(1R,3R)-1,3-dimethyl-2-prop-2-ynyl-3,4-dihydro-1H-isoquinoline

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 四氢异喹啉
• 英文名称: (1R,3R)-1,3-dimethyl-2-prop-2-ynyl-3,4-dihydro-1H-isoquinoline
• 化学式: C₁₄H₁₇N
• 分子量: 199.29
• InChiKey: BHWIEIUYCHICBZ-VXGBXAGGSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  15
• 可旋转键数：
  1
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  3.2
• 氢给体数：
  0
• 氢受体数：
  1

文献信息

• GAPDH cascade inhibitor compounds and methods of use and treatment of stress induced disorders including mental illness
  申请人：THE JOHNS HOPKINS UNIVERSITY

  公开号：US10292980B2

  公开（公告）日：2019-05-21

  In DN-DISC1 mice, a mouse model for major mental illnesses, the model that expresses pathological phenotypes relevant to schizophrenia, mood disorders, and addiction simultaneously, the inventors of the present invention found pronounced levels of oxidative stress in the prefrontal cortex, but not in the striatum. These mice also displayed greater amounts of GAPDH-Siah1 binding, a protein-protein interaction that is activated under exposure to oxidative stress. The present inventors investigated the role of oxidative stress in other organ systems. As detailed herein, the inventors found that GAPDH-Siah1 binding was increased in mouse models of cardiac failure. It was also found, that certain novel analogs of deprenyl, significantly inhibited GAPDH-Siah1 binding in cardiac tissue. Thus, with experimental data provided herein, it is clear that this GAPDH-Siah1 binding cascade is a crucial mechanism involved in major mental illness, such as schizophrenia, mood disorders, and addiction, as well as in stress-associated diseases involving other organs where GAPDH is expressed. The present invention provides compounds and composition comprising analogs of deprenyl and their use in the inhibition of nuclear GAPDH-Siah1 binding and the activation of p300 and MEF2. Also provided herein are methods of prevention and treatment of stress induced disorders of the body, including, for example, major mental illness, such as schizophrenia, mood disorders, and addiction, as well as in stress-associated diseases involving other organs, such as cardiac hypertrophy, in vivo, comprising administering to a mammal a therapeutically effective amount of analogs of deprenyl.

  本发明的发明者在 DN-DISC1 小鼠（一种重大精神疾病的小鼠模型，该模型同时表达与精神分裂症、情绪障碍和成瘾相关的病理表型）中发现，前额叶皮层的氧化应激水平明显高于纹状体。这些小鼠还显示出更多的 GAPDH-Siah1 结合，这是一种在暴露于氧化应激下被激活的蛋白质间相互作用。本发明者研究了氧化应激在其他器官系统中的作用。正如本文所详述的，本发明人发现，在心力衰竭的小鼠模型中，GAPDH-Siah1 结合增加。他们还发现，去甲肾上腺素的某些新型类似物能显著抑制心脏组织中 GAPDH-Siah1 的结合。因此，根据本文提供的实验数据，很明显这种 GAPDH-Siah1 结合级联是参与重大精神疾病（如精神分裂症、情绪障碍和成瘾）以及涉及表达 GAPDH 的其他器官的应激相关疾病的重要机制。 本发明提供了包含去甲肾上腺素类似物的化合物和组合物，以及它们在抑制核 GAPDH-Siah1 结合和激活 p300 和 MEF2 中的用途。本发明还提供了预防和治疗应激诱导的机体紊乱的方法，包括例如重大精神疾病，如精神分裂症、情绪紊乱和成瘾，以及体内涉及其他器官的应激相关疾病，如心脏肥大，包括向哺乳动物施用治疗有效量的去甲肾上腺素类似物。
• GAPDH CASCADE INHIBITOR COMPOUNDS AND METHODS OF USE AND TREATMENT OF STRESS INDUCED DISORDERS INCLUDING MENTAL ILLNESS
  申请人：THE JOHNS HOPKINS UNIVERSITY

  公开号：US20150218103A1

  公开（公告）日：2015-08-06

  The present invention provides compounds and composition comprising analogs of deprenyl and their use in the inhibition of nuclear GAPDH-Siahl binding and the activation of p300 and MEF2. Also provided herein are methods of prevention and treatment of stress induced disorders of the body, including, for example, major mental illness, such as schizophrenia, mood disorders, and addiction, as well as stress-associated diseases involving other organs, such as cardiac hypertrophy, in vivo, comprising administering to a mammal a therapeutically effective amount of analogs of deprenyl.
• [EN] GAPDH CASCADE INHIBITOR COMPOUNDS AND METHODS OF USE AND TREATMENT OF STRESS INDUCED DISORDERS INCLUDING MENTAL ILLNESS<br/>[FR] COMPOSÉS INHIBITEURS DE CASCADE DE GAPDH, MÉTHODES D'UTILISATION ET TRAITEMENT DE TROUBLES INDUITS PAR LE STRESS, NOTAMMENT DE TROUBLES MENTAUX
  申请人：UNIV JOHNS HOPKINS

  公开号：WO2014035707A1

  公开（公告）日：2014-03-06

  The present invention provides compounds and composition comprising analogs of deprenyl and their use in the inhibition of nuclear GAPDH-Siahl binding and the activation of p300 and MEF2. Also provided herein are methods of prevention and treatment of stress induced disorders of the body, including, for example, major mental illness, such as schizophrenia, mood disorders, and addiction, as well as stress-associated diseases involving other organs, such as cardiac hypertrophy, in vivo, comprising administering to a mammal a therapeutically effective amount of analogs of deprenyl.