Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH2

• 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: Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH2
• 英文别名: (3S,6R,9S,12R,15S,18S,26S)-18-[[(2S)-2-acetamidohexanoyl]amino]-12-benzyl-9-[3-(diaminomethylideneamino)propyl]-15-(1H-imidazol-5-ylmethyl)-6-(1H-indol-3-ylmethyl)-3-methyl-2,5,8,11,14,17,20-heptaoxo-1,4,7,10,13,16,21-heptazacyclohexacosane-26-carboxamide
• 化学式: C₅₃H₇₄N₁₆O₁₀
• 分子量: 1095.27
• InChiKey: WZIILWAZGXRRFZ-HXFDPMIZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -1.53
• 重原子数：
  79.0
• 可旋转键数：
  17.0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  411.36
• 氢给体数：
  15.0
• 氢受体数：
  12.0

反应信息

• 作为产物：
  描述：

  N-叔丁氧羰基-L-丙氨酸 、 N-叔丁氧羰基-N'-甲苯磺酰基-L-精氨酸 、 NAlpha-BOC-Nε-FMOC-L-赖氨酸 、 BOC-D-色氨酸(Nin-甲酰) 、 alkaline earth salt of/the/ methylsulfuric acid 生成 Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH2
  参考文献：
  名称：

  Biological and Conformational Examination of Stereochemical Modifications Using the Template Melanotropin Peptide, Ac-Nle-c[Asp-His-Phe-Arg-Trp- Ala-Lys]-NH₂, on Human Melanocortin Receptors

  摘要：

  Examination of conformationally constrained melanotropin peptides (Ac-Nle(4)-c[Asp(5)-His-Phe(7)-Arg-Trp(9)-Ala-Lys]-NH2) on four human melanotropin receptors (hMC1R, hMC3R, hMC4R, and hMC5R) resulted in identifying the importance of ligand stereochemistry at positions 5, 7, and 9 for agonist binding affinity and receptor selectivity. A trend in ligand structure-activity relationships emerged for these peptides, with the hMC1R and hMC4R possessing similar tendencies, as did the hMC3R and hMC5R. alpha-MSH (Ac-Ser-Tyr-Ser-Met(4)-Glu-His-Phe(7)-Arg-Trp-Gly-Lys-Pro-Val-NH2), NDP-MSH (Ac-Ser-Tyr-Ser-Nle(4)-Glu-His-D-Phe(7)-Arg-Pro-Val-NH2), and MTII (Ac-Nle(4)-c[Asp(5),D-Phe(7),Lys(10)]-alpha-MSH(4-10)-NH2) were also examined at each of these melanocortin receptors. Interestingly, the linear NDP-MSH possessed greater binding affinity for the hMC3R and hMC5R than did the cyclic analogue MTII. The peptide Ac-Nle-c[Asp-His-Phe-Arg-D-Trp(9)-Ala-Lys]-NH2 demonstrated the greatest differentiation in binding affinity between the hMC1R and hMC4R (78-fold). Analogue Ac-Nle-c[Asp-His-Phe(7)-Arg-Trp-Ala-Lys]-NH2 resulted in micromolar binding affinity (or greater) at the hMC3R and hMC5R, demonstrating the importance of D-Phe(7) for ligand binding potency at these receptors. Ac-c[Asp-His-Phe-Arg-Trp-Ala-Lys]-NH2 resulted in loss of binding affinity at the hMC5R, implicating the importance of Nle(4) (or a hydrophobic residue in this position) for binding to this receptor. Ac-Nle-c[D-Asp(5)-His-Phe-Arg-Trp-Ala-Lys]-NH2 was unable to competitively displace [I-125]NDP-MSH binding at micromolar concentrations on the hMC3R and hMC5R, suggesting the importance of chirality of Asp(5) either for ligand-receptor interactions or for orientation of the side chain lactam bridge and the structural integrity of the peptide conformation. Energy calculations performed for these peptides resulted in the identification of a low-energy ligand conformer family that is common to all the ligands. The differences in ligand binding affinities observed in this study are postulated to be a result of different ligand-receptor complexed interactions and not solely to the ligand structure.

  DOI：

  10.1021/jm960845e

文献信息

• Biological and Conformational Examination of Stereochemical Modifications Using the Template Melanotropin Peptide, Ac-Nle-c[Asp-His-Phe-Arg-Trp- Ala-Lys]-NH₂, on Human Melanocortin Receptors
  作者：Carrie Haskell-Luevano、Gregory Nikiforovich、Shubh D. Sharma、Ying-Kui Yang、Chris Dickinson、Victor J. Hruby、Ira Gantz

  DOI：10.1021/jm960845e

  日期：1997.5.1

  Examination of conformationally constrained melanotropin peptides (Ac-Nle(4)-c[Asp(5)-His-Phe(7)-Arg-Trp(9)-Ala-Lys]-NH2) on four human melanotropin receptors (hMC1R, hMC3R, hMC4R, and hMC5R) resulted in identifying the importance of ligand stereochemistry at positions 5, 7, and 9 for agonist binding affinity and receptor selectivity. A trend in ligand structure-activity relationships emerged for these peptides, with the hMC1R and hMC4R possessing similar tendencies, as did the hMC3R and hMC5R. alpha-MSH (Ac-Ser-Tyr-Ser-Met(4)-Glu-His-Phe(7)-Arg-Trp-Gly-Lys-Pro-Val-NH2), NDP-MSH (Ac-Ser-Tyr-Ser-Nle(4)-Glu-His-D-Phe(7)-Arg-Pro-Val-NH2), and MTII (Ac-Nle(4)-c[Asp(5),D-Phe(7),Lys(10)]-alpha-MSH(4-10)-NH2) were also examined at each of these melanocortin receptors. Interestingly, the linear NDP-MSH possessed greater binding affinity for the hMC3R and hMC5R than did the cyclic analogue MTII. The peptide Ac-Nle-c[Asp-His-Phe-Arg-D-Trp(9)-Ala-Lys]-NH2 demonstrated the greatest differentiation in binding affinity between the hMC1R and hMC4R (78-fold). Analogue Ac-Nle-c[Asp-His-Phe(7)-Arg-Trp-Ala-Lys]-NH2 resulted in micromolar binding affinity (or greater) at the hMC3R and hMC5R, demonstrating the importance of D-Phe(7) for ligand binding potency at these receptors. Ac-c[Asp-His-Phe-Arg-Trp-Ala-Lys]-NH2 resulted in loss of binding affinity at the hMC5R, implicating the importance of Nle(4) (or a hydrophobic residue in this position) for binding to this receptor. Ac-Nle-c[D-Asp(5)-His-Phe-Arg-Trp-Ala-Lys]-NH2 was unable to competitively displace [I-125]NDP-MSH binding at micromolar concentrations on the hMC3R and hMC5R, suggesting the importance of chirality of Asp(5) either for ligand-receptor interactions or for orientation of the side chain lactam bridge and the structural integrity of the peptide conformation. Energy calculations performed for these peptides resulted in the identification of a low-energy ligand conformer family that is common to all the ligands. The differences in ligand binding affinities observed in this study are postulated to be a result of different ligand-receptor complexed interactions and not solely to the ligand structure.