diethyl (2S,4R)-4-amino-1-benzylpyrrolidine-2,4-dicarboxylate | 178963-37-6

• 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: diethyl (2S,4R)-4-amino-1-benzylpyrrolidine-2,4-dicarboxylate
• CAS: 178963-37-6
• 化学式: C₁₇H₂₄N₂O₄
• 分子量: 320.389
• InChiKey: OYQUDSOGMHYDBL-WMLDXEAASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.4
• 重原子数：
  23
• 可旋转键数：
  8
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  81.9
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  diethyl (2S,4R)-4-amino-1-benzylpyrrolidine-2,4-dicarboxylate 在 palladium on activated charcoal 氢气 作用下， 以 乙醇 、 二氯甲烷 为溶剂， 25.0 ℃ 、413.69 kPa 条件下， 反应 4.0h， 生成 1-O-tert-butyl 2-O,4-O-diethyl (2S,4R)-4-[(2-methylpropan-2-yl)oxycarbonylamino]pyrrolidine-1,2,4-tricarboxylate
  参考文献：
  名称：

  Synthesis of the Four Isomers of 4-Aminopyrrolidine-2,4-dicarboxylate:  Identification of a Potent, Highly Selective, and Systemically-Active Agonist for Metabotropic Glutamate Receptors Negatively Coupled to Adenylate Cyclase

  摘要：

  The four isomers of 4-aminopyrrolidine-2,4-dicarboxylate (APDC) were prepared and evaluated for their effects at glutamate receptors in vitro. (2R,4R)-APDC (2a), an aza analog of the nonselective mGluR agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylate ((1S,3R)-ACPD, 1), was found to possess relatively high affinity for metabotropic glutamate receptors (mGluRs) (ACPD-sensitive [H-3]glutamate binding IC50 = 6.49 +/- 1.21 mu M) with no effects on radioligand binding to NMDA, AMPA, or kainate receptors up to 100 mu M. None of the other APDC isomers showed significant mGluR binding affinity, indicating that this interaction is highly stereospecific. Both 1 and 2a were effective in decreasing forskolin-stimulated cAMP formation in the adult rat cerebral cortex (EC(50) = 8.17 +/- 2.21 mu M for 1; EC(50) = 14.51 +/- 5.54 mu M for 2a); however, while 1 was also effective in stimulating basal tritiated inositol monophosphate production in the neonatal rat cerebral cortex (EC(50) = 27.7 +/- 5.2 mu M), 2a (up to 100 mu M) was ineffective in stimulating phosphoinositide hydrolysis in this tissue preparation, further supporting our previous observations that 2a is a highly selective agonist for mGluRs negatively coupled to adenylate cyclase. Microelectrophoretic application of either 1 or 2a to intact rat spinal neurons produced an augmentation of AMPA-induced excitation (95 +/- 10% increase for 1, 52 +/- 6% increase for 2a). Intracerebral injection of 1 (400 nmol) produced characteristic limbic seizures in mice which are not mimicked by 2a (200-1600 nmol, ic). However, the limbic seizures induced by 1 were blocked by systemically administered 2a in a dose-dependent manner (EC(50) = 271 mg/kg, ip). It is concluded that (2R,4R)-APDC (2a) is a highly selective, systemically-active agonist of mGluRs negatively coupled to adenylate cyclase and that selective activation of these receptors in vivo can result in anticonvulsant effects.

  DOI：

  10.1021/jm9601765
• 作为产物：
  描述：

  N-Cbz-trans-4-hydroxy-L-proline ethyl ester 在 palladium on activated charcoal sodium hydroxide 、 氯化亚砜 、 草酰氯 、 氢气 、 二甲基亚砜 、 N,N-二异丙基乙胺 作用下， 以 乙醇 、 二氯甲烷 、 水 为溶剂， -78.0~55.0 ℃ 、413.69 kPa 条件下， 反应 4.5h， 生成 diethyl (2S,4R)-4-amino-1-benzylpyrrolidine-2,4-dicarboxylate
  参考文献：
  名称：

  Synthesis of the Four Isomers of 4-Aminopyrrolidine-2,4-dicarboxylate:  Identification of a Potent, Highly Selective, and Systemically-Active Agonist for Metabotropic Glutamate Receptors Negatively Coupled to Adenylate Cyclase

