(4S,5aR)-5-乙基-2-甲基-4-丙基-4,5,5a,6-四氢二苯并[cd,f]吲哚-9,10-二酚 | 89202-80-2

• 分子结构分类: 有机化合物 - 有机聚合物 - 多肽
• 中文名称: (4S,5aR)-5-乙基-2-甲基-4-丙基-4,5,5a,6-四氢二苯并[cd,f]吲哚-9,10-二酚
• 英文名称: Dyn A-(3-13)
• 英文别名: dynorphin A-(3-13)；Gly-Phe-Leu-Arg-Arg-Ile-Arg-Pro-Lys-Leu-Lys；Dynorphin (3-13)；(2S)-6-amino-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-1-[(2S)-2-[[(2S,3S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[(2-aminoacetyl)amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-3-methylpentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]pyrrolidine-2-carbonyl]amino]hexanoyl]amino]-4-methylpentanoyl]amino]hexanoic acid
• CAS: 89202-80-2
• 化学式: C₆₄H₁₁₄N₂₂O₁₂
• 分子量: 1383.75
• InChiKey: PFFZBADPABUCLS-SLDTZEJCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -4.1
• 重原子数：
  98
• 可旋转键数：
  48
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.69
• 拓扑面积：
  591
• 氢给体数：
  19
• 氢受体数：
  18

反应信息

• 作为产物：
  描述：

  Fmoc-甘氨酸 、 Fmoc-L-亮氨酸 、 Fmoc-L-脯氨酸 、 Fmoc-L-苯丙氨酸 、 Fmoc-L-异亮氨酸 、 FMOC-赖氨酸 、 FMOC-L-精氨酸 在 1-羟基苯并三唑 、 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 N,N-二异丙基乙胺 、 哌啶 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 1.33h， 生成 (4S,5aR)-5-乙基-2-甲基-4-丙基-4,5,5a,6-四氢二苯并[cd,f]吲哚-9,10-二酚
  参考文献：
  名称：

  Discovery of Amphipathic Dynorphin A Analogues to Inhibit the Neuroexcitatory Effects of Dynorphin A through Bradykinin Receptors in the Spinal Cord

  摘要：

  We hypothesized that under chronic pain conditions, up-regulated dynorphin A (Dyn A) interacts with bradykinin receptors (BRs) in the spinal cord to promote hyperalgesia through an excitatory effect, which is opposite to the well-known inhibitory effect of opioid receptors Considering the structural dissimilarity between Dyn A and endogenous BR ligands, bradykinin (BK) and kallidin (1(1)), this interaction could not be predicted, but it allowed us to discover a potential neuroexcitatory target. Well-known BR ligands, BK, [des-Arg(10), Leu(9)]-kallidin (DALKD), and HOE140 showed different binding profiles at rat brain BRs than that previously reported. These results suggest that neuronal BRs in the rat central nervous system (CNS) may be pharmacologically distinct from those previously defined in non-neuronal tissues. Systematic structure activity relationship (SAR) study at the rat brain BRs was performed, and as a result, a new key structural feature of Dyn A for BR recognition was identified: amphipathicity. NMR studies of two lead ligands, Dyn A-(4-11) 7 and [des-Arg(7)]-Dyn A-(4-11) 14, which showed the same high binding affinity, confirmed that the Arg residue in position 7, which is known to be crucial for Dyn A's biological activity, is not necessary, and that a type I beta-turn structure at the C-terminal part of both ligands plays an important role in retaining good binding affinities at the BRs. Our lead ligand 14 blocked Dyn A-(2-13) 10-induced hyperalgesic effects and motor impairment in in vivo assays using naive rats. In a model of peripheral neuropathy, intrathecal (i.th.) administration of ligand 14 reversed thermal hyperalgesia and mechanical hypersensitivity in a dose-dependent manner in nerve-injured rats. Thus, ligand 14 may inhibit abnormal pain states by blocking the neuroexcitatory effects of enhanced levels of Dyn A, which are likely to be mediated by BRs in the spinal cord.

  DOI：

  10.1021/ja501677q

文献信息

• Discovery of Amphipathic Dynorphin A Analogues to Inhibit the Neuroexcitatory Effects of Dynorphin A through Bradykinin Receptors in the Spinal Cord
  作者：Yeon Sun Lee、Dhanasekaran Muthu、Sara M. Hall、Cyf Ramos-Colon、David Rankin、Jackie Hu、Alexander J. Sandweiss、Milena De Felice、Jennifer Yanhua Xie、Todd W. Vanderah、Frank Porreca、Josephine Lai、Victor J. Hruby

  DOI：10.1021/ja501677q

  日期：2014.5.7

  We hypothesized that under chronic pain conditions, up-regulated dynorphin A (Dyn A) interacts with bradykinin receptors (BRs) in the spinal cord to promote hyperalgesia through an excitatory effect, which is opposite to the well-known inhibitory effect of opioid receptors Considering the structural dissimilarity between Dyn A and endogenous BR ligands, bradykinin (BK) and kallidin (1(1)), this interaction could not be predicted, but it allowed us to discover a potential neuroexcitatory target. Well-known BR ligands, BK, [des-Arg(10), Leu(9)]-kallidin (DALKD), and HOE140 showed different binding profiles at rat brain BRs than that previously reported. These results suggest that neuronal BRs in the rat central nervous system (CNS) may be pharmacologically distinct from those previously defined in non-neuronal tissues. Systematic structure activity relationship (SAR) study at the rat brain BRs was performed, and as a result, a new key structural feature of Dyn A for BR recognition was identified: amphipathicity. NMR studies of two lead ligands, Dyn A-(4-11) 7 and [des-Arg(7)]-Dyn A-(4-11) 14, which showed the same high binding affinity, confirmed that the Arg residue in position 7, which is known to be crucial for Dyn A's biological activity, is not necessary, and that a type I beta-turn structure at the C-terminal part of both ligands plays an important role in retaining good binding affinities at the BRs. Our lead ligand 14 blocked Dyn A-(2-13) 10-induced hyperalgesic effects and motor impairment in in vivo assays using naive rats. In a model of peripheral neuropathy, intrathecal (i.th.) administration of ligand 14 reversed thermal hyperalgesia and mechanical hypersensitivity in a dose-dependent manner in nerve-injured rats. Thus, ligand 14 may inhibit abnormal pain states by blocking the neuroexcitatory effects of enhanced levels of Dyn A, which are likely to be mediated by BRs in the spinal cord.