(2-碘-5-硝基苯基)(1-((1-甲基哌啶-2-基)甲基)-1H-吲哚-3-基)甲酮 | 444912-48-5

• 物质功能分类: 生物化工 - 抑制剂 - G蛋白偶联受体(GPCR & G Protein)
• 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: (2-碘-5-硝基苯基)(1-((1-甲基哌啶-2-基)甲基)-1H-吲哚-3-基)甲酮
• 中文别名: (R,S)-3-(2-碘-5-硝基苯甲酰)-1-(1-甲基-2-哌啶甲基)-1H-吲哚
• 英文名称: (2-iodo-5-nitrophenyl)-[1-[(1-methylpiperidin-2-yl)methyl]indol-3-yl]methanone
• 英文别名: AM1241；(2-iodo-5-nitrophenyl)(1-(1-methylpiperidin-2-ylmethyl)-1H-indol-3-yl)methanone；(2-iodo-5-nitrophenyl)(1-((1-methylpiperidin-2-yl)methyl)-1H-indol-3-yl)methanone
• CAS: 444912-48-5
• 化学式: C₂₂H₂₂IN₃O₃
• 分子量: 503.339
• InChiKey: ZUHIXXCLLBMBDW-UHFFFAOYSA-N

物化性质

• 沸点：
  630.7±55.0 °C(Predicted)
• 密度：
  1.60±0.1 g/cm3(Predicted)
• 溶解度：
  DMSO：60℃时约18mg/mL

计算性质

• 辛醇/水分配系数(LogP)：
  4.7
• 重原子数：
  29
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  71.1
• 氢给体数：
  0
• 氢受体数：
  4

安全信息

• 危险品标志：
  Xn
• 安全说明：
  S22,S26,S36/37,S45
• 危险类别码：
  R36/37/38,R42/43
• WGK Germany：
  3

制备方法与用途

生物活性

AM1241是一种选择性的cannabinoid CB2 receptor激动剂，Ki为3.4 nM，比作用于CB1受体选择性高82倍。

体外研究

在免疫细胞化学研究中，AM1241作用于炎症卡拉胶模型，抑制脊髓Fos蛋白表达，Fos蛋白是神经元活动标记。 AM1241作为蛋白兴奋剂，在多种实验观察中显示出不同结果（如钙内流、细胞外信号调节蛋白激酶(ERK)磷酸化和cAMP测量）。在cAMP实验中，当forskolin浓度降低时，拮抗作用变为兴奋作用。AM1241与人CB2受体的高亲和力结合Ki为7 nM,而与人CB1受体结合亲和力弱80多倍，这些结果均来自从表达重组人CB2和CB1受体的稳定HEK和CHO细胞系中制备的膜。

体内研究

AM1241处理热刺激的后肢具有镇痛作用，这种作用具有剂量依赖性。AM1241的A50(产生50% 效果的镇痛剂量)是847μg/kg，最大可能影响为(100% MPE)3.3 mg/kg。AM1241按A50为 103μg/kg的剂量腹腔注射处理也具有镇痛效果，同样表现出剂量依赖性。CB2受体选择性拮抗剂 AM630抑制AM1241的镇痛机能,而CB1受体选择性拮抗剂 AM251没有此作用效果。AM1241 不会造成体温过低、全身僵硬中枢神经系统（CNS）受大麻素影响，及 行为损伤或活性受抑制，而混合的CB1/CB2 受体兴奋剂WIN55,212-2则会造成以上四种影响。 AM1241 (100, 330 μg/kg 腹腔注射)抑制卡拉胶诱导的热痛觉过敏及异常性疼痛。CB2拮抗剂 SR144528而非CB1 拮抗剂SR141716A可阻断以上抑制作用。

靶点

Target	Value
CB2	3.4 nM(Ki)
CB1	280 nM(Ki)

反应信息

• 作为产物：
  描述：

  2-iodo-5-nitrobenzoyl chloride 在 乙基溴化镁 、 sodium hydride 、 zinc(II) chloride 作用下， 生成 (2-碘-5-硝基苯基)(1-((1-甲基哌啶-2-基)甲基)-1H-吲哚-3-基)甲酮
  参考文献：
  名称：

  In vitro pharmacological characterization of AM1241: a protean agonist at the cannabinoid CB₂ receptor?

