dynorphin<4-13> | 80238-77-3

• 分子结构分类: 有机化合物 - 有机聚合物 - 多肽
• 英文名称: dynorphin<4-13>
• 英文别名: dynorphin[4-13]
• CAS: 80238-77-3
• 化学式: C₆₂H₁₁₁N₂₁O₁₁
• 分子量: 1326.7
• InChiKey: PPTCIDZWQHPSCH-MIVUVDQZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -2.3
• 重原子数：
  94.0
• 可旋转键数：
  46.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.69
• 拓扑面积：
  554.17
• 氢给体数：
  21.0
• 氢受体数：
  16.0

反应信息

• 作为产物：
  描述：

  Z-Phe-Leu-Arg(Mds)-Arg(Mds)-Ile-Arg(Mds)-Pro-Lys(Boc)-Leu-Lys(Boc)-OBut 在 茴香硫醚 、 三氟乙酸 作用下， 反应 2.0h， 以43%的产率得到dynorphin<4-13>
  参考文献：
  名称：

  Use of the 4-methoxy-2,6-dimethylbenzenesulfonyl (Mds) group to synthesize dynorphin (1-13) and related peptides.

  摘要：

  报道了采用4-甲氧基-2,6-二甲基苯磺酰基(Mds)保护精氨酸胍基功能合成与强啡肽[1-13]氨基酸序列相对应的十三肽H-Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Ile-Arg-Pro-Lys-Leu-Lys-OH及相关截短肽[4-13]、[8-11]和[8-13]的方法。为合成强啡肽[1-13]，制备了三个片段1-3、4-10和11-13，并将其作为构建该肽氨基酸序列的模块。通过在50°C下用三氟乙酸-硫代茴香醚处理2小时来实现完全保护肽的最终脱保护，并且通过CM-纤维素柱色谱纯化这种合成肽。其他截短肽[4-13]、[8-11]和[8-13]以与强啡肽[1-13]相同的方式合成。Mds保护基团适用于含有精氨酸的肽的合成这一应用得到了确认。

  DOI：

  10.1248/cpb.29.2592

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.