L-tryptophan 3,5-bis(trifluoromethyl)benzyl ester hydrochloride

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: L-tryptophan 3,5-bis(trifluoromethyl)benzyl ester hydrochloride
• 英文别名: tryptophan 3',5'-(bistrifluoromethyl)benzyl ester hydrochloride；H-Trp-OBzl(CF3)2*HCl；Tryptophan 3,5-bis(trifluoromethyl)benzyl ester hydrochloride；[3,5-bis(trifluoromethyl)phenyl]methyl (2S)-2-amino-3-(1H-indol-3-yl)propanoate;hydrochloride
• 化学式: C₂₀H₁₆F₆N₂O₂*ClH
• 分子量: 466.811
• InChiKey: IRENWXZGXVQOPQ-NTISSMGPSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.24
• 重原子数：
  31
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  68.1
• 氢给体数：
  3
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  L-tryptophan 3,5-bis(trifluoromethyl)benzyl ester hydrochloride 在 N-甲基吗啉 、 盐酸 、 1-羟基苯并三唑 作用下， 以 1,4-二氧六环 、 N,N-二甲基甲酰胺 为溶剂， 反应 1.0h， 生成 H-Tyr-D-Ala-Gly-Phe-Phe-Pro-Leu-Trp-O-3,5-Bzl(CF3)2*TFA
  参考文献：
  名称：

  Design, Synthesis, and Biological Evaluation of Novel Bifunctional C-Terminal-Modified Peptides for δ/μ Opioid Receptor Agonists and Neurokinin-1 Receptor Antagonists

  摘要：

  A series of bifunctional peptides that act as agonists for delta and mu opioid receptors with delta selectivity and as antagonist for neurokinin-1 (NK1) receptors were designed and synthesized for potential application as analgesics in various pain states. The peptides were characterized using radioligand binding assays and functional assays using cell membrane and animal tissue. Optimization was performed on the fifth residue which serves as an address moiety for both receptor recognitions. It had critical effects on both activities at delta/mu opioid receptors and NK1 receptors. Among the synthesized peptides, H-Tyr-D-Ala-Gly-Phe-Met-Pro-Leu-Trp-O-3,5-Bzl(CF3) (2) (5) and H-Tyr-D-Ala-Gly-Phe-Nle-Pro-Leu-Trp-O-3,5-Bzl(CF3)(2) (7) had excellent agonist activity for both delta opioid and mu opioid receptors and excellent antagonist activity for NK1 receptors. These results indicate that the rational design of multifunctional ligands with opioid agonist and neurokinin-1 antagonist activities can be accomplished and may provide a new tool for treatment of chronic and several pain states.

  DOI：

  10.1021/jm061369n
• 作为产物：
  描述：

  N-叔丁氧羰基-L-色氨酸 在 盐酸 、 caesium carbonate 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 32.0h， 生成 L-tryptophan 3,5-bis(trifluoromethyl)benzyl ester hydrochloride
  参考文献：
  名称：

  Identification of L-Tryptophan Derivatives with Potent and Selective Antagonist Activity at the NK1 Receptor

  摘要：

  As part of a program of screening the Merck sample collection, N-ethyl-L-tryptophan benzyl ester was identified as a weak antagonist at the substance P (NK1) receptor. Structure-activity studies showed that the indole ring system could be replaced by 3,4-dichlorophenyl, alpha- or beta-naphthyl, or benzthiophene with retention or only small loss of affinity. It was found that acylation of the tryptophan nitrogen gave compounds with higher affinity than N-ethyl or other basic amines. Optimization of substitution on the benzyl ester led to the identification of the 3,5-bis-(trifluoromethyl)benzyl ester of N-acetyl-L-tryptophan 26 as a potent and selective substance P receptor antagonist. Compound 26 blocked substance P induced dermal extravasation in vivo and was the most potent compound from this structurally novel class of antagonists which further adds to the diversity of small molecules that bind to the (NK1) receptor.

