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
- 来源:
- 关键词:20 year old4-Aminobutyrate aminotransferaseAffectAmericanBlood - brain barrier anatomyBrainCancer PatientChemotherapy-induced peripheral neuropathyComputer ModelsConvulsionsCoupledCrystallizationCrystallographyDiseaseEffectivenessEnzymesEpilepsyGlutamate DecarboxylaseGlutamatesGlutamic AcidGrantHigh Pressure Liquid ChromatographyIn VitroMaintenanceMotor SeizuresNeuronsNeurotransmittersPain managementPoliciesPopulationProductivityPyridoxal PhosphateRegulationSedation procedureSeizuresSpinalStructureTestingTimeTrainingVendorabuse liabilityalpha ketoglutarateanalogbasechemotherapydesigndriving forcegamma-Aminobutyric Acidin vivomass spectrometermental statepainful neuropathyrelating to nervous systemrepairedside effectsuccinic semialdehyde
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)
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RICHARD B SILVERMAN其他文献
RICHARD B SILVERMAN的其他文献
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{{ 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
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10653918 - 财政年份:2021
- 资助金额:
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鸟氨酸转氨酶失活,治疗癌症的新方法
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10185371 - 财政年份:2021
- 资助金额:
$ 9.5万 - 项目类别:
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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:
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- 批准号:
10614423 - 财政年份:2021
- 资助金额:
$ 9.5万 - 项目类别:
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鸟氨酸转氨酶失活,治疗癌症的新方法
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- 资助金额:
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