MOLECULAR MODELING, DESIGN AND EVALUATION OF BDZ-LIGANDS

这项跨学科工作的总体目标是 计算机辅助设计新的治疗剂， 药理学特征，其通过结合到 BDZ/GABA（A）受体（BDZ配体）。为此，我们使用了 理论化学的技术，以确定和表征 受体识别的可靠分子决定因素和 活动，即，激动、拮抗和反向激动。我们已经使用 这些空间和电子性质作为鉴定的标准 已知化合物的合成和新化合物的设计， 可以是具有所需活性的BDZ配体，例如具有 改善的药代动力学特征， 可能具有较少的副作用，例如镇静，乙醇的增效作用， 耐受性和身体依赖性，以及可能 有用的治疗剂本身。这些类似物将是 在理论上进行了表征，并接受了多种药理学 评价，包括受体结合、体外生理学研究 和一系列体内行为终点。迭代交互作用 理论和实验研究的结果之间的关系将被用来 在这项工作中，设计了几代连续的 改进的类似物。同时，我们计划继续 跨学科的努力，以进一步了解的机制， BDZ配体的各种生物活性，并测试，精制和 扩大我们现有的认可和激活标准。为此目的， BDZ配体的新家族将被研究，新的行为和 使用生理学终点，并探索受体异质性。中 第三个相关的努力，我们计划使用计算机辅助技术， 明确表征并开发BDZ结合位点的结构 在GABA受体的α亚基中。这些程序将涉及 识别结合位点中的关键氨基酸，二级 结构化算法，蛋白质数据库的系统搜索， 已知X射线结构和能量优化程序。综合起来看， 这项多学科、多方面研究的结果应该会导致 优化设计的新BDZ配体和进一步了解 他们的行动机制。

The overall goal of this proposed interdisciplinary effort is the computer-aided design of new therapeutic agents with improved pharmacological profiles which exert their effect by binding to the BDZ/GABA(A) receptor (BDZ ligands). To this end, we have used the techniques o f theoretical chemistry to identify and characterize reliable molecular determinants of receptor recognition and types of activity, i,e., agonism, antagonism, and inverse agonim. We have used these steric and electronic properties as criteria for the identification of known compounds and the design of new ones to be synthesized which could be BDZ ligands with desired activity such as antagonists with improved pharmacokinetic characteristics, medium efficacy agonists which may have less side effects such as sedation, potentiation of ethanol, tolerance and physical dependence, and inverse agonists which may be useful therapeutic agents in themselves. These analogs will be characterized theoretically and subjected to diverse pharmacological evaluations including receptor binding, in vitro physiological studies and a spectrum of in vivo behavioral endpoints. Iterative interaction between the results of theoretical and expeerimental studies will be used throughout this work to design several generations of continuously improved analogs. In a parallel effort, we plan to continue interdisciplinary effort to further understand the mechanisms of the various biological activities of the BDZ ligands and to test, refine and expand our existing criteria for recognition and activation. To this end, new families of BDZ ligands will be studied, new behavioral and physiological end points used, and receptor heterogeneity explored. In a third related effort, we plan to use computer-assisted techniques to explicitly characterize and develop a structure for the BDZ binding site in the alpha-subunit of the GABA receptor. These procedures will involve identification of key amino acids in the binding site, secondary structure algorithms, a systematic search of a data base of proteins with known X-ray structure and energy optimization procedures. Taken together, the results of this multidisciplinary, mulifaceted study should lead to both optimally designed new BDZ ligands and to further understanding of their mechanisms of action.