Mechanistic studies of the GYKI Compounds

GYKI 化合物的机理研究

基本信息

批准号：
7662827
负责人：
LI NIU
金额：
$ 31.7万
依托单位：
STATE UNIVERSITY OF NEW YORK AT ALBANY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-03-06 至 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7662827
关键词：
AMPA Receptors Affect Amyotrophic Lateral Sclerosis Benzodiazepines Binding Cells Classification Drug Receptors Epilepsy Future GluR2 subunit AMPA receptor Glutamate Receptor Glutamates Goals Individual Investigation Ion Channel Isoxazoles Kainic Acid Receptors Kinetics Lasers Measurement Measures Mediating Molecular Conformation N-Methyl-D-Aspartate Receptors N-Methylaspartate NR1 gene Nerve Degeneration Neuroprotective Agents Pharmaceutical Preparations Physiologic pulse Process Property Propionates Protein Isoforms RNA Splicing Research Resolution Role Series Site Stroke Structure-Activity Relationship Techniques Testing Therapeutic Time Variant Whole-Cell Recordings Work base chemical group design drug candidate excitotoxicity inhibitor/antagonist kainate millisecond nervous system disorder photolysis public health relevance receptor research study

AMPA Receptors Affect Amyotrophic Lateral Sclerosis Benzodiazepines Binding Cells Classification Drug Receptors Epilepsy Future GluR2 subunit AMPA receptor Glutamate Receptor Glutamates Goals Individual Investigation Ion Channel Isoxazoles Kainic Acid Receptors Kinetics Lasers Measurement Measures Mediating Molecular Conformation N-Methyl-D-Aspartate Receptors N-Methylaspartate NR1 gene Nerve Degeneration Neuroprotective Agents Pharmaceutical Preparations Physiologic pulse Process Property Propionates Protein Isoforms RNA Splicing Research Resolution Role Series Site Stroke Structure-Activity Relationship Techniques Testing Therapeutic Time Variant Whole-Cell Recordings Work base chemical group design drug candidate excitotoxicity inhibitor/antagonist kainate millisecond nervous system disorder photolysis public health relevance receptor research study

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项目摘要

DESCRIPTION (provided by applicant): Excessive activation of the 1-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) subtype of ionotropic glutamate receptors has been implicated as a leading contributor to a number of neurological diseases, such as epilepsy, stroke and amyotrophic lateral sclerosis (ALS). Using inhibitors as neuroprotective drugs to dampen the excessive receptor activity has been a long pursued therapeutic strategy. 2,3-Benzodiazepine derivatives, also known as GYKI compounds, are inhibitors of AMPA receptors, and they represent a class of the most promising drug candidates developed to date. However, the quantitative, functional activities of these compounds on AMPA receptors remain poorly defined. This is because AMPA receptors open their channels in the microsecond time domain and desensitize even in the millisecond time region. Yet, current kinetic techniques do not have sufficient time resolutions required to characterize the kinetic mechanism of channel opening and the mechanism of inhibitor/drug- receptor interaction. In this proposal, we will systematically elucidate the mechanism of action for a series of 19 GYKI compounds, measure their potency on specific AMPA receptor subunits, and characterize the structure-activity relationship, including the number of inhibitory sites on a receptor and whether any two sites interact with each other (i.e., the binding of two inhibitors to their sites can be independent or negatively affected by binding of either one first). To achieve the specific aims, we will carry out a number of experiments, including a laser- pulse photolysis study with the ?s time resolution to investigate the effect of a GYKI compound on the channel-opening rate process of an AMPA receptor. The kinetic investigation of these compounds, relevant to the time scale within which all receptor forms are still functional, has not been previously possible. Our results on the receptor properties and the structure-activity relationship of these compounds will be valuable for rational design and synthesis of subunit- and conformation-selective GYKI compounds with higher potency so that AMPA receptor activities can be controlled more quantitatively. PUBLIC HEALTH RELEVANCE: We propose to systematically characterize a group of GYKI compounds, which are inhibitors on AMPA glutamate ion channel receptors. These compounds are candidates for developing potential drugs to treat a number of neurological diseases involving AMPA receptors.

描述（由申请人提供）：1-氨基-3-羟基-5-甲基-4-异恶唑丙酸酯（AMPA）亚型谷氨酸受体亚型的过度激活已被视为导致多种神经学疾病的主要促进者，例如多种神经学疾病，例如癫痫，骨膜骨骼，息肉和amyytroplics corperscer（erake and andy scrorsis）。将抑制剂作为神经保护药物来抑制过度的受体活性一直是一种长期以来的治疗策略。 2,3-苯并二氮卓类衍生物，也称为Gyki化合物，是AMPA受体的抑制剂，它们代表了迄今为止开发的最有前途的候选药物。但是，这些化合物在AMPA受体上的定量功能活性仍然很差。这是因为AMPA受体在微秒时间域中打开其通道，即使在毫秒的时间区域也脱敏。然而，当前的动力学技术没有足够的时间分辨率来表征通道打开的动力学机制和抑制剂/药物受体相互作用的机制。在该提案中，我们将系统地阐明一系列19种gyki化合物的作用机制，衡量它们对特定AMPA受体亚基的效力，并表征结构活性关系，包括受体上的抑制位点的数量，包括任何两个位点的抑制作用，以及是否彼此相互作用（即两种抑制剂都可以与该站点相互影响），或者均可对其进行粘合或对其进行粘合。为了达到特定目标，我们将进行许多实验，包括具有分辨率的激光脉冲光解研究，以研究Gyki化合物对AMPA受体通道开放率过程的影响。对这些化合物的动力学研究与以前无法使用所有受体形式的时间尺度有关。我们对这些化合物的受体特性和结构活性关系的结果对于合理的设计和合成亚基和构象选择性的Gyki化合物具有较高效力，因此可以更定量地控制AMPA受体活动。公共卫生相关性：我们建议系统地表征一组Gyki化合物，它们是AMPA谷氨酸离子通道受体的抑制剂。这些化合物是开发潜在药物来治疗许多涉及AMPA受体的神经系统疾病的候选者。