deltorphin C | 122752-15-2

• 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: deltorphin C
• 英文别名: H-Tyr-D-Ala-Phe-Asp-Val-Val-Gly-NH2；Tyr-D-Ala-Phe-Asp-Val-Val-Cly-NH2；[D-Ala²]deltorphin-I；[125I]-deltorphin I；deltorphin I；(3S)-3-[[(2S)-2-[[(2R)-2-[[(2S)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]propanoyl]amino]-3-phenylpropanoyl]amino]-4-[[(2S)-1-[[(2S)-1-[(2-amino-2-oxoethyl)amino]-3-methyl-1-oxobutan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-4-oxobutanoic acid
• CAS: 122752-15-2
• 化学式: C₃₇H₅₂N₈O₁₀
• mdl: MFCD00080071
• 分子量: 768.867
• InChiKey: CJAORFIPPWIGPG-QXYJMILXSA-N

物化性质

• 沸点：
  1242.4±65.0 °C(Predicted)
• 密度：
  1.284±0.06 g/cm3(Predicted)
• 溶解度：
  在 50% 乙腈/水中可溶解至 0.40 mg/ml

计算性质

• 辛醇/水分配系数(LogP)：
  -1.7
• 重原子数：
  55
• 可旋转键数：
  21
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.459
• 拓扑面积：
  301
• 氢给体数：
  10
• 氢受体数：
  11

制备方法与用途

生物活性

Deltorphin I 是一种高亲和力的选择性 δ-阿片受体 (δ-opioid receptor) 激动剂。

靶点

δ-opioid receptor

体内研究

连续4天，每天两次给予小鼠20μg Deltorphin I，会导致对Deltorphin I镇痛效果的耐受性增加。第1天至第4天之间，注射后10分钟的峰值镇痛反应从8.36±0.28秒减少到4.53±0.14秒。同时给予每天两次的小剂量褪黑素（0.5、1 和 2.5 mg/kg）和 Deltorphin I（20 μg/mouse），可以在统计学意义上显著减轻对Deltorphin I镇痛效果的耐受性，并且这种作用具有剂量依赖性。

反应信息

• 作为反应物：
  描述：

  Langlois reagent 、 deltorphin C 在 [Ir(dF(CF₃)ppy)₂(dtbbpy)](PF₆) 、 溶剂黄146 作用下， 以 水 、 乙腈 为溶剂， 以17%的产率得到
  参考文献：
  名称：

  肽的保护基团自由基 C–H 三氟甲基化†

  摘要：

  已经开发了两种基于自由基的方法，使用化学计量氧化剂或可见光光氧化还原催化来实现天然肽中芳基 C-H 键的三氟甲基化。所报道的方法能够在生物相容性条件下衍生化酪氨酸和色氨酸侧链，并且报道了许多涉及具有多达51个氨基酸的完全未受保护的肽的例子。这种化学的发展增加了越来越多的化学方法，用于选择性修饰复杂肽中的氨基酸残基。将三氟甲基直接掺入生物聚合物中可以研究一系列生物和生化系统，初步结果表明该方法可以扩展到掺入其他氟烷基用于生物共轭应用。

  DOI：

  10.1039/c8sc00368h
• 作为产物：
  描述：

  Boc-Tyr-D-Ala-Phe-OH 在 N-甲基吗啉 、 1-羟基苯并三唑 、 N,N'-二环己基碳二亚胺 、 三氟乙酸 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 27.0h， 生成 deltorphin C
  参考文献：
  名称：

  Unique sequence in deltorphin C confers structural requirement for δ opioid receptor selectivity

  摘要：

  A series of deltorphin C (H-Tyr-D-Ala-Phe-Asp-Val-Val-Gly-NH2) analogues were synthesized to assess the consequences of changing anionic and hydrophobic residues on delta receptor selectivity. Analogues with altered C-terminal groups, inverted sequences, or esterified with tert-butyl, benzyl, or ethyl groups revealed that high delta selectivity required an unmodified amino acid sequence. Shifts of Asp and hydrophobic residues decreased delta selectivity due to loss in delta affinity (5- to almost-equal-to 700-fold); mu affinity was unchanged or increased 14-fold. Suppression of charge or deamidation diminished delta selectivity through reduced delta and modified mu affinities. Data provide evidence that a negative charge does not a priori guarantee high selectivity and specific alignment of anionic and hydrophobic residues might facilitate optimum spatial configuration which complements the 8 receptor binding site.

