H-(2R,3S)β-MeTrp-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-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: H-(2R,3S)β-MeTrp-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2
• 英文别名: H-D-Trp(bR-Me)-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2；(2R)-N-[(2S,3R)-1-amino-3-hydroxy-1-oxobutan-2-yl]-2-[[(2S,3R)-2-[[(2S)-2-[[(2R)-2-[[(2S)-2-[[(2R)-2-[[(2R,3R)-2-amino-3-(1H-indol-3-yl)butanoyl]amino]-3-sulfanylpropanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-3-hydroxybutanoyl]amino]-3-methyl-3-sulfanylbutanamide
• 化学式: C₅₄H₇₄N₁₄O₁₁S₂
• 分子量: 1159.4
• InChiKey: YCWDHLPZIHIYNZ-HOGAGRAASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.1
• 重原子数：
  81
• 可旋转键数：
  29
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  432
• 氢给体数：
  18
• 氢受体数：
  15

反应信息

• 作为反应物：
  描述：

  H-(2R,3S)β-MeTrp-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 在 potassium hexacyanoferrate(III) 作用下， 以 水 、 乙腈 为溶剂， 反应 2.0h， 以72.4%的产率得到H-(2R,3S)β-MeTrp-c[Cys-Tyr-D-Trp-Arg-Thr-Pen]-Thr-NH2
  参考文献：
  名称：

  Opiate Aromatic Pharmacophore Structure−Activity Relationships in CTAP Analogues Determined by Topographical Bias, Two-Dimensional NMR, and Biological Activity Assays

  摘要：

  Topographically constrained analogues of the highly mu-opioid-receptor-selective antagonist CTAP (H-D-Phe-c[Cys-Tyr-D-Trp-Arg-Thr-Pen]-Thr-NH2, 1) were prepared by solid-phase peptide synthesis. Replacement of the D-Phe residue with conformationally biased beta-methyl derivatives of phenylalanine or tryptophan (2R,3R; 2R,3S; 2S,3R; 2S,3S) yielded peptides that displayed widely varying types of biological activities. In an effort to correlate the observed biological activities of these analogues with their structures, two-dimensional H-1 NMR and molecular modeling was performed. Unlike the parent (1), which is essentially a pure mu antagonist with weak delta agonist activities in the MVD bioassay, the diastereomeric beta-MePhe(1)-containing peptides exhibited simultaneous delta agonism and mu antagonism by the (2R,3R)-containing isomer 2; mu antagonism by the (2R,3S)-containing isomer 3; weak mu agonism by the (2S,3R)-containing isomer 4; and delta agonism by the (2S,3S)-containing isomer 5. Incorporation of beta-MeTrp isomers into position 1 led to peptides that were mu antagonists (2R,3R), 8; (2R,3S), 9, or essentially inactive (<10%) in the MVD and GPI assays (2S,3R), 10; (2S,3S), 11. Interestingly, in vivo antinociceptive activity was predicted by neither MVD nor GPI bioactivity. When D-Trp was incorporated in position 1, the result (7) is a partial, yet relatively potent mu agonist which also displayed weak delta agonist activity. Molecular modeling based on 2D NMR revealed that low energy conformers of peptides with similar biological activities had similar aromatic pharmacophore orientations and interaromatic distances. Peptides that exhibit mu antagonism have interaromatic distances of 7.0-7.9 Angstrom and have their amino terminal aromatic moiety pointing in a direction opposite to the direction that the amino terminus points. Peptides with delta opioid activity displayed an interaromatic distance of <7 Angstrom and had their amino terminal aromatic moiety pointing in the same direction as the amino terminus.

  DOI：

  10.1021/jm9900218
• 作为产物：
  描述：

  N-Boc-O-苄基-L-苏氨酸 、 丁氧羰基-O-2,6-二氯苄基-L-酪氨酸 、 Boc-cysteine(4-Me-Bn) 、 N^α-Boc-(2R,3R)-β-MeTrp (Nⁱⁿ-MeS) 、 alkaline earth salt of/the/ methylsulfuric acid 、 alkaline earth salt of/the/ methylsulfuric acid 以127.9 mg的产率得到H-(2R,3S)β-MeTrp-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2
  参考文献：
  名称：

  Opiate Aromatic Pharmacophore Structure−Activity Relationships in CTAP Analogues Determined by Topographical Bias, Two-Dimensional NMR, and Biological Activity Assays

