUMYL-PINACA，CUMYL-5F-PINACA及其相关类似物的合成，表征和药理作用。所有枯基衍生的SC在CB 1（EC 50 = 0.43–12.3 nM）和CB 2（EC 50= 11.3–122 nM）受体在膜电位的荧光测定中，具有CB 1活化的选择性（是CB 2的3.1–53倍）。使用生物遥测法在大鼠中评估了CUMYL-PICA和CUMYL-5F-PICA，并以1 mg / kg的剂量诱发了体温过低和心动过缓。通过用CB 1而不是CB 2拮抗