N-(4-(2-苯甲酰基肼碳基)苄基)-3-氯-4-氟苯磺酰胺 | 852918-02-6

• 物质功能分类: 生物 - 细胞培养 - 添加剂
• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: N-(4-(2-苯甲酰基肼碳基)苄基)-3-氯-4-氟苯磺酰胺
• 中文别名: 4-[[[(3-氯-4-氟苯基)磺酰基]氨基]甲基]苯甲酸2-苯甲酰基酰肼；TCN-21
• 英文名称: 3-chloro-4-fluoro-N-[(4-{[2-(phenylcarbonyl)hydrazino]carbonyl}phenyl)methyl]benzenesulfonamide
• 英文别名: 3-chloro-4-fluoro-N-[4-[[2-(phenylcarbonyl)hydrazino]carbonyl]benzyl]benzenesulphonamide；3-chloro-4-fluoro-N-[4-[[2-(phenylcarbonyl)hydrazino]carbonyl]benzyl]benzenesulfonamide；N-{4-[(2-benzoylhydrazino)carbonyl]benzyl}-3-chloro-4-fluorobenzenesulfonamide；TCN 201；TCN-201；TCN201；N-(4-(2-benzoylhydrazinecarbonyl)benzyl)-3-chloro-4-fluorobenzenesulfonamide；N-[[4-(benzamidocarbamoyl)phenyl]methyl]-3-chloro-4-fluorobenzenesulfonamide
• CAS: 852918-02-6
• 化学式: C₂₁H₁₇ClFN₃O₄S
• 分子量: 461.901
• InChiKey: FYIBXBFDXNPBSF-UHFFFAOYSA-N

物化性质

• 溶解度：
  DMSO：可溶，5mg/mL（澄清溶液）

计算性质

• 辛醇/水分配系数(LogP)：
  3.03
• 重原子数：
  31.0
• 可旋转键数：
  6.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.05
• 拓扑面积：
  104.37
• 氢给体数：
  3.0
• 氢受体数：
  4.0

制备方法与用途

生物活性

TCN 201 是一种有效的、选择性和非竞争性的 GluN1/GluN2A NMDA 受体拮抗剂，其 pIC50 值为 6.8。相较于 GluN1/GluN2B NMDA 受体（pIC50 < 4.3），TCN 201 对 GluN1/GluN2A NMDA 受体具有选择性。

靶点

• pIC50: 6.8 (GluN1/GluN2A NMDA 受体)

体外研究

TCN 201（化合物 1）在 oocytes 中表现出对 GluN1/GluN2A NMDAR 的选择性抑制作用，其 pIC50 值为 6.8，而对 GluN1/GluN2B NMDAR 的 pIC50 值小于 4.3。在 oocytes 中，TCN 201（10 μM）仅产生轻微的抑制作用；在 10-30 μM 浓度下，其对抗 NMDAR 介导的反应具有亚型和肌苷依赖性，并且比 TCN 213 更具效力。在 oocytes 中，TCN 201（0.1-100 μM）未完全阻断 NMDAR 介导的响应。此外，在 rat 脑皮层神经元中，TCN 201（10 μM）对抗 NMDAR 介导的电流显示出与其 ifenprodil 敏感性呈负相关的关系；在 chick 视网膜中，TCN 201（1-9 μM）能够抑制脑室扩展抑郁 (CSD)。

体内研究

在 rat 中，TCN-201（10 mg/kg, i.p.）未能影响 CSD 血氧水平依赖性 (BOLD) 反应。

反应信息

• 作为反应物：
  描述：

  N-(4-(2-苯甲酰基肼碳基)苄基)-3-氯-4-氟苯磺酰胺 在 氯化亚砜 作用下， 反应 1.0h， 以92%的产率得到3-chloro-4-fluoro-N-[4-(5-phenyl-1,3,4-oxadiazol-2-yl)benzyl]benzenesulfonamide
  参考文献：
  名称：

  GluN2A选择性NMDA受体拮抗剂TCN-201的苯甲酰肼部分的系统变异

  摘要：

  含有N-甲基-D-天冬氨酸受体（NMDAR）的GluN2A是中枢神经系统中的重要离子通道，并且高度参与几种不同的神经生理学过程以及神经病理生理学过程。但是，目前尚不清楚这些过程中含NMDAR的GluN2A的贡献。因此，需要高选择性的化合物来进一步研究这些离子通道。2010年，TCN-201（2）被报道为最早的选择性负变构调节剂之一。而2的结合位点并且最近已经报道了苯磺酰胺部分的取代方式的影响，二酰基肼部分与连接的苯基部分的详细的结构-活性-关系仍然缺失。为了检查这些部分和结合位点之间的关键相互作用，合成了具有修饰的二酰基肼部分的几种TCN-201类似物。通过使用表达非洲爪蟾的GluN1a / GluN2A的两电极电压钳（TEVC）实验记录了负变构效应卵母细胞。我们的数据得出的结论是，末端苯基部分与GluN1a亚基Arg755的胍基部分发生阳离子-π相互作用，这对高活性起着至关重要的作用。另