  DOI：

  10.1016/0223-5234(92)90113-f

文献信息

• Conformationally restricted deltorphin analogs
  作者：Peter W. Schiller、Grazyna Weltrowska、Thi M. D. Nguyen、Brian C. Wilkes、Nga N. Chung、Carole Lemieux

  DOI：10.1021/jm00099a025

  日期：1992.10

  of Phe3 in [D-Ala2]deltorphin I with 2-aminoindan-2-carboxylic acid (Aic) or L- or D-2-aminotetralin-2-carboxylic acid (Atc) resulted in agonist compounds which retained the high delta receptor selectivity of the parent peptide. Substitution of a tetrahydroisoquinoline-3-carboxylic acid (Tic) residue in the 2-position of [D-Ala2]deltorphin I and of [Phe4,Nle6]deltorphin produced a partial delta agonist

  通过在肽序列的2或3位上掺入环状苯丙氨酸类似物或通过各种侧链至侧链环化来合成构象受限的deltorphin类似物。在mu，delta和kappa受体选择性结合测定以及豚鼠回肠（GPI）和小鼠输精管（MVD）生物测定中测试了化合物。用2-氨基茚满-2-羧酸（Aic）或L-或D-2-氨基四氢-2-羧酸（Atc）取代[D-Ala2] deltorphin I中的Phe3产生保留高δ受体的激动剂化合物母体肽的选择性。在[D-Ala2] deltorphin I和[Phe4，Nle6] deltorphin的2-位上取代四氢异喹啉-3-羧酸（Tic）残基产生部分δ激动剂，H-Tyr-Tic-Phe-Asp- Val-Val-Gly-NH2，和纯δ拮抗剂，分别为H-Tyr-Tic-Phe-Phe-Leu-Nle-Asp-NH2。后者的拮抗剂表现出高的δ选择性（Ki mu / Kiδ＝ 502），并且在
• Probing the Stereochemical Requirements for Receptor Recognition of δ Opioid Agonists through Topographic Modifications in Position 1
  作者：Xinhua Qian、Mark D. Shenderovich、Katalin E. Kövér、Peg Davis、Robert Horváth、Teresa Zalewska、Henry I. Yamamura、Frank Porreca、Victor J. Hruby

  DOI：10.1021/ja954241w

  日期：1996.1.1

  A series of side-chain constrained tyrosine derivatives, 2‘,6‘-dimethyl-β-methyltyrosines (TMT), has been designed and incorporated into position 1 of the highly selective δ opioid agonists DPDPE (Tyr-d-Pen2-Gly-Phe-d-Pen5-OH) and deltorphin I (DELT I, Tyr-d-Ala-Phe-Asp-Val-Val-Gly-NH2). Molecular mechanics calculations on isolated TMT residues and nuclear magnetic resonance (NMR) studies of the TMT1-containing

  一系列侧链受限的酪氨酸衍生物 2',6'-二甲基-β-甲基酪氨酸 (TMT) 已被设计并整合到高选择性 δ 阿片类激动剂 DPDPE (Tyr-d-Pen2-Gly- Phe-d-Pen5-OH）和德尔托芬 I（DELT I，Tyr-d-Ala-Phe-Asp-Val-Val-Gly-NH2）。分离的 TMT 残基的分子力学计算和 DMSO 中含有 TMT1 的肽的核磁共振 (NMR) 研究表明，TMT 的四种立体异构体中的每一种都有利于侧链 χ1 扭转角的一个特定旋转异构体。因此，将四个 TMT 异构体替换为 Tyr1 使我们能够通过芳香侧链的三个交错旋转异构体、gauche (-)、反式和 gauche (+) 进行系统构象扫描，并探索受体在侧链构象的关系。
• Helix-Inducing α-Aminoisobutyric Acid in Opioid Mimetic Deltorphin C Analogues
  作者：Sharon D. Bryant、Remo Guerrini、Severo Salvadori、Clementina Bianchi、Roberto Tomatis、Martti Attila、Lawrence H. Lazarus

