H-Dmt-D-Arg-Aba-Gly-NMe-3',5'-(CF₃)₂-Bn | 1286708-14-2

• 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: H-Dmt-D-Arg-Aba-Gly-NMe-3',5'-(CF₃)₂-Bn
• 英文别名: Dmt-D-Arg-Aba-Gly-NMe-3','′-(CF3)2-Bn；SBCHM1；H-2′,6′-dimethyltyrosine-D-Arg-(4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one)-Gly-NMe-3′,5′-(CF₃)₂-Bn；(R)-2-((S)-2-amino-3-(4-hydroxy-2,6-dimethylphenyl)propanamido)-N-((S)-2-(2-((3,5-bis(trifluoromethyl)benzyl)(methyl)amino)-2-oxoethyl)-3-oxo-2,3,4,5-tetrahydro-1H-benzo[c]azepin-4-yl)-5-guanidinopentanamide；(2R)-2-[[(2S)-2-amino-3-(4-hydroxy-2,6-dimethylphenyl)propanoyl]amino]-N-[(4S)-2-[2-[[3,5-bis(trifluoromethyl)phenyl]methyl-methylamino]-2-oxoethyl]-3-oxo-4,5-dihydro-1H-2-benzazepin-4-yl]-5-(diaminomethylideneamino)pentanamide
• CAS: 1286708-14-2
• 化学式: C₃₉H₄₆F₆N₈O₅
• 分子量: 820.835
• InChiKey: UXNDGPPTVKDIOD-QAXCHELISA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  58
• 可旋转键数：
  14
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  210
• 氢给体数：
  6
• 氢受体数：
  13

反应信息

• 作为产物：
  描述：

  3,5-双三氟甲基苄基氯 在 三乙基硅烷 、 1-羟基苯并三唑 、 N,N-二异丙基乙胺 、 N,N'-二环己基碳二亚胺 、 三氟乙酸 作用下， 以 二氯甲烷 、 水 为溶剂， 反应 35.0h， 生成 H-Dmt-D-Arg-Aba-Gly-NMe-3',5'-(CF₃)₂-Bn
  参考文献：
  名称：

  Synthesis and biological evaluation of compact, conformationally constrained bifunctional opioid agonist – Neurokinin-1 antagonist peptidomimetics

  摘要：

  A reported mixed opioid agonist neurokinin 1 receptor (NK1R) antagonist 4 (Dmt-D-Arg-Aba-Gly-(3 ',5 '-(CF3)(2))NMe-benzyl) was modified to identify important features in both pharmacophores. The new dual ligands were tested in vitro and subsequently two compounds (lead structure 4 and one of the new analogues 22, Dmt-D-Arg-Aba-beta-Ala-NMe-Bn) were selected for in vivo behavioural assays, which were conducted in acute (tail-flick) and neuropathic pain models (cold plate and von Frey) in rats. Compared to the parent opioid compound 33 (without NK1R pharmacophore), hybrid 22 was more active in the neuropathic pain models. Attenuation of neuropathic pain emerged from NK1R antagonism as demonstrated by the pure NK1R antagonist 6. Surprisingly, despite a lower in vitro activity at NK1R in comparison with 4, compound 22 was more active in the neuropathic pain models. Although potent analgesic effects were observed for 4 and 22, upon chronic administration, both manifested a tolerance profile similar to that of morphine and cross tolerance with morphine in a neuropathic pain model in rat. (C) 2014 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2014.12.033

文献信息

• Design of Novel Neurokinin 1 Receptor Antagonists Based on Conformationally Constrained Aromatic Amino Acids and Discovery of a Potent Chimeric Opioid Agonist-Neurokinin 1 Receptor Antagonist
  作者：Steven Ballet、Debby Feytens、Koen Buysse、Nga N. Chung、Carole Lemieux、Suneeta Tumati、Attila Keresztes、Joost Van Duppen、Josephine Lai、Eva Varga、Frank Porreca、Peter W. Schiller、Jozef Vanden Broeck、Dirk Tourwé

  DOI：10.1021/jm1016285

  日期：2011.4.14

  A screening of conformationally constrained aromatic amino acids as base cores for the preparation of new NK1 receptor antagonists resulted in the discovery of three new NK1 receptor antagonists, 19 [Ac-Aba-Gly-NH-3′,5′-(CF3)2-Bn], 20 [Ac-Aba-Gly-NMe-3′,5′-(CF3)2-Bn], and 23 [Ac-Tic-NMe-3′,5′-(CF3)2-Bn], which were able to counteract the agonist effect of substance P, the endogenous ligand of NK1R

  筛选构象受限的芳香族氨基酸作为制备新 NK1 受体拮抗剂的基础核心，发现了三种新的 NK1 受体拮抗剂，19 [Ac-Aba-Gly-NH-3',5'-(CF 3 ) 2 -Bn]、20 [Ac-Aba-Gly-NMe-3',5'-(CF 3 ) 2 -Bn] 和23 [Ac-Tic-NMe-3',5'-(CF 3 ) 2 -Bn]，能够抵消物质 P（NK1R 的内源性配体）的激动作用。该系列中最活跃的 NK1 拮抗剂，20 [Ac-Aba-Gly-NMe-3',5'-(CF 3 ) 2-Bn]，然后用于设计一种新型、有效的嵌合阿片类激动剂-NK1受体拮抗剂，35 [Dmt - d -Arg-Aba-Gly-NMe-3',5'-(CF 3 ) 2 -Bn ]，它结合了已建立的 Dmt 1 -DALDA 激动剂阿片类药效团（H- Dmt - d -Arg-Phe-Lys-NH 2）和20的 N