DESIGN OF NEW BENZODIAZEPINE LIGANDS AS MEMORY ENHANCERS

这些研究的总体目标是通过计算机辅助发现新型苯二氮卓受体（BDZR）配体，以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其在认知增强治疗中最佳利用的长期障碍。这里提出的设计策略增加了本研究中确定的配体在抽搐特性和上下文记忆功能障碍衰减之间更好地分离的可能性。第一代3D药效团鉴定的先导化合物将筛选BDZR结合活性、镇静和惊厥特性，并在简单的认知功能障碍模型中评估其减轻认知障碍的能力。这一I期SBIR将产生两个有用的结果：1)第一代新型BDZR化合物在情境记忆终点具有显著的逆激动剂特性，缺乏惊厥活性；2)第二代先导化合物是在完善的3D药效团基础上确定的，为未来的评估做好准备。因此，这两组化合物都有潜力作为认知障碍的记忆增强剂进行II期测试。鉴于目前可用的治疗药物的临床成功有限，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对治疗产生重大影响。拟议的商业应用：目前，在开发治疗认知障碍的药理学策略方面，仅取得了有限的成功。这些策略的重点是通过使用毒蕈碱激动剂和胆碱酯酶抑制剂，药物诱导胆碱能神经元活性的增加。这种有限成功的一个可能原因是，有效的策略可能既需要增强存活神经元过程的功能，又需要保留皮质乙酰胆碱神经通路典型的高度复杂的传递模式。一种有希望的替代方法，满足这些要求，得到大量报告证据和我们之前的研究的支持，是通过调节氨基丁酸能抑制途径调节乙酰胆碱神经通路来减轻老年性痴呆相关认知功能障碍的策略。这种治疗认知障碍的替代方法成功率更高，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.