  DOI：

  10.1016/j.ejmech.2018.09.006
• 作为产物：
  描述：

  4-((3-氯-4-氟苯基磺酰胺)甲基)苯甲酸 、 苯甲酰肼 在 (1-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylaminomorpholinocarbenium hexafluorophosphate 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 为溶剂， 以78%的产率得到N-(4-(2-苯甲酰基肼碳基)苄基)-3-氯-4-氟苯磺酰胺
  参考文献：
  名称：

  Systematic variation of the benzenesulfonamide part of the GluN2A selective NMDA receptor antagonist TCN-201

  摘要：

  GluN2A subunit containing N-methyl-D-aspartate receptors (NMDARs) are highly involved in various physiological processes in the central nervous system, but also in some diseases, such as anxiety, depression and schizophrenia. However, the role of GluN2A subunit containing NMDARs in pathological processes is not exactly elucidated. In order to obtain potent and selective inhibitors of GluN2A subunit containing NMDARs, the selective negative allosteric modulator 2 was systematically modified at the benzenesulfonamide part. The activity of the test compounds was recorded in two electrode voltage clamp experiments using Xenopus laevis oocytes expressing exclusively NMDARs with GluN1a and GluN2A subunits. It was found that halogen atoms in 3-position of the benzenesulfonamide part result in high GluN2A antagonistic activity. With an IC50 value of 204 nM the 3-bromo derivative 5i (N-{4-[(2-benzoylhydrazino) carbonyl]benzyl}-3-bromobenzenesulfonamide) has 2.5-fold higher antagonistic activity than the lead compound 2 and represents our new lead compound. (C) 2017 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2017.02.018

文献信息

• A DRUG SCREENING PLATFORM FOR RETT SYNDROME
  申请人：The Regents of the University of California

  公开号：EP2841067A2

  公开（公告）日：2015-03-04
• DRUG SCREENING PLATFORM FOR RETT SYNDROME
  申请人：THE REGENTS OF THE UNIVERSITY OF CALIFORNIA

  公开号：US20150119327A1

  公开（公告）日：2015-04-30

  The invention provides a method for restoring a neural cell having a deficiency or alteration in glutamatergic pathway affecting neuron and/or glial function comprising contacting the cell with a NMDA receptor antagonist(s) and/or modulator(s) of a glutamatergic pathway, thereby restoring the neural cell having a deficiency or alteration in glutamatergic pathways affecting neuron and/or glial function.
• [EN] A DRUG SCREENING PLATFORM FOR RETT SYNDROME<br/>[FR] PLATE-FORME DE CRIBLAGE DE MÉDICAMENTS POUR LE SYNDROME DE RETT
  申请人：UNIV CALIFORNIA

  公开号：WO2013163455A2

  公开（公告）日：2013-10-31
• [EN] A HIGH-THROUGHPUT ASSAY METHOD FOR IDENTIFYING ALLOSTERIC NMDA RECEPTOR MODULATORS<br/>[FR] MÉTHODE DE DOSAGE À HAUT DÉBIT POUR IDENTIFIER DES MODULATEURS DU RÉCEPTEUR DE NMDA ALLOSTÉRIQUES
  申请人：NOVARTIS AG

  公开号：WO2017109709A2

  公开（公告）日：2017-06-29

  A novel, high-throughput assay and methods to study N-methyl-D-aspartate receptors (NMDARs). The method allows for rapid comparisons of different subunits, the ability to measure effects of agonists for both the glycine binding site and the glutamate binding 5 site. The methods leverage the use of weak glycine and glutamate sites binding antagonists rather than to ketamine or MK-801 to mitigate against cellular toxicity and to retain the ligand binding site in a ligand-free state. The method can use baculovirus vectors to introduce titratable amounts of different receptor subunits. The assay replicates the pharmacology of NMDARs in response to known antagonists and allosteric 10 modulators, as well as sensitivity to magnesium.
• Systematic variation of the benzenesulfonamide part of the GluN2A selective NMDA receptor antagonist TCN-201
  作者：Sebastian L. Müller、Julian A. Schreiber、Dirk Schepmann、Nathalie Strutz-Seebohm、Guiscard Seebohm、Bernhard Wünsch

  DOI：10.1016/j.ejmech.2017.02.018

  日期：2017.3

  GluN2A subunit containing N-methyl-D-aspartate receptors (NMDARs) are highly involved in various physiological processes in the central nervous system, but also in some diseases, such as anxiety, depression and schizophrenia. However, the role of GluN2A subunit containing NMDARs in pathological processes is not exactly elucidated. In order to obtain potent and selective inhibitors of GluN2A subunit containing NMDARs, the selective negative allosteric modulator 2 was systematically modified at the benzenesulfonamide part. The activity of the test compounds was recorded in two electrode voltage clamp experiments using Xenopus laevis oocytes expressing exclusively NMDARs with GluN1a and GluN2A subunits. It was found that halogen atoms in 3-position of the benzenesulfonamide part result in high GluN2A antagonistic activity. With an IC50 value of 204 nM the 3-bromo derivative 5i (N-4-[(2-benzoylhydrazino) carbonyl]benzyl}-3-bromobenzenesulfonamide) has 2.5-fold higher antagonistic activity than the lead compound 2 and represents our new lead compound. (C) 2017 Elsevier Masson SAS. All rights reserved.