(4S,7S,13S)-13-[(S)-2-Amino-3-(4-hydroxy-phenyl)-propionylamino]-3,3,14,14-tetramethyl-7-[(S)-1-(4-nitro-phenyl)-ethyl]-6,9,12-trioxo-1,2-dithia-5,8,11-triaza-cyclotetradecane-4-carboxylic acid | 129073-55-8

• 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: (4S,7S,13S)-13-[(S)-2-Amino-3-(4-hydroxy-phenyl)-propionylamino]-3,3,14,14-tetramethyl-7-[(S)-1-(4-nitro-phenyl)-ethyl]-6,9,12-trioxo-1,2-dithia-5,8,11-triaza-cyclotetradecane-4-carboxylic acid
• 英文别名: (4S,7S,13S)-13-[[(2S)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]-3,3,14,14-tetramethyl-7-[(1S)-1-(4-nitrophenyl)ethyl]-6,9,12-trioxo-1,2-dithia-5,8,11-triazacyclotetradecane-4-carboxylic acid
• CAS: 129073-55-8
• 化学式: C₃₁H₄₀N₆O₉S₂
• 分子量: 704.825
• InChiKey: YOHHACNTFXDZSG-RVWMBUSMSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.5
• 重原子数：
  48
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  296
• 氢给体数：
  7
• 氢受体数：
  12

反应信息

• 作为产物：
  描述：

  BOC-甘氨酸 、 Boc-L-酪氨酸 、 N^α-(tert-butyloxycarbonyl)-S-(p-methylbenzyl)-D-penicillamine 、 N^a-tert-butoxycarbonyl-erythro-β-methyl-D,L-p-nitrophenylalanine 生成 (4S,7R,13S)-13-[(S)-2-Amino-3-(4-hydroxy-phenyl)-propionylamino]-3,3,14,14-tetramethyl-7-[(R)-1-(4-nitro-phenyl)-ethyl]-6,9,12-trioxo-1,2-dithia-5,8,11-triaza-cyclotetradecane-4-carboxylic acid 、 (4S,7S,13S)-13-[(S)-2-Amino-3-(4-hydroxy-phenyl)-propionylamino]-3,3,14,14-tetramethyl-7-[(S)-1-(4-nitro-phenyl)-ethyl]-6,9,12-trioxo-1,2-dithia-5,8,11-triaza-cyclotetradecane-4-carboxylic acid
  参考文献：
  名称：

  Topographically designed analogs of [cyclic] [D-Pen2,D-Pen5]enkephalin

  摘要：

  The conformationally restricted, cyclic disulfide-containing delta-opioid receptor selective enkephalin analogue [D-Pen2, D-Pen5]enkephalin (1, DPDPE) was systematically modified topographically by addition of a methyl group at either the pro-S or pro-R position of the beta-carbon of an L-Phe4 or D-Phe4 residue to give [(2S,3S)-beta-MePhe4]DPDPE (2), [(2R,3R)-beta-MePhe4]DPDPE (3), [(2S,3R)-beta-MePhe4]DPDPE (4), and [(2R,3S)-beta-MePhe4]DPDPE (5). The four corresponding isomers were prepared in which the beta-methylphenylalanine residue was p-nitro substituted, that is with a beta-methyl-p-nitrophenylalanine (beta-Me-p-NO2Phe) residue, to give [(2S,3S)-beta-Me-p-NO2Phe4]DPDPE (6), [(2R,3R)-beta-Me-p-NO2Phe4]DPDPE (7),[(2S,3R)-beta-Me-p-NO2Phe4]DPDPE (8), and [(2R,3S)-beta-Me-p-NO2Phe4]DPDPE (9), respectively. The potency and selectivity (delta vs mu-opioid receptor) were evaluated by radioreceptor binding assays in the rat brain using [H-3]CTOP (mu-ligand) and [H-3]DPDPE (delta-ligand) and by bioassay with mouse vas deferens (MVD, delta-receptor assay) and guinea pig ileum (GPI, mu-receptor assay). The eight analogues of DPDPE showed highly variable binding and bioassay activities particularly at the delta-opioid receptor (4 orders of magnitude), but also at the mu-opioid receptor, which led to large differences (3 orders of magnitude) in receptor selectivity. For example, [(2S,3S)-beta-MePhe4]DPDPE (2) is 1800-fold selective in binding to the delta vs mu-receptor, making it one of the most selective delta-opioid receptor ligands in the enkephalin series as assessed by the rat brain binding assay, whereas the corresponding (2R,3R)-beta-Me-p-NO2phe-containing analogue 9 is only 4.5-fold selective (nonselective) in this same assay. On the other hand, in the bioassay systems, [(2S,3S)-beta-Me-p-NO2Phe4]DPDPE (5) is more potent than DPDPE and 8800-fold selective for the MVD (delta-receptor) vs the GPI (mu-receptor), making it the most highly selective ligand in this series for the delta-opioid receptor on the basis of these bioassays. In these assay systems, the (2R,3S)-beta-MePhe4-containing analogue 5 had very weak potency and virtually no receptor selectivity (4.4-fold). These results demonstrate that topographical modification alone in a conformationally restricted peptide ligand can significantly modulate both potency and receptor selectivity of peptide ligands that have multiple sites of biological activity and suggest that this approach may have general application to peptide ligand design.

