(7S,9aS)-4,9-Dioxo-decahydro-3a,8-diaza-cyclopentacyclooctene-7-carboxylic acid (benzhydryl-carbamoyl)-methyl ester | 200399-56-0

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 肽模拟物
• 英文名称: (7S,9aS)-4,9-Dioxo-decahydro-3a,8-diaza-cyclopentacyclooctene-7-carboxylic acid (benzhydryl-carbamoyl)-methyl ester
• 英文别名: N(1)Pro-Glu(1)-OGly-NHbenzhydryl；[2-(benzhydrylamino)-2-oxoethyl] (3S,10aS)-1,6-dioxo-2,3,4,5,8,9,10,10a-octahydropyrrolo[1,2-a][1,4]diazocine-3-carboxylate
• CAS: 200399-56-0
• 化学式: C₂₅H₂₇N₃O₅
• 分子量: 449.506
• InChiKey: WBVLVQNLQYEKTL-PMACEKPBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  33
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  105
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (7S,9aS)-4,9-Dioxo-decahydro-3a,8-diaza-cyclopentacyclooctene-7-carboxylic acid (benzhydryl-carbamoyl)-methyl ester 在 氨 作用下， 以 1,4-二氧六环 为溶剂， 反应 72.0h， 以70.5%的产率得到(7S,9aS)-4,9-Dioxo-decahydro-3a,8-diaza-cyclopentacyclooctene-7-carboxylic acid amide
  参考文献：
  名称：

  TRH mimetics: Differentiation of antiamnesic potency from antidepressant effect

  摘要：

  For the purpose of rational modification of the TRH molecule, we were pursuing an approach that consists of two steps: (1) 'obligatory' replacement of histidine with glutamine in TRH and (2) the application of conformational constraints for putative bioactive conformation I stabilized by an intramolecular hydrogen bond between C-terminal carboxamide proton and alpha-carbonyl of histidyl (glutaminyl), and conformation II formed by an intramolecular hydrogen bond between alpha-carbonyl of pyroglutamyl and prolinamide proton. Significant antiamnesic potency was discovered in the passive avoidance test (ECS and Scopolamine induced amnesia) for conformation II mimic (8S,10aS)-8-carbamoyl-1,2,3,6,7,8,9,10a-octahydro-5H,10H-pyrrolo [1,2-a][1,4]diazocin-5,10-dione (2) at doses of 0.1 and 1.0 mg/kg. EEG analysis indicates a mild activating effect of compound 2 on EEG, which is similar to that of piracetam and differs from hard amphetamine activation. Conformation I mimic 3-(2-carbamoylethyl)-2,3,6,7,8,8a-hexahydro-1H,4H-pyrrolo[1,2-a] pyrazin-1,4-dione (1) exhibited an antidepressant effect at a dose of 1 mg/kg. The transition from two putative quasi-cyclic bioactive conformations of TRH and its obligatory similar analogue [Gln(2)]-TRH to their cyclic mimics led to differentiation of antiamnesic and antidepressant activity of TRH. (C) 1997 Elsevier Science Ltd.

  DOI：

  10.1016/s0968-0896(97)00141-7
• 作为产物：
  描述：

  (S)-1-{(S)-4-[(Benzhydryl-carbamoyl)-methoxycarbonyl]-4-tert-butoxycarbonylamino-butyryl}-pyrrolidine-2-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester 在 盐酸 、 三乙胺 作用下， 以 1,4-二氧六环 、 乙腈 为溶剂， 反应 3.5h， 生成 (7S,9aS)-4,9-Dioxo-decahydro-3a,8-diaza-cyclopentacyclooctene-7-carboxylic acid (benzhydryl-carbamoyl)-methyl ester
  参考文献：
  名称：

