MOLECULAR STUDY OF GABA AND BENZODIAZEPINE RECEPTORS

GABA 和苯二氮卓受体的分子研究

• 批准号: 3376925
• 负责人: JOHN F. TALLMAN
• 金额: $ 16.59万
• 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/3376925
• 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.

本申请集中在纯化和表征的 参与精神药理作用的蛋白质复合物 苯二氮卓类 使用苯二氮卓类（3-氨基氯硝西泮），这可以是 本发明提供了一种与固体基质偶联的用于纯化所述化合物的方法， 苯二氮卓受体蛋白正在开发中。 沿着 苯二氮卓受体，有可能同时纯化高和 γ-氨基丁酸的中等亲和力结合位点。 的 这些位点的动力学、化学计量和分子性质是 研究了 针对纯化复合物的单克隆抗体正在 制备和几种方法来检测这些不同的属性 正在研制抗体。 这些物质的物理作用点 将抗体与它们的药理学活性进行比较， 目标是确定各种药物作用部位的接近程度。 纯化的蛋白质将被重建到模型系统中，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，更大的可靠性， 预测作用于这些位点的药物的作用可以在 临床前水平。 由于慢性过敏性疾病引起的复合物变化（脱敏） 还将研究苯二氮卓类药物给药或GABA过度活性 在模型膜系统中。 通过研究GABA-苯二氮卓受体的分子结构， 复杂的，我们希望获得更深入的了解药理学 精神活性化合物，如地西泮、利西氮和泮。 这些化合物是世界上最广泛的处方药之一， 治疗广泛性焦虑和睡眠障碍。 我们的研究将 提供了深入了解这些条件的病因和发展 更有效的治疗。