QSAR STUDIES OF ANXIOLYTICS FOR LOW ABUSE POTENTIAL

在持续的协调努力中，使用 理论化学、合成化学、受体结合和 动物实验，两个主要目标将得到解决：（1） 分子特性的鉴定和表征 导致四种苯二氮卓受体调节的每一种 活动和对抗，以及它们之间的关系， 可能的多种BZ受体类型的体内活性。 (2)设计 新的类似物与激动剂的特定组合， 拮抗剂活性，可能是低焦虑选择性药物， 滥用潜力 为了实现第一个主要目标， 每种激动剂活性的要求将通过以下方式确定： 计算的构象和电子的比较 苯并二氮杂卓的性质和三种更具体的 抗焦虑药 以类似的方式， 三种类型中每种活性的拮抗要求 具有不同选择性的有效苯并二氮杂拮抗剂将是 研究了 在一项平行的努力中， BZ受体异质性的研究将继续使用计算机- 进行的受体结合实验的辅助分析 多种选择性和非选择性激动剂和拮抗剂 完成BZ受体位点。 这些理论和 实验研究应该会导致对 需要选择性激动和拮抗作用。 在第二个主要的努力中，激动作用的分子指标和 拮抗作用将被用于设计和合成候选的高- 亲和性，选择性激动剂/拮抗剂。 受体结合和 将进行动物试验研究以检验这些假设。 这些化合物的体内效力将被评估为： BZ的四大活动，即，抗焦虑药，抗惊厥药， 镇静催眠和肌肉松弛的特性。 可能 也将确定对这些行动的反对意见。 类似物 显示选择性或激动剂和拮抗剂的组合 将监测活性以增强CNS神经元的活性。 乙醇和巴比妥酸盐的影响。 身体依赖责任 将通过确定拮抗剂是否可以 突然出现戒断症状。 有可能在这些 新的类似物将是低滥用潜力的抗焦虑选择性药物 不会增强乙醇的中枢神经系统抑制作用， 巴比妥类药物。

In a continued coordinated effort, using the techniques of theoretical chemistry, synthetic chemistry, receptor-binding and animal testing, two major objectives will be addressed: (1) Identification and characterization of molecular properties leading to each of the four benzodiazepine-receptor modulated activities and antagonism to them and the relationship of these in vivo activities to possible multiple BZ-receptor types. (2) Design of new analogs with specific combinations of agonist and antagonist activities which could be anxioselective agents of low abuse potential. To accomplish the first major objective, common molecular requirements for each agonist activity will be determined by comparisons of calculated conformational and electronic properties of benzodiazepines and three more specific classes of anxioloytic agents. In a similar fashion, common molecular requirements for antagonism to each activity in three types of potent benzodiazepine antagonists with varying selectivity will be investigated. In a parallel effort, studies to clarify the question of BZ receptor heterogeneity will continue using computer- assisted analysis of receptor-binding experiments conducted with a variety of selective and nonselective agonists and antagonists that complete for the BZ receptor site(s). These theortical and experimental studies together should lead to the understanding of requirements for selective agonism and antogonism. In a second major effort, molecular indicators of agonism and antagonism will be used to design and synthesize candidate high- affinity, selective agonist/antagonists. Receptor-binding and animal-testing studies will be performed to test these hypotheses. The in vivo potency of these compounds will be assessed for the four major activities of the BZs, i.e., anxiolytic, anticonvulsant, sedative-hypnotic, and muscle-relaxant properties. Possible antagonism to these actions will also be determined. Analogs that display selectivity or a combination of agonist and antagonist activity will be monitored for potentiation of the CNS depressant effects of ethanol and barbiturates. Physical-dependence liability will be assessed by determining whether antagonists can precipitate withdrawal symptoms. It is possible that among these new analogs will be anxioselective agents of low abuse potential that will not potentiate the CNS depressant effects of ethanol and barbiturates.