  DOI：

  10.1021/jm00035a006

文献信息

• BIFUNCTIONAL ANALGESIC COMPOUNDS FOR OPIOID RECEPTOR AGONISTS AND NEUROKININ-1 RECEPTOR ANTAGONISTS
  申请人：Hruby Victor

  公开号：US20080039404A1

  公开（公告）日：2008-02-14

  The present invention provides a novel chimeric compound comprising an agonist opioid receptor binding moiety at its N-terminus and an antagonist neurokinin-1 (NK1) receptor binding moiety at its C-terminus for producing analgesia, a pharmaceutical composition comprising the chimeric compound, a method of making the compound, and a method of treating pain using the novel chimeric compounds.

  本发明提供了一种新型嵌合化合物，其包括在其N-末端具有激动剂阿片受体结合基团和在其C-末端具有拮抗剂神经激肽-1（NK1）受体结合基团，用于产生镇痛作用，以及包括该嵌合化合物的药物组合物、制备该化合物的方法，以及使用该新型嵌合化合物治疗疼痛的方法。
• A flexible approach to the design of new potent substance P receptor ligands
  作者：R Millet、L Goossens、K Bertrand-Caumont、J-F Goossens、R Houssin、J-P Hénichart

  DOI：10.1211/0022357011776324

  日期：2010.2.18

  propose new selective NK1 ligands with high affinity. Structure-activity relationships showed that the Trp-OBzl(CF3)2 moiety is essential for NK1 affinity and that the introduction of building units such as spirolactam, lactam or proline, leading to a constrained peptide, increased selectivity for NK1 receptors. These compounds constitute a useful starting point for new substance P antagonists and represent

  优先选择P物质的速激肽NK1受体的小分子拮抗剂的开发提供了一个极好的机会，可以将这些分子作为新型治疗剂用于多种疾病，例如抑郁症，呕吐或哮喘。GR71251先前已被确认为有效的选择性P受体拮抗剂。因此，我们基于GR71251的C端序列进行了新的伪肽类似物的合成。对NK1和NK2受体的结合亲和力的评估使我们能够提出具有高亲和力的新型选择性NK1配体。构效关系表明，Trp-OBzl（CF3）2部分对于NK1亲和力至关重要，并且引入诸如螺内酰胺，内酰胺或脯氨酸之类的建筑单元会导致肽段受限，对NK1受体的选择性增加。这些化合物构成了新物质P拮抗剂的有用起点，并代表了诱人的先导系列，可用于进一步研究特定NK1拮抗剂的设计。
• Synthesis and biological evaluation of new opioid agonist and neurokinin-1 antagonist bivalent ligands
  作者：Ruben Vardanyan、Vlad K. Kumirov、Gary S. Nichol、Peg Davis、Erika Liktor-Busa、David Rankin、Eva Varga、Todd Vanderah、Frank Porreca、Josephine Lai、Victor J. Hruby

  DOI：10.1016/j.bmc.2011.08.027

  日期：2011.10

  Newly designed bivalent ligands-opioid agonist/NK1-antagonists have been synthesized. The synthesis of new starting materials-carboxy-derivatives of Fentanyl (1a-1c) was developed. These products have been transformed to 'isoimidium perchlorates' (2a-c). The new isoimidium perchlorates have been successfully implemented in nucleophilic addition reactions, with L-tryptophan 3,5-bis(trifluoromethyl)benzyl ester to give the target compounds-amides (3a-c). Perchlorates (2a-c) successfully undergo reactions with other nucleophiles such as alcohols, amines or hydrazines. The obtained compound 3b exhibited mu-opioid agonist activity and NK1-antagonist activity and may serve as a useful lead compound for the further design of a new series of opioid agonist/NK1-antagonist compounds. Published by Elsevier Ltd.
• MEDICATED SPRAY FOR TREATMENT OF SUBSTANCE ABUSE, OVERDOSE, ADDICTION AND IMPULSE CONTROL DISORDERS
  申请人：GOOBERMAN Lance L.

  公开号：US20200352917A1

  公开（公告）日：2020-11-12

  A method to treat carfentanyl overdose comprising administrating a pharmaceutical formulation in the form of liquid solution for spray administration by the nasal and/or buccal route containing naltrexone as active ingredient in amounts greater than 1%.
• US8026218B2
  申请人：——

  公开号：US8026218B2

  公开（公告）日：2011-09-27