  摘要：

  The four isomers of 4-aminopyrrolidine-2,4-dicarboxylate (APDC) were prepared and evaluated for their effects at glutamate receptors in vitro. (2R,4R)-APDC (2a), an aza analog of the nonselective mGluR agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylate ((1S,3R)-ACPD, 1), was found to possess relatively high affinity for metabotropic glutamate receptors (mGluRs) (ACPD-sensitive [H-3]glutamate binding IC50 = 6.49 +/- 1.21 mu M) with no effects on radioligand binding to NMDA, AMPA, or kainate receptors up to 100 mu M. None of the other APDC isomers showed significant mGluR binding affinity, indicating that this interaction is highly stereospecific. Both 1 and 2a were effective in decreasing forskolin-stimulated cAMP formation in the adult rat cerebral cortex (EC(50) = 8.17 +/- 2.21 mu M for 1; EC(50) = 14.51 +/- 5.54 mu M for 2a); however, while 1 was also effective in stimulating basal tritiated inositol monophosphate production in the neonatal rat cerebral cortex (EC(50) = 27.7 +/- 5.2 mu M), 2a (up to 100 mu M) was ineffective in stimulating phosphoinositide hydrolysis in this tissue preparation, further supporting our previous observations that 2a is a highly selective agonist for mGluRs negatively coupled to adenylate cyclase. Microelectrophoretic application of either 1 or 2a to intact rat spinal neurons produced an augmentation of AMPA-induced excitation (95 +/- 10% increase for 1, 52 +/- 6% increase for 2a). Intracerebral injection of 1 (400 nmol) produced characteristic limbic seizures in mice which are not mimicked by 2a (200-1600 nmol, ic). However, the limbic seizures induced by 1 were blocked by systemically administered 2a in a dose-dependent manner (EC(50) = 271 mg/kg, ip). It is concluded that (2R,4R)-APDC (2a) is a highly selective, systemically-active agonist of mGluRs negatively coupled to adenylate cyclase and that selective activation of these receptors in vivo can result in anticonvulsant effects.

  DOI：

  10.1021/jm9601765

文献信息

• Synthesis of the Four Isomers of 4-Aminopyrrolidine-2,4-dicarboxylate:  Identification of a Potent, Highly Selective, and Systemically-Active Agonist for Metabotropic Glutamate Receptors Negatively Coupled to Adenylate Cyclase
  作者：James A. Monn、Matthew J. Valli、Bryan G. Johnson、Craig R. Salhoff、Rebecca A. Wright、Trevor Howe、Ann Bond、David Lodge、Larry A. Spangle、Jonathan W. Paschal、Jack B. Campbell、Kelly Griffey、Joseph P. Tizzano、Darryle D. Schoepp

  DOI：10.1021/jm9601765

  日期：1996.1.1

  The four isomers of 4-aminopyrrolidine-2,4-dicarboxylate (APDC) were prepared and evaluated for their effects at glutamate receptors in vitro. (2R,4R)-APDC (2a), an aza analog of the nonselective mGluR agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylate ((1S,3R)-ACPD, 1), was found to possess relatively high affinity for metabotropic glutamate receptors (mGluRs) (ACPD-sensitive [H-3]glutamate binding IC50 = 6.49 +/- 1.21 mu M) with no effects on radioligand binding to NMDA, AMPA, or kainate receptors up to 100 mu M. None of the other APDC isomers showed significant mGluR binding affinity, indicating that this interaction is highly stereospecific. Both 1 and 2a were effective in decreasing forskolin-stimulated cAMP formation in the adult rat cerebral cortex (EC(50) = 8.17 +/- 2.21 mu M for 1; EC(50) = 14.51 +/- 5.54 mu M for 2a); however, while 1 was also effective in stimulating basal tritiated inositol monophosphate production in the neonatal rat cerebral cortex (EC(50) = 27.7 +/- 5.2 mu M), 2a (up to 100 mu M) was ineffective in stimulating phosphoinositide hydrolysis in this tissue preparation, further supporting our previous observations that 2a is a highly selective agonist for mGluRs negatively coupled to adenylate cyclase. Microelectrophoretic application of either 1 or 2a to intact rat spinal neurons produced an augmentation of AMPA-induced excitation (95 +/- 10% increase for 1, 52 +/- 6% increase for 2a). Intracerebral injection of 1 (400 nmol) produced characteristic limbic seizures in mice which are not mimicked by 2a (200-1600 nmol, ic). However, the limbic seizures induced by 1 were blocked by systemically administered 2a in a dose-dependent manner (EC(50) = 271 mg/kg, ip). It is concluded that (2R,4R)-APDC (2a) is a highly selective, systemically-active agonist of mGluRs negatively coupled to adenylate cyclase and that selective activation of these receptors in vivo can result in anticonvulsant effects.