New Inactivators of GABA Aminotransferase for Epilepsy and Neuropathic Pain

用于治疗癫痫和神经性疼痛的新型 GABA 转氨酶灭活剂

基本信息

  • 批准号:
    10647271
  • 负责人:
  • 金额:
    $ 9.5万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-09-15 至 2024-06-30
  • 项目状态:
    已结题

项目摘要

Project Summary The two principal neurotransmitters involved in the regulation of brain neuronal activity are γ-aminobutyric acid (GABA), one of the most widely distributed inhibitory neurotransmitters, and L-glutamic acid, an excitatory neurotransmitter. The concentration of GABA is regulated by two pyridoxal 5'-phosphate (PLP)-dependent enzymes, L-glutamic acid decarboxylase (GAD), which catalyzes the conversion of L-glutamate to GABA, and GABA aminotransferase (GABA-AT), which degrades GABA to succinic semialdehyde and converts α- ketoglutarate to L-glutamic acid. When the concentration of GABA diminishes below a threshold level, convulsions result; raising GABA levels terminates the seizure. When epilepsy is defined broadly as any disease characterized by recurring convulsive seizures, then over 1% of the entire world population (including >3 million Americans) can be classified as having epilepsy. One approach to raise GABA levels is with a molecule that crosses the blood-brain barrier (BBB) and inhibits/inactivates GABA-AT. This effectively dampens excessive neural activity without affecting basal neuronal firing. Neuropathic pain, including chemotherapy-induced peripheral neuropathy (a problem for more than 60% of cancer patients treated with chemotherapy), affects 3- 17% of the world population. Inadequate current treatments of pain are exacerbated by adverse side effects, such as abuse liability, sedation, and altered mental status, which limit treatment utility. Two features of neuropathic pain that have been identified are reduced GABA levels and spinal GABAergic inhibitory function. The objective of this proposal is to design and evaluate new mechanism-based inactivator analogs of our previously successful GABA-AT inactivators to enhance potency and elucidate inactivation mechanisms using computer modeling and crystallography (Dr. Dali Liu does our crystal structures) as the driving force for design. New inactivators are being designed for selective GABA-AT inactivation. The effectiveness of our new molecules will be tested by my collaborator, Dr. Andrea Hohmann, for their effect on various neuropathic pains, including chemotherapy-induced peripheral neuropathy. Specific Aims 1-3 in grant R01 NS123057 describes a multitude of molecules that were proposed to synthesize for testing as inactivators of GABA-AT. Our 20-year old HPLC/mass spectrometer has been repaired multiple times and now has not functioned in over 8 months. This dramatically diminishes our productivity to synthesize new molecules, making the time to analyze and identify intermediates and products very long. Consequently, the following aim is proposed: Specific Aim 1. Purchase and installation of a new mass spectrometer coupled with high-performance liquid chromatography. A routine training/maintenance policy will be established, assisted by the vendor.
项目总结

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

RICHARD B SILVERMAN其他文献

RICHARD B SILVERMAN的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('RICHARD B SILVERMAN', 18)}}的其他基金

New Inactivators of GABA Aminotransferase for Epilepsy and Neuropathic Pain
用于治疗癫痫和神经性疼痛的新型 GABA 转氨酶灭活剂
  • 批准号:
    10278302
  • 财政年份:
    2021
  • 资助金额:
    $ 9.5万
  • 项目类别:
New Inactivators of GABA Aminotransferase for Epilepsy and Neuropathic Pain
用于治疗癫痫和神经性疼痛的新型 GABA 转氨酶灭活剂
  • 批准号:
    10653918
  • 财政年份:
    2021
  • 资助金额:
    $ 9.5万
  • 项目类别:
Ornithine Aminotransferase Inactivation, a New Approach for Treatment of Cancers
鸟氨酸转氨酶失活,治疗癌症的新方法
  • 批准号:
    10185371
  • 财政年份:
    2021
  • 资助金额:
    $ 9.5万
  • 项目类别:
New Inactivators of GABA Aminotransferase for Epilepsy and Neuropathic Pain
用于治疗癫痫和神经性疼痛的新型 GABA 转氨酶灭活剂
  • 批准号:
    10447703
  • 财政年份:
    2021
  • 资助金额:
    $ 9.5万
  • 项目类别:
Ornithine Aminotransferase Inactivation, a New Approach for Treatment of Cancers
鸟氨酸转氨酶失活,治疗癌症的新方法
  • 批准号:
    10614423
  • 财政年份:
    2021
  • 资助金额:
    $ 9.5万
  • 项目类别:
Ornithine Aminotransferase Inactivation, a New Approach for Treatment of Cancers
鸟氨酸转氨酶失活,治疗癌症的新方法
  • 批准号:
    10390338
  • 财政年份:
    2021
  • 资助金额:
    $ 9.5万
  • 项目类别:
Selective inhibition of nitric oxide synthase for multiple indications
选择性抑制一氧化氮合酶用于多种适应症
  • 批准号:
    10385805
  • 财政年份:
    2019
  • 资助金额:
    $ 9.5万
  • 项目类别:
Selective inhibition of nitric oxide synthase for multiple indications
选择性抑制一氧化氮合酶用于多种适应症
  • 批准号:
    10611534
  • 财政年份:
    2019
  • 资助金额:
    $ 9.5万
  • 项目类别:
Selective inhibition of nitric oxide synthase for multiple indications
选择性抑制一氧化氮合酶用于多种适应症
  • 批准号:
    9919591
  • 财政年份:
    2019
  • 资助金额:
    $ 9.5万
  • 项目类别:
Chemistry of Life Processes Predoctoral Training Program
生命过程化学博士前培训项目
  • 批准号:
    8475188
  • 财政年份:
    2013
  • 资助金额:
    $ 9.5万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了