  DOI：10.1021/jm9700530

  日期：1997.8.1

  The achiral symmetric alpha-aminoisobutyric acid (Aib) replaced the critical N-terminal residues of the amphibian skin opioid deltorphin C (H-Tyr-D-Ala-Phe-Asp-Val-Val-Gly-NH2) without detriment to the physicochemical requirements for delta opioid receptor recognition. Substitutions by the alpha,alpha-dialkyl amino acid in place of D-Ala(2) or Phe(3), or both, exhibited high delta receptor affinity (K-i delta = 0.12-3.6 nM) and 5-9-fold greater selectivity (K-i mu/K-i delta = 5000-8500) than the parent compound. This is the first definitive demonstration that the D-chirality of alanine and the aromaticity of phenylalanine are replaceable by an achiral alpha,alpha-dialkylated residue without detrimental effects on ligand binding. Incorporation of the mono-alpha-alkyl amino acid L- or D-Ala at the third position also produced highly selective delta ligands (K-i mu/K-i delta = 2000-3500), albeit with reduced delta affinities (K-i delta = 6-15 nM). Replacement of the anionic residue Asp(4) by Aib yielded an opioid peptide that fit two-site binding models for the delta receptor (eta = 0.763; P < 0.0001) and displayed dual high affinity for both delta and mu receptors, emphasizing the repulsive effect by a negative charge at mu receptor sites and the insignificance of Asp for delta affinity. Molecular dynamics conformational analyses suggested that Aib residues caused distinct changes in deltorphin C secondary structure when substituted for D-Ala(2), Asp(4) and simultaneously D-Ala(2) and Phe(3) but not when substituted for Phe(3). These conformational changes might be critical factors for the proper orientation of reactive constituents of residues in the N-terminal region of deltorphin C. Disparities between binding data and functional bioassays of [Aib(3)] indicated that Phe(3) was required for bioactivity in mouse vas deferens but not for interaction with delta opioid receptors in rat brain membranes.
• Sivanandaiah, K. M.; Babu, V. V. Suresh; Renukeshwar, H. C., Indian Journal of Chemistry - Section B Organic and Medicinal Chemistry, 1993, vol. 32, # 4, p. 465 - 467
  作者：Sivanandaiah, K. M.、Babu, V. V. Suresh、Renukeshwar, H. C.、Gangadhar, B. P.

  DOI：——

  日期：——
• Unique sequence in deltorphin C confers structural requirement for δ opioid receptor selectivity
  作者：LH Lazarus、S Salvadori、P Grieco、WE Wilson、R Tomatis

  DOI：10.1016/0223-5234(92)90113-f

  日期：1992.11

  A series of deltorphin C (H-Tyr-D-Ala-Phe-Asp-Val-Val-Gly-NH2) analogues were synthesized to assess the consequences of changing anionic and hydrophobic residues on delta receptor selectivity. Analogues with altered C-terminal groups, inverted sequences, or esterified with tert-butyl, benzyl, or ethyl groups revealed that high delta selectivity required an unmodified amino acid sequence. Shifts of Asp and hydrophobic residues decreased delta selectivity due to loss in delta affinity (5- to almost-equal-to 700-fold); mu affinity was unchanged or increased 14-fold. Suppression of charge or deamidation diminished delta selectivity through reduced delta and modified mu affinities. Data provide evidence that a negative charge does not a priori guarantee high selectivity and specific alignment of anionic and hydrophobic residues might facilitate optimum spatial configuration which complements the 8 receptor binding site.