MOLECULAR STUDY OF GABA AND BENZODIAZEPINE RECEPTORS

GABA 和苯二氮卓受体的分子研究

• 批准号: 3376924
• 负责人: JOHN F. TALLMAN
• 金额: $ 16.24万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-01-01 至 1987-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3376924
• 关键词: affinity chromatography; affinity labeling; antibody; benzodiazepines; brain metabolism; electrofocusing; gamma aminobutyrate; gel electrophoresis; high performance liquid chromatography; ion transport; membrane reconstitution /synthesis; radioimmunoassay; radiotracer

This application focuses upon the purification and characterization of the complex of proteins involved in the psychopharmacological actions of the benzodiazepines. Using a benzodiazepine (3-aminoclonazepam), which can be coupled to a solid matrix, a method for the purification of the benzodiazepine receptor protein is being developed. Along with the benzodiazepine receptor, it is possible to copurify both high and intermediate affinity binding sites for Gamma-aminobutyric acid. The kinetics, stoichiometry and molecular properties of these sites are investigated. Monoclonal antibodies against the purified complex are being prepared and several methods for detecting different properties of these antibodies are being developed. The physical locus of action of these antibodies will be compared to their pharmacological activities with the goal of defining the proximity of the sites of action of various drugs. The purified proteins will be reconstituted into a model system to directly study their action. It is expected that by a careful examination of the biochemical parameters of receptor function, greater reliability in predicting the actions of drugs which act at these sites can be made at a preclinical level. Changes (desensitization) in the complex due to chronic benzodiazepine administration or overactivity of GABA will also be studied in the model membrane system. By studying the molecular structure of the GABA-benzodiazepine receptor complex, we expect to gain greater insight into the pharmacology of psychoactive compounds such as diazepam, chlodiazepoxide and flurazepam. These compounds are among the most widely prescribed drugs in the world for the treatment of generalized anxiety and sleep disorders. Our studies will provide insights into the etiology of these conditions and the development of more effective therapy.

这项应用主要集中在提纯和表征 与人的精神药理作用有关的蛋白质复合体 苯二氮卓类。使用苯二氮卓类(3-氨氯硝基安定)，它可以是 一种耦合到固体基质上的提纯方法 苯二氮卓类受体蛋白正在开发中。以及 苯二氮卓类受体，可以同时与高水平和高水平的 伽马-氨基丁酸的中间亲和结合部位。这个 这些位置的动力学、化学计量和分子性质是 调查过了。针对纯化的复合体的单抗正在进行中 以及检测这些物质的不同性质的几种方法 抗体正在研发中。它们的物理作用轨迹 抗体将与它们的药理活性进行比较 目标是定义各种药物作用部位的接近程度。 纯化的蛋白质将被重组到一个模型系统中，以直接 研究他们的行动。预计，通过仔细检查 受体功能的生化参数，更可靠 预测在这些部位起作用的药物的作用可以在一个 临床前水平。慢性疾病引起的复合体的变化(脱敏) 服用苯二氮卓类药物或GABA活性过高也将被研究。 在模型膜系统中。 通过研究GABA-苯二氮卓类受体的分子结构 复杂，我们希望获得更多的药理学的了解 精神活性化合物，如安定、氯氮卓酮和氟西潘。 这些化合物是世界上使用最广泛的处方药之一 广泛性焦虑和睡眠障碍的治疗。我们的研究将 提供对这些情况的病因和发展的洞察 更有效的治疗方法。