(2S)-5-(diaminomethylideneamino)-2-[[(2S)-3-(4-hydroxyphenyl)-2-[[(2S)-2-[4-(2-methylpropyl)phenyl]propanoyl]amino]propanoyl]amino]pentanamide | 1190366-69-8

• 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: (2S)-5-(diaminomethylideneamino)-2-[[(2S)-3-(4-hydroxyphenyl)-2-[[(2S)-2-[4-(2-methylpropyl)phenyl]propanoyl]amino]propanoyl]amino]pentanamide
• CAS: 1190366-69-8
• 化学式: C₂₈H₄₀N₆O₄
• 分子量: 524.663
• InChiKey: ZQVNXFPNPXEQDW-NWVWQQAFSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  38
• 可旋转键数：
  14
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  186
• 氢给体数：
  6
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  (S)-(+)-布洛芬 在 N-甲基吗啉 、 水 、 (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate 、 1-羟基苯并三唑 、 三氟乙酸 、 lithium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 29.0h， 生成 (2S)-5-(diaminomethylideneamino)-2-[[(2S)-3-(4-hydroxyphenyl)-2-[[(2S)-2-[4-(2-methylpropyl)phenyl]propanoyl]amino]propanoyl]amino]pentanamide
  参考文献：
  名称：

  Chemical Conjugation of the Neuropeptide Kyotorphin and Ibuprofen Enhances Brain Targeting and Analgesia

  摘要：

  The pharmaceutical potential of natural analgesic, peptides is mainly hampered by their inability to cross the blood-brain barrier, BBB. Increasing peptide-cell membrane Ibuprofen affinity through drug design is a promising strategy to overcome this limitation. To address this challenge, we grafted ibuprofen (IBP), a nonsteroidal anti-inflammatory drug, to kyotorphin (L-Tyr-L-Arg, KTP), an analgesic neuropeptide unable to cross BBB. Two new KTP derivatives, IBP-KTP (IbKTP-OH) and IBP-KTP-amide (IbKTP-NH2), were synthesized and characterized for membrane interaction, analgesic activity and mechanism of action. Ibuprofen enhanced peptide-membrane interaction, endowing a specificity for anionic fluid bilayers. A direct correlation between anionic lipid affinity and analgesic effect was established, IbKTP-NH2 being the most potent analgesic (from 25 mu mol.kg(-1)). In vitro, IbKTP-NH2 caused the biggest shift in the membrane surface charge of BBB endothelial cells, as quantified using zeta-potential dynamic light scattering. Our results suggest that IbKTP-NH2 crosses the BBB and acts by activating both opioid dependent and independent pathways.

  DOI：

  10.1021/mp2003016

文献信息

• Chemical Conjugation of the Neuropeptide Kyotorphin and Ibuprofen Enhances Brain Targeting and Analgesia
  作者：Marta M. B. Ribeiro、Antónia R. T. Pinto、Marco M. Domingues、Isa Serrano、Montserrat Heras、Eduard R. Bardaji、Isaura Tavares、Miguel A. Castanho

  DOI：10.1021/mp2003016

  日期：2011.10.3

  The pharmaceutical potential of natural analgesic, peptides is mainly hampered by their inability to cross the blood-brain barrier, BBB. Increasing peptide-cell membrane Ibuprofen affinity through drug design is a promising strategy to overcome this limitation. To address this challenge, we grafted ibuprofen (IBP), a nonsteroidal anti-inflammatory drug, to kyotorphin (L-Tyr-L-Arg, KTP), an analgesic neuropeptide unable to cross BBB. Two new KTP derivatives, IBP-KTP (IbKTP-OH) and IBP-KTP-amide (IbKTP-NH2), were synthesized and characterized for membrane interaction, analgesic activity and mechanism of action. Ibuprofen enhanced peptide-membrane interaction, endowing a specificity for anionic fluid bilayers. A direct correlation between anionic lipid affinity and analgesic effect was established, IbKTP-NH2 being the most potent analgesic (from 25 mu mol.kg(-1)). In vitro, IbKTP-NH2 caused the biggest shift in the membrane surface charge of BBB endothelial cells, as quantified using zeta-potential dynamic light scattering. Our results suggest that IbKTP-NH2 crosses the BBB and acts by activating both opioid dependent and independent pathways.