Mechanistic studies of the GYKI Compounds

GYKI 化合物的机理研究

基本信息

批准号：
8423011
负责人：
LI NIU
金额：
$ 27.91万
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 2016-08-31
项目状态：
已结题

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.

描述（由申请人提供）：离子型谷氨酸受体的 1-氨基-3-羟基-5-甲基-4-异恶唑丙酸酯 (AMPA) 亚型的过度激活已被认为是许多神经系统疾病的主要原因，例如如癫痫、中风和肌萎缩侧索硬化症（ALS）。使用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追求的治疗策略。 2,3-苯二氮卓衍生物，也称为GYKI化合物，是AMPA受体的抑制剂，是迄今为止开发的一类最有前途的候选药物。然而，这些化合物对 AMPA 受体的定量功能活性仍不清楚。这是因为 AMPA 受体在微秒时间域内打开通道，甚至在毫秒时间域内也会脱敏。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。在本提案中，我们将系统地阐明一系列 19 种 GYKI 化合物的作用机制，测量它们对特定 AMPA 受体亚基的效力，并表征构效关系，包括受体上的抑制位点数量以及是否存在任何两个位点彼此相互作用（即，两个抑制剂与其位点的结合可以是独立的，也可以受到任一先结合的负面影响）。为了实现特定目标，我们将进行一系列实验，包括以μs时间分辨率进行激光脉冲光解研究，以研究GYKI化合物对AMPA受体通道开放速率过程的影响。这些化合物的动力学研究，与所有受体形式仍然发挥功能的时间尺度相关，以前是不可能的。我们对这些化合物的受体性质和构效关系的研究结果对于合理设计和合成具有更高效力的亚基和构象选择性GYKI化合物具有重要意义，从而可以更定量地控制AMPA受体活性。