N^α-<(tert-butyloxy)carbonyl>-(2S,3R)-2-(1-benzindanyl)glycine | 146000-59-1

• 分子结构分类: 有机化合物 - 苯类化合物 - 萘
• 英文名称: N^α-<(tert-butyloxy)carbonyl>-(2S,3R)-2-(1-benzindanyl)glycine
• 英文别名: N-Boc-(2S,3R)-benzindanylglycine
• CAS: 146000-59-1
• 化学式: C₂₀H₂₃NO₄
• 分子量: 341.407
• InChiKey: RPHHCCQCZQVOKJ-WBVHZDCISA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.85
• 重原子数：
  25.0
• 可旋转键数：
  3.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  75.63
• 氢给体数：
  2.0
• 氢受体数：
  3.0

反应信息

• 作为反应物：
  描述：

  N^α-<(tert-butyloxy)carbonyl>-(2S,3R)-2-(1-benzindanyl)glycine 、 三氟乙酸 以 二氯甲烷 为溶剂， 反应 0.5h， 生成 (R)-L-1-benzindanylglycine trifluoroacetic acid salt
  参考文献：
  名称：

  Design and Synthesis of Side-Chain Conformationally Restricted Phenylalanines and Their Use for Structure-Activity Studies on Tachykinin NK-1 Receptor

  摘要：

  Constrained analogues of phenylalanine have been conceptually designed for analyzing the binding pockets of Phe(7) (S-7) and Phe(8) (S-8), two aromatic residues important for the pharmacological properties of SP, i.e., L-tetrahydroisoquinoleic acid, L-diphenylalanine, L-9-fluorenylglycine (Flg), 2-indanylglycine, the diastereomers of L-1-indanylglycine (Ing) and L-1-benz[f]indanylglycine (Bfi), and the Z and E isomers of dehydrophenylalanine (Delta(z)Phe, Delta(E)Phe). Binding studies were performed with appropriate ligands and tissue preparations allowing the discrimination of the three tachykinin binding sites, NK-1, NK-2, and NK-3. The potencies of these agonists were evaluated in the guinea pig ileum bioassay. According to the binding data, we can conclude that the S-7 subsite is small, only the gauche (-) probe [(2S,3S)-Ing(7)]SP presents a high affinity for specific NK-1 binding sites. Surprisingly, the [Delta(E)Phe(7)]SP analogue, which projects the aromatic ring toward the trans orientation, is over 40-fold more potent than the Z isomer, [Delta(Z)Phe(7)]SP. A plausible explanation of these conflictual results Is that either the binding protein quenches the minor trans rotamer of [(2S,3S)-Ing(7)]SP in solution or this constrained amino acid side chain rotates when inserted in the protein. In position 8, the high binding affinities of [Flg(8)]SP and [(2S,3S)-Bfi(8)]SP suggest that the S-8 subsite is large enough to accept two aromatic rings in the gauche (-) and one aromatic ring in the trans direction. Peptides bearing two conformational probes in positions 7, 8, or 9 led to postulate that S-7, S-8, and S-9 subsites are independent from each other. The volumes available for side chains 7 and 8 can be estimated to be close to 110 and 240 Angstrom(3), respectively. The large volume of the S-8 subsite raises question on the localization of the SP-binding site in the NK-1 receptor. If SP were to bind in the transmembrane domains, the cleft defined by the seven transmembrane segments must rearrange during the binding process in order to bind a peptide in an ac-helical structure and at least one large binding subsite in position 8. Thus, indirect topographical analysis with constrained amino acids might contribute to the analysis of the receptor/ligand dynamics. Finally, this study demonstrates that a good knowledge of the peptidic backbone structure and a combination of constrained amino acids are prerequisites to confidently attribute the preferred orientation(s) of an amino acid side chain.

  DOI：

  10.1021/jm00037a009
• 作为产物：
  描述：

  (2S,3R)-2-(1-benzindanyl)glycinesultam 在 sodium sulfide 、 碳酸氢钠 作用下， 以 四氢呋喃 、 乙醇 为溶剂， 反应 13.0h， 生成 N^α-<(tert-butyloxy)carbonyl>-(2S,3R)-2-(1-benzindanyl)glycine
  参考文献：
  名称：

  Asymmetric synthesis of the diastereoisomers of L-1-indanylglycine and L-1-benz[f]indanylglycine, χ1,χ2-constrained side-chain derivatives of L-phenylalanine and L-2-naphthylalanine

  摘要：

  The diastereoisomers of L-1-indanylglycine and L-1-benz[f]indanylglycine, novel topographic tools and anologues of phenylalanine and 2-naphtylalanine, were synthesized from a sultam-derived glycine imine synthon alkylated by judicious electrophiles, and subsequent hydrolysis and sultam-cleavage. An X-ray analysis on one alkylation product established the beta-configuration.

  DOI：

  10.1016/0957-4166(92)80003-f

文献信息

• Tachykinin NK-1 receptor probed with constrained analogues of substance P
  作者：Sandrine Sagan、Hubert Josien、Philippe Karoyan、Alié Brunissen、Gérard Chassaing、Solange Lavielle

  DOI：10.1016/s0968-0896(96)00230-1

  日期：1996.12

  The action of rotameric probes introduced either in position 7 or 8 in the sequence of substance P (SP) was investigated, i.e. L-tetrahydroisoquinoleic acid (Tie), L-fluorenylglycine (Flg), L-diphenylalanine (Dip), the diastereoisomers of L-1-indanylglycine (Ing) and L-benz[f]indanylglycine (Bfi), the Z- and E-isomers of dehydrophenylalanine and dehydronaphthylalanine (Delta(Z)Phe, Delta(E)Phe, Delta(Z)Nal, Delta(E)Nal) and L-o,o'-dimethylphenylalanine (Dmp). The aim of this study was the topographical characterization of the binding subsites of human NK-1 receptor expressed in CHO cells, especially the S-7 and S-8 subsites, corresponding to residues Phe(7) and Phe(8) of substance P. According to the binding potencies of these substituted-SP analogues, the S-7 binding subsite is smaller than the S-8 subsite: the S-7 subsite accepts only one aromatic nucleus, while the S-8 can accommodate three coplanar nuclei altogether. These findings are compatible with the idea that the S, binding subsite may reside in the extracellular loops of the hNK-1 receptor. NK-1 agonists bind to human NK-1 receptor and activate the production of both inositol phosphates and cyclic AMP. As already quoted for septide, [pGlu(6), Pro(9)]SP(6-11), discrepancies are observed between affinity (K-i) and activity (EC(50)) values for IPs production. While a weak correlation between K-i and EC(50) values for IPs production could be found (r=0.70), an excellent correlation could be demonstrated between their affinities (K-i) and their potencies (EC(50)) for cAMP production (r=0.97). The high potency (EC(50)) observed for 'septide-like' molecules on PI hydrolysis, compared to their affinity is not an artefact related to the high level of NK-1 receptors expressed on CHO cells since a good correlation was found between EC(50) values obtained for PI hydrolysis and those measured for spasmogenic activity in guinea pig ileum bioassay (r=0.94). Copyright (C) 1996 Elsevier Science Ltd