(3SR,4aRS,6SR,8aRS)-6--1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid | 128073-48-3

• 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: (3SR,4aRS,6SR,8aRS)-6--1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid
• 英文别名: (+/-)-(phosphonomethyl)-decahydroisoquinoline-3-carboxylic acid；LY 274614；(3R,4aS,6R,8aS)-6-(phosphonomethyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid
• CAS: 128073-48-3；136109-04-1；137433-06-8；143343-68-4；143343-69-5；143343-72-0；143343-74-2；143343-75-3；147331-87-1；147331-88-2
• 化学式: C₁₁H₂₀NO₅P
• 分子量: 277.257
• InChiKey: STIRHCNEGQQBOY-DOLQZWNJSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -2.9
• 重原子数：
  18
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.91
• 拓扑面积：
  107
• 氢给体数：
  4
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  聚合甲醛 、 (3SR,4aRS,6SR,8aRS)-6--1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid 在 palladium on activated charcoal 氢气 作用下， 以 乙醇 、 水 为溶剂， 50.0 ℃ 、413.68 kPa 条件下， 以60%的产率得到(3SR,4aRS,6SR,8aRS)-3-methyl-6-(phosphonomethyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid
  参考文献：
  名称：

  6-Substituted decahydroisoquinoline-3-carboxylic acids as potent and selective conformationally constrained NMDA receptor antagonists

  摘要：

  We have prepared a series of 6-substituted decahydroisoquinoline-3-carboxylic acids, and structurally similar analogs, as potential N-methyl-D-aspartate receptor antagonists. There is a large body of evidence to support the use of such compounds as cerebroprotective agents in a variety of acute and chronic neurodegenerative disorders, where some component of glutamate-mediated excitotoxicity may exist. The compounds prepared were evaluated in vitro in both receptor binding assays ([H-3]CGS19755, [H-3]AMPA, and [H-3]kainic acid) and in a cortical wedge preparation (versus NMDA, AMPA, and kainic acid) to determine affinity, potency, and selectivity. The new amino acids were also evaluated in vivo for their ability to block NMDA-induced lethality in mice. We synthesized many of the possible diastereomers of the decahydroisoquinoline nucleus in order to examine the spatial and steric requirements for affinity at the NMDA receptor and activity as NMDA antagonists. From our structure-activity relationship we identified two potent and selective NMDA receptor antagonists, the phosphonate- and tetrazole-substituted amino acids 31a and 32a, respectively, that show good activity in animals following systemic administration. For example, 31a and 32a selectively displaced [H-3]CGS19755 binding with IC50s of 55 +/- 14 and 856 +/- 136 nM, respectively, and selectively antagonized responses due to NMDA in a cortical wedge preparation with IC50s of 0.15 +/- 0.01 and 1.39 +/- 0.29-mu-M, respectively. And compounds 31a and 32a blocked NMDA-induced lethality in mice with minimum effective doses of 1.25 and 2.5 mg/kg (intraperitoneal), respectively. These novel amino acids are among some of the most potent NMDA antagonists described thus far, and are excellent candidates for development as neuroprotective agents for a number of CNS disorders.

  DOI：

  10.1021/jm00097a012
• 作为产物：
  描述：

  (3SR,4aRS,8aRS)-6-(phosphonomethylidene)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid 在 palladium on activated charcoal 氢气 作用下， 以 水 为溶剂， 40.0 ℃ 、413.68 kPa 条件下， 以70%的产率得到(3SR,4aRS,6SR,8aRS)-6--1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid
  参考文献：
  名称：

  6-Substituted decahydroisoquinoline-3-carboxylic acids as potent and selective conformationally constrained NMDA receptor antagonists

  摘要：

  We have prepared a series of 6-substituted decahydroisoquinoline-3-carboxylic acids, and structurally similar analogs, as potential N-methyl-D-aspartate receptor antagonists. There is a large body of evidence to support the use of such compounds as cerebroprotective agents in a variety of acute and chronic neurodegenerative disorders, where some component of glutamate-mediated excitotoxicity may exist. The compounds prepared were evaluated in vitro in both receptor binding assays ([H-3]CGS19755, [H-3]AMPA, and [H-3]kainic acid) and in a cortical wedge preparation (versus NMDA, AMPA, and kainic acid) to determine affinity, potency, and selectivity. The new amino acids were also evaluated in vivo for their ability to block NMDA-induced lethality in mice. We synthesized many of the possible diastereomers of the decahydroisoquinoline nucleus in order to examine the spatial and steric requirements for affinity at the NMDA receptor and activity as NMDA antagonists. From our structure-activity relationship we identified two potent and selective NMDA receptor antagonists, the phosphonate- and tetrazole-substituted amino acids 31a and 32a, respectively, that show good activity in animals following systemic administration. For example, 31a and 32a selectively displaced [H-3]CGS19755 binding with IC50s of 55 +/- 14 and 856 +/- 136 nM, respectively, and selectively antagonized responses due to NMDA in a cortical wedge preparation with IC50s of 0.15 +/- 0.01 and 1.39 +/- 0.29-mu-M, respectively. And compounds 31a and 32a blocked NMDA-induced lethality in mice with minimum effective doses of 1.25 and 2.5 mg/kg (intraperitoneal), respectively. These novel amino acids are among some of the most potent NMDA antagonists described thus far, and are excellent candidates for development as neuroprotective agents for a number of CNS disorders.

