Anesthetics: Cellular & Molecular Actions

GRANT=6521568；P01GM 全麻药达到临床预期效果的机制尚不完全清楚。本计划中提出的工作旨在定义麻醉剂类固醇的分子靶点(S)，并阐明在这些靶点上的作用导致麻醉的方式。其基本思想是，类固醇麻醉剂作用于蛋白质上的特定位置，特别是参与神经元之间形成转移的蛋白质。拟议的研究将建立在该计划前几个时期取得的一系列进展的基础上，这些进展为类固醇的作用部位和作用机制提供了见解。该计划的目标之一是确定类固醇对几类膜通道的作用，包括GABA-A受体、谷氨酸能受体和甘氨酸能受体。该计划的第二个目标是确定类固醇与一个特定靶点--GABA-A受体相互作用的结构基础。这项工作将包括补充研究，以修改受体的结构，并检查由特定部位的光激活类固醇类似物标记的结构。该计划的第三个目标是阐明类固醇对其分子靶标的作用机制。该计划的最终目标是阐明类固醇对其分子靶标的作用机制。最终目标是将药理学和生理学结果与麻醉的产生或仅在整个动物水平上定义的其他状态相关联。虽然重点是麻醉剂类固醇，但该计划将包括检查额外的麻醉剂，以便与类固醇进行比较。 每个项目都涉及麻醉剂类固醇在细胞和分子水平上的作用的一个或另一个方面。作为一个整体，该计划将整合这些互补性研究，并为新化合物的继续开发和对行为状态的干燥影响的分析提供资源。

GRANT=6521568;P01GM The mechanisms by which general anesthetics have their clinically desired effects are not yet fully understood. The work proposed in this Program is designed to define the molecular target(s) for anesthetic steroids and to clarify the way in which action at these targets results in anesthesia. The underlying idea is that steroid anesthetics act at defined sites on proteins and, in particular, the proteins involved in formation transfer between neurons. The proposed research will build on a series of advances made in proceeding periods of the Program, which have provided insights into the sites and mechanisms of action for steroids. One objective of the Program is to define the actions of steroids on several classes of membrane channel, including GABA-A receptors, glutamatergic receptors and glycinergic receptors. The second objective of the Program is to define the structural basis for steroid interaction with one specific target, the GABA-A receptor. This work will involve complementary studies to modify the structure of the receptor and to examine the structures labeled by site-specific photo-activated steroid analogues. The third objective of the Program is to clarify the mechanisms by which steroids have their actions on their molecular targets. The final objective of the Program is to clarify the mechanisms by which steroids have their actions on their molecular targets. The final objective is to correlate the pharmacological and physiological results with the production of anesthesia or other states defined only at the level of the whole animal. Although the focus is anesthetic steroids, the Program will include examination of additional anesthetics for comparison to the steroids. Each project addresses one or other aspect of the action of anesthetic steroids at the cellular and molecular level. The Program as a whole will integrate these complementary studies and provide the resources for continued development of novel compounds and for assays of dry effects on behavioral states.