  摘要：

  Background and purpose:The CB2 receptor has been proposed as a novel target for the treatment of pain, and CB2 receptor agonists defined in in vitro assays have demonstrated analgesic activity in animal models. Based on its in vivo analgesic efficacy, AM1241 has been classified as a CB2‐selective agonist. However, in vitro characterization of AM1241 in functional assays has not been reported.Experimental approach:In this study, AM1241 was characterized across multiple in vitro assays employing heterologous recombinant receptor expression systems to assess its binding potencies at the human CB2 and CB1 receptors and its functional efficacies at the human CB2 receptor.Key results:AM1241 exhibited distinct functional properties depending on the assay conditions employed, a unique profile in contrast to those of the agonist CP 55,940 and the inverse agonist SR144528. AM1241 displayed neutral antagonist activities in FLIPR and cyclase assays. However, when cyclase assays were performed using lower forskolin concentrations for stimulation, AM1241 exhibited partial agonist efficacy. In addition, it behaved as a partial agonist in ERK (or MAP) kinase assays.Conclusions and implications:The unusual phenomenon of inconsistent functional efficacies suggests that AM1241 is a protean agonist at the CB2 receptor. We postulate that functional efficacies displayed by protean agonists in various assay systems may depend on the levels of receptor constitutive activities exhibited in the assay systems, and therefore, efficacies observed in in vitro assays may not predict in vivo activities.British Journal of Pharmacology (2006) 149, 145–154. doi:10.1038/sj.bjp.0706838

  DOI：

  10.1038/sj.bjp.0706838

文献信息

• HYDRAZONE MODULATORS OF CANNABINOID RECEPTORS
  申请人：Attala Mohamed Naguib

  公开号：US20100197755A1

  公开（公告）日：2010-08-05

  Hydrazone compounds which modulate cannabinoid receptors are presented. Pharmaceutical compositions containing these compounds, methods of using these compounds as modulators of cannabinoid receptors and processes for synthesizing these compounds are also described herein.

  本文介绍了调节大麻素受体的腙类化合物。还描述了含有这些化合物的制药组合物，使用这些化合物作为大麻素受体调节剂的方法以及合成这些化合物的过程。
• Neuroprotective CB2 receptor agonists
  申请人：THE CLEVELAND CLINIC FOUNDATION

  公开号：US10835521B2

  公开（公告）日：2020-11-17

  A method of treating or preventing a neuroinflammatory and/or neurodegenerative disease in a subject by administering a pharmaceutically effective amount of a CB2 receptor agonist is described. The CB2 receptor agonist can be a compound according to formula I (structurally represented) or a pharmaceutically acceptable salt thereof, with R1 and R2 functional groups as defined herein. Administration of the CB2 receptor agonist activates CB2 receptors in the microglia, and can restore synaptic plasticity, cognition, and memory in subjects having elevated levels of amyloid-13 peptide in the brain.

  本文描述了一种通过施用药学有效量的 CB2 受体激动剂来治疗或预防受试者的神经炎症和/或神经退行性疾病的方法。CB2 受体激动剂可以是根据式 I（结构表示）的化合物或其药学上可接受的盐，其 R1 和 R2 官能团如本文所定义。施用 CB2 受体激动剂可激活小胶质细胞中的 CB2 受体，并可恢复大脑中淀粉样蛋白-13 肽水平升高的受试者的突触可塑性、认知和记忆。
• ASSOCIATIONS ANTI-DOULEUR COMPRENANT UN DERIVE DE DIHYDROIMIDAZOPYRAZINE
  申请人：Societe de Conseils de Recherches et d'Applications Scientifiques (S.C.R.A.S) SAS

  公开号：EP1827495A2

  公开（公告）日：2007-09-05
• USE OF CBX CANNABINOID RECEPTOR MODULATORS AS POTASSIUM CHANNEL MODULATORS
  申请人：Solvay Pharmaceuticals GmbH

  公开号：EP2012775A1

  公开（公告）日：2009-01-14
• PHARMACEUTICAL COMPOSITIONS COMPRISING CBX CANNABINOID RECEPTOR MODULATORS AND POTASSIUM CHANNEL MODULATORS
  申请人：Solvay Pharmaceuticals GmbH

  公开号：EP2026798A1

  公开（公告）日：2009-02-25