CELLULAR AND MOLECULAR TARGETS OF GENERAL ANESTHETICS

描述(摘自应用)：该计划项目的目标是促进对全麻药在突触前和突触后的细胞和分子作用机制的理解，特别是异氟醚和异丙酚。该方案由四个项目组成，由一个科学和行政核心联系在一起。在项目1中，将建立一组异丙酚类似物之间关于非洲爪哇蝌蚪翻正反射丧失的定量构效关系，并与调节重组γ-氨基丁酸A(GABAA)受体的定量构效关系进行比较。在项目2中，将利用光学和生化技术研究异氟醚和异丙酚对培养的海马神经元突触前囊泡融合和内吞作用的影响。在项目3中，异氟醚和异丙酚与GABAA受体中特定氨基酸残基的相互作用将使用取代半胱氨酸可及性方法进行探索。科学和行政核心将负责组织和管理该小组一年两次的会议，与科学咨询委员会和特邀发言者一起，合成新的异丙酚类似物以供项目1和3研究，并在每个项目进行生理测量时测量实验盐液中异氟醚和异丙酚的浓度。拟议的计划将专注于全麻药在中央突触的分子作用部位。这些信息将有助于进一步表征全身麻醉药体内复杂药理的多个靶点，并可能导致更安全的药物的开发。

DESCRIPTION (taken from application): The objective of this proposed program project is to advance understanding of the cellular and molecular mechanisms of action of general anesthetics at both pre- and postsynaptic sites, with particular emphasis on isoflurane and propofol. The program consists of four projects linked together by a Scientific and Administrative Core. In Project 1, quantitative structure-activity relations will be established among a group of propofol analogs for loss of righting reflex in Xenopus laevis tadpoles, and compared with that for the modulation of recombinant gamma-aminobutyric acidA (GABAA) receptors. In Project 2, the effects of isoflurane and propofol on presynaptic vesicle fusion and endocytosis will be studied in cultured hippocampal neurons, using both optical and biochemical techniques. In Project 3, interactions of isoflurane and propofol with specific amino acid residues in the GABAA receptor will be probed using the substituted cysteine accessibility method. The Scientific and Administrative Core will serve to organize and administer twice-yearly meetings of the group, together with a Scientific Advisory Board and guest speakers, synthesize novel analogs of propofol for study in Projects 1 and 3), and measure the concentrations of isoflurane and propofol present in the experimental salines at the time of the physiological measurements made in each project. The proposed program will focus on the molecular sites of action of general anesthetics at central synapses. Such information will aid in further characterization of the multiple targets underlying the complex in vivo pharmacology of general anesthetics, and may lead to the development of safer agents.