MOLECULAR MODELING, DESIGN AND EVALUATION OF BDZ-LIGANDS

这项拟议的跨学科工作的总体目标是 具有改进的新型治疗剂的计算机辅助设计 药理概况通过与细胞结合发挥作用 BDZ/GABA(A)受体(BDZ配体)。为此，我们使用了 理论化学的鉴定和表征技术 受体识别的可靠分子决定因素和受体类型 活性，即激动感、对抗性和反向激动感。我们已经使用了 这些空间和电子性质作为鉴定的标准 已知化合物和将要合成的新化合物的设计 可以是具有预期活性的BDZ配体，如具有以下活性的拮抗剂 改善的药代动力学特征，中效激动剂 可能有较少的副作用，如镇静，乙醇的增强， 耐受性和身体依赖性，以及可能是 有用的治疗剂本身。这些类比将是 具有理论上的特点并受到不同的药理作用的影响 评估，包括受体结合，体外生理学研究 以及一系列体内行为终结点。迭代交互作用 在理论研究和实验研究的结果之间，将使用 在这项工作中，设计了几代连续的 改进的类比。同时，我们计划继续 跨学科努力，以进一步了解 BDZ配体的各种生物活性以及测试、提纯和 扩大我们现有的认可和激活标准。为此， 将研究BDZ配体的新家族，新的行为和 使用生理终点，并探索受体的异质性。在一个 第三项相关工作，我们计划使用计算机辅助技术来 明确表征和开发BDZ结合位点的结构 在GABA受体的阿尔法亚单位中。这些程序将涉及 二级结合部位关键氨基酸的鉴定 结构算法，对蛋白质数据库的系统搜索 已知的X射线结构和能量优化程序。加在一起， 这项多学科、多方面的研究结果应该导致 既优化设计了新型BDZ配体，又进一步了解了 它们的作用机制。

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.