MOLECULAR MECHANISMS OF BARBITURATES AT GABA-A RECEPTORS

许多具有中枢神经结构的不同类别的化合物 系统(CNS)的抑制作用，如巴比妥类，一般 麻醉剂、神经类固醇、酒精和苯二氮卓类药物，调节 GABAA受体(GABAA-R)介导的突触抑制 哺乳动物中枢神经系统。在许多情况下，这很可能是主要的机制 通过这些药物引起急性中毒，提供临床上有用的 治疗，施加副作用，和/或调解滥用责任。分子 这些试剂与GABAA-R的相互作用性质不是很好 了解并，除苯二氮类药物外， 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 含有部分人GABAA-R亚基和互补的 相关的甘氨酸受体或GABA Rho亚单位( ‘GABAc受体’)。特别是，拟议的研究将侧重于 巴比妥酸盐。这些嵌合体被选择来结合同源配体- 受巴比妥酸盐(例如，GABA-R)调节的门控受体亚单位 与对巴比妥酸盐调制不敏感的那些(例如，RO1 亚基)，以获得有关其分子性质的信息 互动。

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.