  摘要：

  Topographically constrained analogues of the highly mu-opioid-receptor-selective antagonist CTAP (H-D-Phe-c[Cys-Tyr-D-Trp-Arg-Thr-Pen]-Thr-NH2, 1) were prepared by solid-phase peptide synthesis. Replacement of the D-Phe residue with conformationally biased beta-methyl derivatives of phenylalanine or tryptophan (2R,3R; 2R,3S; 2S,3R; 2S,3S) yielded peptides that displayed widely varying types of biological activities. In an effort to correlate the observed biological activities of these analogues with their structures, two-dimensional H-1 NMR and molecular modeling was performed. Unlike the parent (1), which is essentially a pure mu antagonist with weak delta agonist activities in the MVD bioassay, the diastereomeric beta-MePhe(1)-containing peptides exhibited simultaneous delta agonism and mu antagonism by the (2R,3R)-containing isomer 2; mu antagonism by the (2R,3S)-containing isomer 3; weak mu agonism by the (2S,3R)-containing isomer 4; and delta agonism by the (2S,3S)-containing isomer 5. Incorporation of beta-MeTrp isomers into position 1 led to peptides that were mu antagonists (2R,3R), 8; (2R,3S), 9, or essentially inactive (<10%) in the MVD and GPI assays (2S,3R), 10; (2S,3S), 11. Interestingly, in vivo antinociceptive activity was predicted by neither MVD nor GPI bioactivity. When D-Trp was incorporated in position 1, the result (7) is a partial, yet relatively potent mu agonist which also displayed weak delta agonist activity. Molecular modeling based on 2D NMR revealed that low energy conformers of peptides with similar biological activities had similar aromatic pharmacophore orientations and interaromatic distances. Peptides that exhibit mu antagonism have interaromatic distances of 7.0-7.9 Angstrom and have their amino terminal aromatic moiety pointing in a direction opposite to the direction that the amino terminus points. Peptides with delta opioid activity displayed an interaromatic distance of <7 Angstrom and had their amino terminal aromatic moiety pointing in the same direction as the amino terminus.

  DOI：

  10.1021/jm9900218

文献信息

• Opiate Aromatic Pharmacophore Structure−Activity Relationships in CTAP Analogues Determined by Topographical Bias, Two-Dimensional NMR, and Biological Activity Assays
  作者：G. Gregg Bonner、Peg Davis、Dagmar Stropova、Sidney Edsall、Henry I. Yamamura、Frank Porreca、Victor J. Hruby

  DOI：10.1021/jm9900218

  日期：2000.2.1

  Topographically constrained analogues of the highly mu-opioid-receptor-selective antagonist CTAP (H-D-Phe-c[Cys-Tyr-D-Trp-Arg-Thr-Pen]-Thr-NH2, 1) were prepared by solid-phase peptide synthesis. Replacement of the D-Phe residue with conformationally biased beta-methyl derivatives of phenylalanine or tryptophan (2R,3R; 2R,3S; 2S,3R; 2S,3S) yielded peptides that displayed widely varying types of biological activities. In an effort to correlate the observed biological activities of these analogues with their structures, two-dimensional H-1 NMR and molecular modeling was performed. Unlike the parent (1), which is essentially a pure mu antagonist with weak delta agonist activities in the MVD bioassay, the diastereomeric beta-MePhe(1)-containing peptides exhibited simultaneous delta agonism and mu antagonism by the (2R,3R)-containing isomer 2; mu antagonism by the (2R,3S)-containing isomer 3; weak mu agonism by the (2S,3R)-containing isomer 4; and delta agonism by the (2S,3S)-containing isomer 5. Incorporation of beta-MeTrp isomers into position 1 led to peptides that were mu antagonists (2R,3R), 8; (2R,3S), 9, or essentially inactive (<10%) in the MVD and GPI assays (2S,3R), 10; (2S,3S), 11. Interestingly, in vivo antinociceptive activity was predicted by neither MVD nor GPI bioactivity. When D-Trp was incorporated in position 1, the result (7) is a partial, yet relatively potent mu agonist which also displayed weak delta agonist activity. Molecular modeling based on 2D NMR revealed that low energy conformers of peptides with similar biological activities had similar aromatic pharmacophore orientations and interaromatic distances. Peptides that exhibit mu antagonism have interaromatic distances of 7.0-7.9 Angstrom and have their amino terminal aromatic moiety pointing in a direction opposite to the direction that the amino terminus points. Peptides with delta opioid activity displayed an interaromatic distance of <7 Angstrom and had their amino terminal aromatic moiety pointing in the same direction as the amino terminus.