Attenuation of Memory Impairment Using BDZR Ligands

描述(申请人提供)：随着美国人口老龄化，阿尔茨海默病的发病率将急剧上升。阿尔茨海默型老年性痴呆(SDAT)是由胆碱能系统进行性衰竭、记忆受损和功能减退引起的。这些方法往往会引起直接的突触后刺激，导致持续的、紧张性的神经元活动，不利于正常的认知处理，这是一个严重的缺陷。另一种改善与胆碱能功能低下相关的认知能力下降的策略是使用大脑自身的内部控制系统之一，即胆碱能输入的GABA能抑制调制，以增强胆碱能兴奋在海马体中的影响。使用跨学科的方法，我们建议证明，开发出的化合物可以与含有Alpha5亚单位的GABA-A受体的子集特异地相互作用，几乎只在海马锥体细胞上发现，可以被设计成抑制GABA介导的CI进入神经元的通道。这将有效地抵消由胆碱能功能减退引起的背景记忆缺陷。我们打算通过应用我们开发的一种独特的计算工具来实现这一点，在该工具中，行为数据和体外结合和激活数据都被用来建立模型(称为3D药效团)，该模型反映了BDZR配体固有的基本化学特征，这对增强上下文记忆至关重要。先前开发的3D识别药效团随后帮助我们确定GABAA受体的Alpha5亚单位是GABAA能影响上下文记忆的关键元件。这一阶段SBIR建议的总体目标是使用上下文记忆3D药效团中包含的信息(识别和激活)来指导候选化合物的合成，这些候选化合物具体地与包含AS亚单位的GABA-A受体上的苯二氮卓类结合部位结合，并导致GABA介导的氯电流的强烈减少，从而最佳地增强上下文记忆功能，同时将不良副作用降至最低。这一提议的成功将证明开发高效、激活特异性BDZR配体的可行性，该配体能够缓解因胆碱能功能减退而导致的上下文记忆缺陷。这将为在第二阶段应用中寻找最有希望的先导化合物奠定基础，该应用旨在解决在老龄化和SDAT中观察到的认知衰退的严重问题。

DESCRIPTION (provided by applicant): As the U.S. population ages, the incidence of Alzheimer s disease will rise dramatically. Senile dementia of the Alzheimer's type (SDAT) arises from progressive failure of the cholinergic system, impairing memory and hypofunction. These approaches tend to elicit direct postsynaptic stimulation, causing constant, tonic neuronal activity unfavorable to normal cognitive processing, which is a serious drawback. An alternative but largely unexploited strategy for ameliorating cogninve decline associated with cholinergic hypofunction is to use one of the brain's own internal control systems, GABAergic inhibitory modulation of cholinergic inputs, to augment the impact of cholinergic excitation in the hippocampus. Using an interdisciplinary approach, we propose to demonstrate that compounds developed to specifically interact with a subset of GABA-A receptors containing the alpha5 subunit, found almost exclusively on pyramidal cells of the hippocampus, can be designed to dampen GABA-mediated CI- passage into the neuron. This would effectively counteract contextual memory deficits caused by cholinergic hypofunction. We intend to achieve this through the application of a unique computational tool we have developed in which both behavioral data and in vitro binding and activation data are used to build models (known as 3D pharmacophores) that reflects the essential chemical features inherent to BDZR ligands crucial to enhancing contextual memory. The previously developed 3D recognition pharmacophore has subsequently aided us in identifying the alpha 5 subunit of the GABAA receptor as a key element in GABAergic influence on contextual memory. The overall goal of this Phase I SBIR proposal is to use the information contained within contextual memory 3D pharmacophores (both recognition and activation) to direct the synthesis of candidate compounds that specifically, bind to the benzodiazepine binding site on GABA-A receptors containing the as subunit and cause a strong reduction in GABA-mediated Cl- currents, thereby optimal enhancing contextual memory function while simultaneously minimizing undesirable side-effects. The success of this proposal will demonstrate the viability of developing highly efficacious, activation-specific BDZR ligands capable of alleviating contextual memory deficits attributed to cholinergic hypofunction. This will lay the groundwork for pursuing the most promising lead compounds in a Phase II application aimed at addressing the serious problem of cognitive decline observed in aging and SDAT.