(D-丙2,D-亮5)-脑啡肽 | 63631-40-3

• 物质功能分类: 生物化工 - 多肽
• 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
• 中文名称: (D-丙2,D-亮5)-脑啡肽
• 中文别名: (D-丙2)-D-亮脑啡肽
• 英文名称: (R)-2-[(S)-2-(2-{(R)-2-[(S)-2-Amino-3-(4-hydroxy-phenyl)-propionylamino]-propionylamino}-acetylamino)-3-phenyl-propionylamino]-4-methyl-pentanoic acid
• 英文别名: [D-Ala2, D-Leu5]-Enkephalin；(2R)-2-[(2S)-2-{2-[(2R)-2-[(2S)-2-amino-3-(4-hydroxyphenyl)propanamido]propanamido]acetamido}-3-phenylpropanamido]-4-methylpentanoic acid；2,D-Leu⁵>Leu-enkephalin；2, D-Leu⁵>nekephalin；2,D-Leu⁵>enkephalin；[D-Ala², D-Leu⁵]Leu-enkephalin；Dadle；(2R)-2-[[(2S)-2-[[2-[[(2R)-2-[[(2S)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]propanoyl]amino]acetyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoic acid
• CAS: 63631-40-3
• 化学式: C₂₉H₃₉N₅O₇
• mdl: MFCD00076411
• 分子量: 569.658
• InChiKey: ZHUJMSMQIPIPTF-IBURTVSXSA-N

物化性质

• 熔点：
  >167°C (dec.)
• 沸点：
  991.9±65.0 °C(Predicted)
• 密度：
  1.257±0.06 g/cm3(Predicted)
• 溶解度：
  可溶于DMSO（少许）、甲醇（少许）

计算性质

• 辛醇/水分配系数(LogP)：
  -1.9
• 重原子数：
  41
• 可旋转键数：
  15
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.413
• 拓扑面积：
  200
• 氢给体数：
  7
• 氢受体数：
  8

安全信息

• 储存条件：
  -15°C

制备方法与用途

DADLE（[D-Ala2, D-Leu5]-Enkephalin）是一种水溶性多肽类阿片受体激动剂。

反应信息

• 作为反应物：
  描述：

  (D-丙2,D-亮5)-脑啡肽 、 2,5-dioxopyrrolidin-1-yl 2-(6,7,8,9-tetrachloro-1,4-dioxaspiro[4.4]nona-6,8-dien-2-yl)acetate 在 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成
  参考文献：
  名称：

  用于生物正交标记的易于获得的两亲性环戊二烯

  摘要：

  描述了基于环戊二烯支架的一类新型生物正交试剂。二烯 6,7,8,9-四氯-1,4-二氧螺[4,4]nona-6,8-二烯（四氯环戊二烯缩酮，TCK）具有两亲性和自正交性，具有显着的稳定性。二烯与反式环辛烯和内式双环壬炔快速反应，但与二苯并氮杂环辛炔 (DIBAC) 反应缓慢，从而可以使用与 DIBAC 快速反应的相互正交叠氮化物进行串联标记研究。TCK 类似物由廉价的市售起始材料分三步合成。

  DOI：

  10.1021/jacs.8b02978
• 作为产物：
  描述：

  Fmoc-4,5-didehydro-DL-leucine 在 钯 p-Benzyloxybenzyl alcohol resin 、 氢气 、 N,N'-二环己基碳二亚胺 作用下， 以 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 4.0h， 生成 (D-丙2,D-亮5)-脑啡肽
  参考文献：
  名称：

  Hasegawa, Hiroshi; Shinohara, Yoshihiko; Baba, Shigeo, Journal of the Chemical Society. Perkin transactions I, 1990, # 10, p. 2641 - 2644

  摘要：

  DOI：

文献信息

• ——
  作者：Olafur S. Gudmundsson、Giovanni M. Pauletti、Wei Wang、Daxian Shan、Huijuan Zhang、Binghe Wang、Ronald T. Borchardt

