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1. 发明授权

US10016414B2 Modulation of ubiquitination of synaptic proteins for the treatment of neurodegenerative and psychiatric disorders 有权
公开(公告)号：US10016414B2
公开(公告)日：2018-07-10
申请号：US13884705
申请日：2011-11-14
申请人： Maria Morabito , Michael Bianchetta
发明人： Maria Morabito , Michael Bianchetta
IPC分类号： A61K31/496 , A61K31/519 , A61K31/00 , A61K31/155 , A61K31/381 , A61K31/4035 , A61K31/4155 , A61K31/4164 , A61K31/435 , A61K31/4439 , A61K31/4709 , A61K31/5513
CPC分类号： A61K31/496 , A61K31/00 , A61K31/155 , A61K31/381 , A61K31/4035 , A61K31/4155 , A61K31/4164 , A61K31/435 , A61K31/4439 , A61K31/4709 , A61K31/519 , A61K31/5513
摘要： The instant invention is based, at least in part, on a newly-identified proteasome-independent signaling function of ubiquitinated PSD-95. Mdm2 inhibitors, Mdm4 inhibitors, PSD-95 inhibitors, and/or enantiomers and/or derivatives thereof decrease endocytosis via preventing PSD-95 ubiquitination, and thereby increase AMPAR, NMDAR, D1 dopamine receptor surface expression in response to a given stimulus (e.g., NMDA, Aβ). Accordingly, the invention provides methods for modulating AMPARs, NMDARs, or D1 dopamine receptors in a neuronal cell by contacting the neuronal cell with an Mdm2 and/or Mdm4 inhibitor or PSD-95 inhibitor and/or enantiomers and/or derivatives thereof. Mdm2 and/or Mdm4 inhibitors decrease the enzymatic activity of the respective proteins, and/or interactions with their respective substrates. Mdm2 and Mdm4 inhibitors and/or PSD-95 inhibitors of the invention are contemplated for use in the treatment of neurological disorders, neurodevelopmental disorders, and psychiatric disorders. The invention also provides methods to screen for new Mdm2 and Mdm4 inhibitors and PSD-95 inhibitors and/or enantiomers and/or derivatives thereof.

2. 发明申请

US20130331398A1 MODULATION OF UBIQUITINATION OF SYNAPTIC PROTEINS FOR THE TREATMENT OF NEURODEGENERATIVE AND PSYCHIATRIC DISORDERS 有权
标题翻译：用于治疗神经损伤和心理疾病的SYNPTE蛋白质的调节
公开(公告)号：US20130331398A1
公开(公告)日：2013-12-12
申请号：US13884705
申请日：2011-11-14
申请人： Maria Morabito , Michael Bianchetta
发明人： Maria Morabito , Michael Bianchetta
IPC分类号： A61K31/496 , A61K31/519
CPC分类号： A61K31/496 , A61K31/00 , A61K31/155 , A61K31/381 , A61K31/4035 , A61K31/4155 , A61K31/4164 , A61K31/435 , A61K31/4439 , A61K31/4709 , A61K31/519 , A61K31/5513
摘要： The instant invention is based, at least in part, on a newly-identified proteasome-independent signaling function of ubiquitinated PSD-95. Mdm2 inhibitors, Mdm4 inhibitors, PSD-95 inhibitors, and/or enantiomers and/or derivatives thereof de-crease endocytosis via preventing PSD-95 ubiquitination, and thereby increase AMPAR, NMDAR, D1 dopamine receptor surface expression in response to a given stimulus (e.g., NMDA, Aβ). Accordingly, the invention provides methods for modulating AM-PARS, NMDARs, or D1 dopamine receptors in a neuronal cell by contacting the neuronal cell with an Mdm2 and/or Mdm4 inhibitor or PSD-95 inhibitor and/or enantiomers and/or derivatives thereof. Mdm2 and/or Mdm4 inhibitors decrease the enzymatic activity of the respective proteins, and/or interactions with their respective substrates. Mdm2 and Mdm4 inhibitors and/or PSD-95 inhibitors of the invention are contemplated for use in the treatment of neurological disorders, neurodevelopmental disorders, and psychiatric disorders. The invention also provides methods to screen for new Mdm2 and Mdm4 inhibitors and PSD-95 inhibitors and/or enantiomers and/or derivatives thereof.
摘要翻译：本发明至少部分地基于泛素化PSD-95的新鉴定的蛋白酶体独立的信号传导功能。 Mdm2抑制剂，Mdm4抑制剂，PSD-95抑制剂和/或其对映异构体和/或其衍生物通过防止PSD-95泛素化来减少内吞作用，从而响应于给定的刺激增加AMPAR，NMDAR，D1多巴胺受体表面表达（例如，NMDA，Abeta）。因此，本发明提供了通过使神经元细胞与Mdm2和/或Mdm4抑制剂或PSD-95抑制剂和/或对映异构体和/或其衍生物接触来调节神经元细胞中的AM-PARS，NMDAR或D1多巴胺受体的方法。 Mdm2和/或Mdm4抑制剂降低相应蛋白质的酶活性，和/或与其各自底物的相互作用。本发明的Mdm2和Mdm4抑制剂和/或PSD-95抑制剂被考虑用于治疗神经障碍，神经发育障碍和精神疾病。本发明还提供筛选新的Mdm2和Mdm4抑制剂和PSD-95抑制剂和/或其对映异构体和/或其衍生物的方法。

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