(Aib³)deltorphin C

• 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: (Aib³)deltorphin C
• 英文别名: (S)-3-(2-{(R)-2-[(S)-2-Amino-3-(4-hydroxy-phenyl)-propionylamino]-propionylamino}-2-methyl-propionylamino)-N-{(S)-1-[(S)-1-(carbamoylmethyl-carbamoyl)-2-methyl-propylcarbamoyl]-2-methyl-propyl}-succinamic acid；(3S)-3-[[2-[[(2R)-2-[[(2S)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]propanoyl]amino]-2-methylpropanoyl]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
• 化学式: C₃₂H₅₀N₈O₁₀
• 分子量: 706.797
• InChiKey: ALLCKKBLFVTNDT-CUUBPCRASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -3.1
• 重原子数：
  50
• 可旋转键数：
  19
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  301
• 氢给体数：
  10
• 氢受体数：
  11

反应信息

• 作为产物：
  描述：

  Fmoc-L-缬氨酸 、 Fmoc-L-天冬氨酸 、 Fmoc-D-丙氨酸 、 Fmoc-2-氨基异丁酸 、 alkaline earth salt of/the/ methylsulfuric acid 生成 (Aib³)deltorphin C
  参考文献：
  名称：

  Helix-Inducing α-Aminoisobutyric Acid in Opioid Mimetic Deltorphin C Analogues

  摘要：

  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.

  DOI：

  10.1021/jm9700530

文献信息

• 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.