  DOI：

  10.1021/jm00097a012

文献信息

• ACTIVATION OF HISTONE DEACETYLASE 1 (HDAC1) PROTECTS AGAINST DNA DAMAGE AND INCREASES NEURONAL SURVIVAL
  申请人：Tsai Li-Huei

  公开号：US20100075926A1

  公开（公告）日：2010-03-25

  The invention provides methods and compounds for the treatment of neurological disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, ALS (Amyotrophic Lateral Sclerosis), traumatic brain injury, ischemic brain injury or a stroke. In one aspect the compounds are HDAC1 activators. Exemplary HDAC1 activators include metal chelators, iron chelators, deferoxamin, flavonoids, compounds comprising a catechol moity, ginkgetin K, Chembridge 5104434, sciadopilysin, tetrahydrogamboic acid, TAM-11, LY 235959, CGS 19755, SK&F 97541, etidronic acid, levonordefrin, methyldopa, ampicillin trihydrate, D-aspartic acid, gamma-D-glutamylaminomethylsulfonic acid, phenazopyridine to hydrochloride, oxalamine citrate salt, podophyllotoxin, SK&F 97541, (+-)-4-amino-3-(5-chloro-2-thienyl)-butanoic acid, (RS)-(tetrazol-5-yl) glycine, R(+)-SKF-81297, gambogic acid, and derivatives thereof.
• [EN] ACTIVATIQN OF HISTONE DEACETYLASE 1 (HDAC1) PROTECTS AGAINST DNA DAMAGE AND INCREASES NEURONAL SURVIVAL<br/>[FR] L'ACTIVATION DE L'HISTONE DÉSACÉTYLASE 1 (HDAC1) PROTÈGE CONTRE DES LÉSIONS DE L'ADN ET AUGMENTE LA SURVIE NEURONALE
  申请人：MASSACHUSETTS INST TECHNOLOGY

  公开号：WO2010011318A2

  公开（公告）日：2010-01-28

  The invention provides methods and compounds for the treatment of neurological disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, ALS (Amyotrophic Lateral Sclerosis), traumatic brain injury, ischemic brain injury or a stroke. In one aspect the compounds are HDACl activators. Exemplary HDACl activators include metal chelators, iron chelators, deferoxamin, flavonoids, compounds comprising a catechol moity, ginkgetin K, Chembridge 5104434, sciadopilysin, tetrahydrogamboic acid, TAM-11, LY 235959, CGS 19755, SK&F 97541, etidronic acid, levonordefrin, methyldopa, ampicillin trihydrate, D-aspartic acid, gamma-D-glutamylaminomethylsulfonic acid, phenazopyridine hydrochloride, oxalamine citrate salt, podophyllotoxin, SK&F 97541, (+-)-4-amino-3-(5- chloro-2-thienyl)-butanoic acid, (RS)-(tetrazol-5-yl) glycine, R(+)-SKF-81297, gambogic acid, and derivatives thereof.
• 6-Substituted decahydroisoquinoline-3-carboxylic acids as potent and selective conformationally constrained NMDA receptor antagonists
  作者：Paul L. Ornstein、Darryle D. Schoepp、M. Brian Arnold、Nancy K. Augenstein、David Lodge、John D. Millar、John Chambers、Jack Campbell、Jonathan W. Paschal

  DOI：10.1021/jm00097a012

  日期：1992.9

  We have prepared a series of 6-substituted decahydroisoquinoline-3-carboxylic acids, and structurally similar analogs, as potential N-methyl-D-aspartate receptor antagonists. There is a large body of evidence to support the use of such compounds as cerebroprotective agents in a variety of acute and chronic neurodegenerative disorders, where some component of glutamate-mediated excitotoxicity may exist. The compounds prepared were evaluated in vitro in both receptor binding assays ([H-3]CGS19755, [H-3]AMPA, and [H-3]kainic acid) and in a cortical wedge preparation (versus NMDA, AMPA, and kainic acid) to determine affinity, potency, and selectivity. The new amino acids were also evaluated in vivo for their ability to block NMDA-induced lethality in mice. We synthesized many of the possible diastereomers of the decahydroisoquinoline nucleus in order to examine the spatial and steric requirements for affinity at the NMDA receptor and activity as NMDA antagonists. From our structure-activity relationship we identified two potent and selective NMDA receptor antagonists, the phosphonate- and tetrazole-substituted amino acids 31a and 32a, respectively, that show good activity in animals following systemic administration. For example, 31a and 32a selectively displaced [H-3]CGS19755 binding with IC50s of 55 +/- 14 and 856 +/- 136 nM, respectively, and selectively antagonized responses due to NMDA in a cortical wedge preparation with IC50s of 0.15 +/- 0.01 and 1.39 +/- 0.29-mu-M, respectively. And compounds 31a and 32a blocked NMDA-induced lethality in mice with minimum effective doses of 1.25 and 2.5 mg/kg (intraperitoneal), respectively. These novel amino acids are among some of the most potent NMDA antagonists described thus far, and are excellent candidates for development as neuroprotective agents for a number of CNS disorders.