DESIGN OF NEW BENZODIAZEPINE LIGANDS AS MEMORY ENHANCERS

这些研究的总体目标是计算机辅助发现新的苯二氮卓类受体（BDZR）配体，用于减轻与老年性痴呆相关的认知功能障碍。 对惊厥电位的担忧是长期以来阻碍其在认知增强疗法中的最佳利用的因素。这里提出的设计策略增加了可能性，在这项研究中确定的配体将有更好的分离惊厥性质和衰减的上下文记忆功能障碍。将筛选用第一代3D药效团鉴定的先导化合物的BDZR结合活性、镇静和惊厥性质，并评价其在认知功能障碍的简单模型中减弱认知障碍的能力。该I期SBIR将产生两个有用的结果：1）第一代新型BDZR化合物，其在缺乏惊厥活性的背景记忆终点处具有显著的反向激动剂性质2）第二代先导化合物，其基于精制的3D药效团鉴定，可用于未来评估。因此，这两组化合物都有可能作为认知障碍的记忆增强剂进行II期试验。鉴于目前可用的治疗剂的临床成功有限，出现一种替代方法来减轻与老年性痴呆相关的认知功能障碍可能会对治疗产生重大影响。拟定商业应用：目前，从目前的努力，只有有限的成功，以开发用于治疗认知障碍的药理学策略。这些策略集中于通过使用毒蕈碱激动剂和胆碱酯酶抑制剂来增加药物诱导的胆碱能神经元活性。这种有限的成功的一个可能的原因是，一个有效的策略是可能需要既增强幸存的神经元过程的功能，并保留高度复杂的传输模式典型的皮质乙酰胆碱神经通路。一个有前途的替代方法，它满足这些要求，大量的证据和我们以前的研究支持，是一种策略，通过调节乙酰胆碱神经通路的GABA能抑制通路的调节，衰减老年性痴呆相关的认知功能障碍。 这种治疗认知障碍的替代方法具有更高的成功概率，因此具有巨大的商业潜力。

The overall goal of these studies is the computer aided discovery of novel benzodiazepine receptor (BDZR) ligands for attenuating cognitive dysfunction associated with senile dementia. Concern about convulsive potential is a long-standing impediment to their optimum utilization in cognitive enhancing therapies. The design strategy proposed here increases the likelihood that ligands identified in this study will have better separation between convulsive properties and attenuation of contextual memory dysfunction. Lead compounds, identified with the first generation 3D pharmacophore, will be screened for BDZR binding activity, sedative and convulsive properties, and evaluated for ability to attenuate cognitive impairment in a simple model of cognitive dysfunction. Two useful outcomes will result from this Phase I SBIR: l) First generation novel BDZR compounds with significant inverse agonist properties at the contextual memory endpoint lacking convulsant activity 2) Second generation lead compounds identified on the basis of a refined 3D pharmacophore ready for future assessment. Hence, both sets of compounds have potential for Phase II testing as memory enhancers in cognitive disorders. Given the limited clinical success of currently available therapeutic agents the emergence of an alternative approach for attenuating cognitive dysfunction associated with senile dementia is likely to have a significant impact on treatment. PROPOSED COMMERCIAL APPLICATION: At present, there has been only limited success from current efforts to develop pharmacological strategies for the treatment of cognitive disorders. These strategies have focused on the drug-induced increase in the activity of cholinergic neurons by the use of muscarinic agonists and cholinesterase inhibitors. A possible reason for this limited success is that an effective strategy is likely to require both augmenting the function of the surviving neuronal processes and preserving the highly complex transmission patterns typical for cortical ACh neural pathways. A promising alternative approach, which meets these requirements, supported by substantial reported evidence and by our prior studies, is a strategy that attenuates senile dementia related cognitive dysfunction by regulating ACh neural pathways via the modulation of GABAergic inhibitory pathways. This alternative approach to the treatment of cognitive disorders has an increased probability of success and hence a large commercial potential.