  DOI：10.1023/a:1018828207920

  日期：——

  did [Leu5]-enkephalin. Cyclic prodrug 2 and DADLE exhibited similar stability when applied to the AP side of the Caco-2 cell monolayer. Prodrug 1 was 665-fold more able to permeate the Caco-2 cell monolayers than was [Leu5]-enkephalin, in part because of its increased enzymatic stability. Prodrug 2 was shown to be approximately 31 fold more able to permeate a Caco-2 cell monolayer than was DADLE. CONCLUSIONS

  为评估阿片样肽[Leu5]-脑啡肽（H-Tyr-Gly-Gly-Phe-Leu-OH）和DADLE（基于香豆酸的环状前药1和2的细胞渗透特性以及化学和酶稳定性） H-Tyr-D-Ala-Gly-Phe-D-Leu-OH）。方法用HPLC测定在HBSS，pH 7.4（Caco-2细胞转运缓冲液）和具有可测量酯酶活性的各种生物介质中，环状前药1和2分别转化为[Leu5]-脑啡肽和DADLE的速率。[Leu5]-脑啡肽，DADLE以及环状前药1和2的细胞渗透特性使用生长在微孔膜上的Caco-2细胞单层进行测量，并通过HPLC进行监测。结果在pH 7.4的HBSS中，环状前药1和2化学降解为中间体，并进一步降解为[Leu5]-脑啡肽和DADLE，分别以化学计量的量。在90％的人血浆和大鼠肝脏匀浆中，环状前药1和2的消失明显快于HBSS（pH 7.4）。用对氧磷（一种已知的丝氨酸依赖性酯酶抑制剂）预
• ——
  作者：Olafur S. Gudmundsson、Kalpana Nimkar、Sanjeev Gangwar、Teruna Siahaan、Ronald T. Borchardt

  DOI：10.1023/a:1018802324759

  日期：——

  side of a Caco-2 cell monolayer, cyclic prodrug 1 exhibited significantly greater stability against peptidase metabolism than did [Leu5]-enkephalin. Cyclic prodrug 2 and DADLE exhibited stability similar to prodrug 1 when applied to the AP side of the Caco-2 cell monolayers. Prodrug 1 was 1680 fold more able to permeate the Caco-2 cell monolayers than was [Leu5]-enkephalin, in part because of its increased

  目的评估阿片肽[Leu5]-脑啡肽（H-Tyr-Gly-Gly-Phe-Leu-OH）和DADLE（H）的基于苯丙酸的环状前药1和2的细胞渗透特性以及化学和酶稳定性-Tyr-D-Ala-Gly-Phe-D-Leu-OH）。方法通过HPLC测定在HBSS，pH 7.4（Caco-2细胞转运缓冲液）和具有可测量酯酶活性的各种生物介质中，环状前药1和2分别转化为[Leu5]-脑啡肽和DADLE的速率。使用生长在微孔膜上的Caco-2细胞单层测量[Leu5]-脑啡肽，DADLE和环状前药1和2的细胞渗透特性，并通过HPLC进行监测。结果在pH 7.4的HBSS中，环状前药1和2以化学计量的量分别降解为[Leu5]-脑啡肽和DADLE。在90％的人类血浆中，环状前药1和2的消失速率比pH 7.4的HBSS快。通过用已知的丝氨酸依赖性酯酶抑制剂对氧磷预处理血浆，可以将90％的人类血浆中这些加快的消失速度降低至在HBSS
• Pentapeptide vom Encephalintyp, Verfahren zur Herstellung derselben und diese enthaltende Arzneimittel
  申请人：Richter Gedeon Vegyészeti Gyár R.T.

  公开号：EP0033504A2

  公开（公告）日：1981-08-12

  Die Anmeldung betrifft Pentapeptide vom Encephalintyp der allgemeinen Formel worin Tyr, Gly, Phe, X und Y die in den Ansprüchen angegebene Bedeutung haben, sowie ein Verfahren zu ihrer Herstellung. Diese Verbindungen können in Arzneimitteln auf dem Gebiet der Therapie, insbesondere zum Beeinflussen desZentralnervensystemes, vor allem als Opiate, verwendet werden.