  TRH mimetics: Differentiation of antiamnesic potency from antidepressant effect

  摘要：

  For the purpose of rational modification of the TRH molecule, we were pursuing an approach that consists of two steps: (1) 'obligatory' replacement of histidine with glutamine in TRH and (2) the application of conformational constraints for putative bioactive conformation I stabilized by an intramolecular hydrogen bond between C-terminal carboxamide proton and alpha-carbonyl of histidyl (glutaminyl), and conformation II formed by an intramolecular hydrogen bond between alpha-carbonyl of pyroglutamyl and prolinamide proton. Significant antiamnesic potency was discovered in the passive avoidance test (ECS and Scopolamine induced amnesia) for conformation II mimic (8S,10aS)-8-carbamoyl-1,2,3,6,7,8,9,10a-octahydro-5H,10H-pyrrolo [1,2-a][1,4]diazocin-5,10-dione (2) at doses of 0.1 and 1.0 mg/kg. EEG analysis indicates a mild activating effect of compound 2 on EEG, which is similar to that of piracetam and differs from hard amphetamine activation. Conformation I mimic 3-(2-carbamoylethyl)-2,3,6,7,8,8a-hexahydro-1H,4H-pyrrolo[1,2-a] pyrazin-1,4-dione (1) exhibited an antidepressant effect at a dose of 1 mg/kg. The transition from two putative quasi-cyclic bioactive conformations of TRH and its obligatory similar analogue [Gln(2)]-TRH to their cyclic mimics led to differentiation of antiamnesic and antidepressant activity of TRH. (C) 1997 Elsevier Science Ltd.

  DOI：

  10.1016/s0968-0896(97)00141-7

文献信息

• Design of a novel cognitive enhancer (8S, 10aS)-8-carbamoyl-1,2,3,6,7,8,9,10a-octahydro-5H,10H-pyrrolo[1,2-a][1,4]diazocin-5,10-dione
  作者：Anatoly A. Mazurov、Sergei A. Andronati、Tamara I. Korotenko、Nikolai I. Sokolenko、Alexei I. Dyadenko、Yuri E. Shapiro、Vitalii Ya. Gorbatyuk、Tatyana A. Voronina

  DOI：10.1016/0960-894x(96)00478-7

  日期：1996.11

  A new cognitive enhancer (8S, 10aS)-8-carbamoyl-1,2,3,6,7,8,9,10a-octahydro-5H, 10H-pyrrolo[1,2-a][1,4]diazocin-5,10-dione (3) has been designed based on the approach consisting of two steps: 1) ''obligatory'' replacement of histidine with glutamine in TRH; 2) the application of conformational constraints for putative bioactive conformation of [Gln(2)]-TRH. 3 reversed on 100% electroconvulsive shock-induced amnesia at doses of 0.1 and 1.0 mg/kg and on 83% scopolamine-induced amnesia at a dose of 1 mg/kg, using passive avoidance test. Copyright (C) 1996 Elsevier Science Ltd
• TRH mimetics: Differentiation of antiamnesic potency from antidepressant effect
  作者：Anatoly A. Mazurov、Sergei A. Andronati、Tamara I. Korotenko、Nikolai I. Sokolenko、Alexei I. Dyadenko、Yury E. Shapiro、Vitalii Ya. Gorbatyuk、Tatyana A. Voronina

  DOI：10.1016/s0968-0896(97)00141-7

  日期：1997.11

  For the purpose of rational modification of the TRH molecule, we were pursuing an approach that consists of two steps: (1) 'obligatory' replacement of histidine with glutamine in TRH and (2) the application of conformational constraints for putative bioactive conformation I stabilized by an intramolecular hydrogen bond between C-terminal carboxamide proton and alpha-carbonyl of histidyl (glutaminyl), and conformation II formed by an intramolecular hydrogen bond between alpha-carbonyl of pyroglutamyl and prolinamide proton. Significant antiamnesic potency was discovered in the passive avoidance test (ECS and Scopolamine induced amnesia) for conformation II mimic (8S,10aS)-8-carbamoyl-1,2,3,6,7,8,9,10a-octahydro-5H,10H-pyrrolo [1,2-a][1,4]diazocin-5,10-dione (2) at doses of 0.1 and 1.0 mg/kg. EEG analysis indicates a mild activating effect of compound 2 on EEG, which is similar to that of piracetam and differs from hard amphetamine activation. Conformation I mimic 3-(2-carbamoylethyl)-2,3,6,7,8,8a-hexahydro-1H,4H-pyrrolo[1,2-a] pyrazin-1,4-dione (1) exhibited an antidepressant effect at a dose of 1 mg/kg. The transition from two putative quasi-cyclic bioactive conformations of TRH and its obligatory similar analogue [Gln(2)]-TRH to their cyclic mimics led to differentiation of antiamnesic and antidepressant activity of TRH. (C) 1997 Elsevier Science Ltd.