N^α-Boc-(2R,3R)β-MePhe

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 苯丙酸
• 英文名称: N^α-Boc-(2R,3R)β-MePhe
• 英文别名: N^α-Boc-(2R,3S)-β-MePhe；(2R,3S)-2-tert-Butoxycarbonylamino-3-phenyl butyric acid；(2R,3S)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-phenylbutanoic acid
• 化学式: C₁₅H₂₁NO₄
• 分子量: 279.336
• InChiKey: XFSLNPBJZAPTMM-CMPLNLGQSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  20
• 可旋转键数：
  6
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  75.6
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  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-Trp(Mts)-OH 、 N^α-Boc-(2R,3R)β-MePhe 、 alkaline earth salt of/the/ methylsulfuric acid 生成 Ac-Nle-c(Asp-His-(2R,3S)-β-MePhe-Arg-Trp-Lys)-NH2
  参考文献：
  名称：

  β-Methylation of the Phe⁷ and Trp⁹ Melanotropin Side Chain Pharmacophores Affects Ligand−Receptor Interactions and Prolonged Biological Activity

  摘要：

  Topographically modified melanotropin side chain pharmacophore residues Phe(7) and Trp(9) in a cyclic peptide template (Ac-Nle(4)-c[Asp-His-Xaa(7)-Arg-Yaa(9)-Lys]-NH2) and Phe(7) in a linear peptide template (Ac-Ser-Tyr-Ser-Nle(4)-Glu-His-Xaa(7)-Arg-Trp-Gly-Lys-Pro-Val-NH2) result in differences in potency and prolonged biological activity in the frog and lizard skin bioassays. These topographic modifications included the four isomers of beta-methylphenylalanine (beta-MePhe)(7) and beta-methyltryptophan (beta-MeTrp)(9) and the two isomers of 1,2,3,4-tetrahydro-beta-carboline (Tea)(9) Modifications in the cyclic template resulted in up to a 1000-fold difference in potency for the beta-MePhe(7) stereoisomeric peptides; up to a 476-fold difference in potency resulted for the beta-MeTrp(9) peptides, and about a 50-fold difference between the Tca(9)-containing peptides. Up to a 40-fold difference in potency resulted for the beta-MePhe(7)? stereoisomeric peptides using the linear template in these assays. The relative potency racing for modifications in the cyclic template of beta-MePhe(7) were 2R,3S > 2S,3S = 2S,3R 2 > 2R,3R in the frog assay and 2S,3R > 2R,3S > 2S,3S > 2R,3R in the lizard assay. The relative potencies for modifications in the cyclic template of beta-MeTrp(9) were 2R,3S > 2R,3R > 2S,3R > 2S,3R in the frog assay and 2S,3S = 2R,3R > 2R,3S > 2S,3R in the lizard assay. The relative potencies for modifications in the cyclic template of Tca(9) were DTca > LTca in both assays, Significant differences in prolonged (residual) activities were also observed for these modified peptides and were dependent upon stereochemistry of the beta-methyl amino acid, peptide template, and bioassay system. Furthermore, comparisons of beta-MeTrp(9) stereoisomeric peptides on the frog, lizard, and human MC1 receptors suggest that structure-activity relationships on both the classical frog and lizard skin bioassays do not necessarily predict corresponding SAR profiles for the human melanocortin receptors, indicating a remarkable species specificity of the MC1 receptor requirements.

  DOI：

  10.1021/jm970018t

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.
• β-Methylation of the Phe⁷ and Trp⁹ Melanotropin Side Chain Pharmacophores Affects Ligand−Receptor Interactions and Prolonged Biological Activity
  作者：Carrie Haskell-Luevano、Kate Toth、Lakmal Boteju、Constatin Job、Ana Maria de L. Castrucci、Mac E. Hadley、Victor J. Hruby

  DOI：10.1021/jm970018t

  日期：1997.8.1

  Topographically modified melanotropin side chain pharmacophore residues Phe(7) and Trp(9) in a cyclic peptide template (Ac-Nle(4)-c[Asp-His-Xaa(7)-Arg-Yaa(9)-Lys]-NH2) and Phe(7) in a linear peptide template (Ac-Ser-Tyr-Ser-Nle(4)-Glu-His-Xaa(7)-Arg-Trp-Gly-Lys-Pro-Val-NH2) result in differences in potency and prolonged biological activity in the frog and lizard skin bioassays. These topographic modifications included the four isomers of beta-methylphenylalanine (beta-MePhe)(7) and beta-methyltryptophan (beta-MeTrp)(9) and the two isomers of 1,2,3,4-tetrahydro-beta-carboline (Tea)(9) Modifications in the cyclic template resulted in up to a 1000-fold difference in potency for the beta-MePhe(7) stereoisomeric peptides; up to a 476-fold difference in potency resulted for the beta-MeTrp(9) peptides, and about a 50-fold difference between the Tca(9)-containing peptides. Up to a 40-fold difference in potency resulted for the beta-MePhe(7)? stereoisomeric peptides using the linear template in these assays. The relative potency racing for modifications in the cyclic template of beta-MePhe(7) were 2R,3S > 2S,3S = 2S,3R 2 > 2R,3R in the frog assay and 2S,3R > 2R,3S > 2S,3S > 2R,3R in the lizard assay. The relative potencies for modifications in the cyclic template of beta-MeTrp(9) were 2R,3S > 2R,3R > 2S,3R > 2S,3R in the frog assay and 2S,3S = 2R,3R > 2R,3S > 2S,3R in the lizard assay. The relative potencies for modifications in the cyclic template of Tca(9) were DTca > LTca in both assays, Significant differences in prolonged (residual) activities were also observed for these modified peptides and were dependent upon stereochemistry of the beta-methyl amino acid, peptide template, and bioassay system. Furthermore, comparisons of beta-MeTrp(9) stereoisomeric peptides on the frog, lizard, and human MC1 receptors suggest that structure-activity relationships on both the classical frog and lizard skin bioassays do not necessarily predict corresponding SAR profiles for the human melanocortin receptors, indicating a remarkable species specificity of the MC1 receptor requirements.