  本申请涉及通式如下的脑啡肽类五肽 其中 Tyr、Gly、Phe、X 和 Y 具有权利要求中给出的含义，以及制备它们的工艺。 这些化合物可用于治疗领域的药物，特别是用于影响中枢神经系统，尤其是作为鸦片制剂。
• Coumarin-based prodrugs 2. Synthesis and bioreversibility studies of an esterase-sensitive cyclic prodrug of dadle, an opioid peptide
  作者：Binghe Wang、Wei Wang、Huijuan Zhang、Daxian Shan、Terrill D. Smith

  DOI：10.1016/s0960-894x(96)00526-4

  日期：1996.12

  A coumarin-based esterase-sensitive cyclic prodrug of an opioid peptide, DADLE, was prepared. The cyclic prodrug quickly released (t(1/2) = 761 min) its original peptide, DADLE, upon esterase catalyzed hydrolysis. Such a system can be used for the preparation of cyclic prodrugs of other biologically active peptides aimed at improving their bioavailability. Copyright (C) 1996 Elsevier Science Ltd
• ——
  作者：Annette Bak、Olafur S. Gudmundsson、Gitte J. Friis、Teruna J. Siahaan、Ronald T. Borchardt

  DOI：10.1023/a:1018854308829

  日期：——

  Purpose. To evaluate the chemical and enzymatic stability, as well as the cellular permeation characteristics, of the acyloxyalkoxy-based cyclic prodrugs (1) under bar and (2) under bar of the opioid peptides [Leu(5)]-enkephalin (H-Tyr-Cly-Gly-Phe-Leu-OH) and DADLE (H-Tyr-D-Ala-Gly-Phe-D-Leu-OH), respectively.Methods. The rates of conversion of (1) under bar and (2) under bar to [Leu(5)]-enkephalin and DADLE, respectively, were measured by HPLC in HBSS, pH = 7.4, and in various biological media (e.g., human plasma and Caco-2 cell and rat liver homogenates) having measurable esterase activity. The cellular permeation and metabolism characteristics of [Leu(5)]-enkephalin, DADLE and the cyclic prodrugs (1) under bar and (2) under bar were measured using Caco-2 cell monolayers grown onto microporous membranes and monitored by HPLC.Results. Cyclic prodrugs (1) under bar and (2) under bar degraded slowly but stoichiometrically to [Leu(5)]-enkephalin and DADLE, respectively, in HBS, pH = 7.4. In homogenates of Caco-2 cells and rat liver, as well as 90% human plasma, the rates of disappearance of the cyclic prodrugs were significantly faster than in HBSS. The stabilities of the cyclic prodrugs (1) under bar and (2) under bar were increased significantly in 90% human plasma and Caco-2 cell homogenates when paraoxon, a potent inhibitor of serine-dependent esterases, was included in the incubation mixtures. A similar stabilizing effect of paraoxon was not observed in 50% rat liver homogenates, but was observed in 10% homogenates of rat liver. When applied to the AP side of a Caco-2 cell monolayer, DADLE and cyclic prodrugs (1) under bar and (2) under bar exhibited significantly greater stability than [Leu(5)]-enkephalin. Based on their physicochemical properties (i.e., lipophilicity), cyclic prodrugs (1) under bar and (2) under bar should have exhibited high permeation across Caco-2 cell monolayers. Surprisingly, the AP-to-BL apparent permeability coefficients (P-App) for cyclic prodrugs (1) under bar and (2) under bar across Caco-2 cell monolayers were significantly lower than the P-App value determined for the metabolically stable opioid peptide DADLE. When the P-App values for cyclic prodrugs (1) under bar and (2) under bar crossing Caco-2, cell monolayers in the BL-to-AP direction were determined, they were shown to be 36 and 52 times greater, respectively, than the AP-to-BL values.Conclusions. Cyclic prodrugs (1) under bar and (2) under bar prepared with an acyloxyalkoxy promoiety, were shown to degrade in biological media (e.g,, 90% human plasma) via an esterase-catalyzed pathway. The degradation of cyclic prodrug (1) under bar, which contained an ester formed with an L-amino acid, degraded more rapidly in esterase-containing media than did prodrug (2) under bar, which contained an ester formed with a D-amino acid. Cyclic prodrugs (1) under bar and (2) under bar showed very low AP-to-BL Caco-2 cell permeability, which did not correlate with their lipophilicities. These low AP-to-BL permeabilities result because of their substrate activity for apically polarized efflux systems.