MOLECULAR MECHANISMS OF BARBITURATES AT GABA-A RECEPTORS

巴比妥类药物在 GABA-A 受体上的分子机制

• 批准号: 2674540
• 负责人: MATTHEW D KRASOWSKI
• 金额: $ 2.08万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-10 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/2674540
• 关键词: GABA receptor; barbiturates; chimeric proteins; electrophysiology; neuropharmacology; receptor binding; receptor sensitivity

Many structurally different classes of compounds with central nervous system (CNS) depressant effects, such as the barbiturates, general anesthetics, neurosteroids, alcohol, and the benzodiazepines, modulate synaptic inhibition mediated by the GABAA receptor (GABAA-R) in the mammalian CNS. In many cases, this is likely to be the primary mechanism by which these drugs induce acute intoxication, provide clinically useful therapy, exert side effects, and/or mediate abuse liability. The molecular nature of the interaction of these agents with the GABAA-R is not well understood and, with the exception of the benzodiazepines, the sites of binding have not been characterized. The goals of the proposed research are to study the pharmacology and electrophysiology of chimeric receptors containing portions of human GABAA-R subunits together with complementary pieces of the related glycine receptors or the GABA rho subunits (the 'GABAc receptor'). In particular, the proposed research will focus on the barbiturates. These chimeras were chosen to combine homologous ligand- gated receptor subunits that are modulated by barbiturates (e.g., GABA-Rs) with those that are insensitive to barbiturate modulation (e.g., the rho1 subunit) to gain information about the molecular nature of the sites of interaction.

许多结构不同的化合物与中枢神经系统 系统（CNS）干扰作用，如巴比妥类药物，一般 麻醉剂、神经类固醇、酒精和苯二氮卓类药物， 突触抑制介导的GABAA受体（GABAA-R）在 哺乳动物中枢神经系统 在许多情况下，这可能是主要机制 这些药物引起急性中毒， 治疗、产生副作用和/或调解滥用倾向。 分子 这些药物与GABAA-R相互作用的性质并不好 除苯二氮卓类药物外， 结合还没有被表征。 拟议研究的目标 是研究嵌合受体的药理学和电生理学 含有人GABAA-R亚基的部分以及互补的 相关的甘氨酸受体或GABArho亚单位的片段（ “GABAc受体”）。 特别是，拟议的研究将集中在 巴比妥类药物。 选择这些嵌合体来结合联合收割机同源配体- 由巴比妥酸盐调节的门控受体亚单位（例如，GABA-Rs） 与对巴比妥酸盐调节不敏感的那些（例如，Rho1 亚基），以获得有关的网站的分子性质的信息， 互动