  DOI：

  10.1021/jm00110a010

文献信息

• Topographically designed analogs of [cyclic] [D-Pen2,D-Pen5]enkephalin
  作者：Victor J. Hruby、Geza Toth、Catherine A. Gehrig、Lung Fa Kao、Richard Knapp、George K. Lui、Henry I. Yamamura、Thomas H. Kramer、P. Davis、Thomas F. Burks

  DOI：10.1021/jm00110a010

  日期：1991.6

  The conformationally restricted, cyclic disulfide-containing delta-opioid receptor selective enkephalin analogue [D-Pen2, D-Pen5]enkephalin (1, DPDPE) was systematically modified topographically by addition of a methyl group at either the pro-S or pro-R position of the beta-carbon of an L-Phe4 or D-Phe4 residue to give [(2S,3S)-beta-MePhe4]DPDPE (2), [(2R,3R)-beta-MePhe4]DPDPE (3), [(2S,3R)-beta-MePhe4]DPDPE (4), and [(2R,3S)-beta-MePhe4]DPDPE (5). The four corresponding isomers were prepared in which the beta-methylphenylalanine residue was p-nitro substituted, that is with a beta-methyl-p-nitrophenylalanine (beta-Me-p-NO2Phe) residue, to give [(2S,3S)-beta-Me-p-NO2Phe4]DPDPE (6), [(2R,3R)-beta-Me-p-NO2Phe4]DPDPE (7),[(2S,3R)-beta-Me-p-NO2Phe4]DPDPE (8), and [(2R,3S)-beta-Me-p-NO2Phe4]DPDPE (9), respectively. The potency and selectivity (delta vs mu-opioid receptor) were evaluated by radioreceptor binding assays in the rat brain using [H-3]CTOP (mu-ligand) and [H-3]DPDPE (delta-ligand) and by bioassay with mouse vas deferens (MVD, delta-receptor assay) and guinea pig ileum (GPI, mu-receptor assay). The eight analogues of DPDPE showed highly variable binding and bioassay activities particularly at the delta-opioid receptor (4 orders of magnitude), but also at the mu-opioid receptor, which led to large differences (3 orders of magnitude) in receptor selectivity. For example, [(2S,3S)-beta-MePhe4]DPDPE (2) is 1800-fold selective in binding to the delta vs mu-receptor, making it one of the most selective delta-opioid receptor ligands in the enkephalin series as assessed by the rat brain binding assay, whereas the corresponding (2R,3R)-beta-Me-p-NO2phe-containing analogue 9 is only 4.5-fold selective (nonselective) in this same assay. On the other hand, in the bioassay systems, [(2S,3S)-beta-Me-p-NO2Phe4]DPDPE (5) is more potent than DPDPE and 8800-fold selective for the MVD (delta-receptor) vs the GPI (mu-receptor), making it the most highly selective ligand in this series for the delta-opioid receptor on the basis of these bioassays. In these assay systems, the (2R,3S)-beta-MePhe4-containing analogue 5 had very weak potency and virtually no receptor selectivity (4.4-fold). These results demonstrate that topographical modification alone in a conformationally restricted peptide ligand can significantly modulate both potency and receptor selectivity of peptide ligands that have multiple sites of biological activity and suggest that this approach may have general application to peptide ligand design.