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Novel GABA-A Modulators as Cognitive Enhancers

作为认知增强剂的新型 GABA-A 调节剂

基本信息

批准号：
8129770
负责人：
JAMES K ROWLETT
金额：
$ 50.92万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-08-15 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8129770
关键词：
3-aminobutyric acid Address Adverse effects Agonist Alzheimer&apos s Disease Aminobutyric Acids Anti-Cholinergics Area Attenuated Benzodiazepines Binding Brain Chloride Channels Chronic Cognition Cognition Disorders Cognitive Cognitive deficits Development Disease Evaluation GABA Receptor Goals Hippocampus (Brain)Human Impaired cognition Lead Learning Ligands Memory Memory impairment Modeling Monkeys Mus Neurodegenerative Disorders Neurons Neuropsychological Tests Nootropic Agents Patients Performance Pharmaceutical Preparations Primates Procedures Proteins Research Retrieval Scopolamine Series Site Temporal Lobe Testing Tg2576 Therapeutic Transgenic Mice Transgenic Organisms Translating age related analog base clinical efficacy cognitive function design drug discovery effective therapy executive function gamma-Aminobutyric Acid in vivo memory process mild neurocognitive impairment mouse model novel novel strategies pharmacophore public health relevance receptor receptor binding research study translational approach

项目摘要

DESCRIPTION (provided by applicant): Compounds that act at the benzodiazepine (BZ) site of the 3-aminobutyric acid type-A (GABAA) receptor have profound effects on memory. For example, there is accumulating evidence that BZ-site inverse agonists, which attenuate GABA's action at the receptor, can act as cognitive enhancing agents. In particular, compounds with selectivity for 15 subunit-containing GABAA receptors appear to have cognition-enhancing effects without the unwanted side effects associated with non-selective compounds. Our proposal will focus on 15GABAA receptors as a target site for developing cognitive enhancing agents for treating Alzheimer's disease. A key rationale for this approach is that GABA neurons in the temporal cortex and associated areas are largely preserved in patients with Alzheimer's disease, and these preserved neurons contain 15GABAA receptors. In order to identify compounds for mechanistic studies, a drug discovery approach will be used in which targeted experiments in mice advance new compounds for evaluation in monkey cognition tasks. In two specific aims, we will evaluate the following hypotheses: (1) Based on a pharmacophore model of GABAA receptors, we predict that increasing activity at specific determinants of the 15GABAA receptor binding pocket (L2), as well as creation of bivalent ligands based on these compounds, will result in behaviorally-active, 15GABAA receptor-selective ligands; and (2) we predict that inverse agonist action at 15GABAA receptors will enhance performance in cognitive tasks in monkeys and transgenic (APPSwe Tg2576) mice. This translational approach should provide important information for identifying lead compounds for development as cognitive enhancing agents for Alzheimer's disease and other cognitive disorders. PUBLIC HEALTH RELEVANCE: Alzheimer's disease is a chronic, progressive, and ultimately fatal neurodegenerative disease, and there currently are few broadly effective treatment options. The overall goal of this application is to explore the potential for new compounds, acting at a brain protein called the "GABA receptor", to enhance cognitive function. Because these compounds appear to be remarkably safe, they may provide a promising new approach for treating memory decline associated with Alzheimer's and other related disorders.

性状（由申请方提供）：作用于3-氨基丁酸A型（GABAA）受体的苯二氮卓类（BZ）位点的化合物对记忆有深远影响。例如，越来越多的证据表明，减弱GABA对受体作用的BZ位点反向激动剂可以作为认知增强剂。特别地，对含有15个亚基的GABAa受体具有选择性的化合物似乎具有认知增强作用，而没有与非选择性化合物相关的不希望的副作用。我们的建议将集中在15 GABAA受体作为开发治疗阿尔茨海默病的认知增强剂的靶点。这种方法的一个关键原理是，颞叶皮层和相关区域的GABA神经元在阿尔茨海默病患者中大部分被保留下来，这些保留的神经元含有15 GABAA受体。为了鉴定用于机理研究的化合物，将使用药物发现方法，其中小鼠中的靶向实验推进新化合物用于在猴认知任务中进行评价。在两个具体目标中，我们将评估以下假设：（1）基于GABAA受体的药效团模型，我们预测在15 GABAA受体结合口袋（L2）的特定决定簇处增加活性，以及基于这些化合物的二价配体的产生，将导致具有行为活性的15 GABAA受体选择性配体;（2）我们预测15 GABAA受体的反向激动剂作用将增强猴子和转基因（APPSwe Tg 2576）小鼠在认知任务中的表现。这种翻译的方法应该提供重要的信息，以确定开发为阿尔茨海默氏病和其他认知障碍的认知增强剂的先导化合物。公共卫生关系：阿尔茨海默病是一种慢性、进行性和最终致命的神经退行性疾病，目前几乎没有广泛有效的治疗选择。该应用的总体目标是探索新化合物的潜力，作用于称为“GABA受体”的大脑蛋白质，以增强认知功能。由于这些化合物似乎非常安全，它们可能为治疗与阿尔茨海默氏症和其他相关疾病相关的记忆衰退提供一种有希望的新方法。