CELLULAR AND MOLECULAR TARGETS OF GENERAL ANESTHETICS

描述（摘自申请）：本计划的目的是促进对全身麻醉剂在突触前和突触后作用的细胞和分子机制的理解，特别强调异氟醚和异丙酚。该计划由四个项目组成，由科学和行政核心联系在一起。在Project 1中，我们将建立一组异丙酚类似物对非洲爪蟾蝌蚪转直反射丧失的定量构效关系，并与重组γ -氨基丁酸（GABAA）受体的调节进行比较。在项目2中，异氟醚和异丙酚对培养海马神经元突触前囊泡融合和内吞作用的影响将采用光学和生化技术进行研究。在Project 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采用取代半胱氨酸可及性方法进行研究。科学和行政核心将与科学顾问委员会和演讲嘉宾一起组织和管理该小组每年两次的会议，为项目1和项目3的研究合成异丙酚的新型类似物，并在每个项目进行生理测量时测量实验盐碱中异氟烷和异丙酚的浓度。该计划将重点研究全身麻醉剂在中枢突触的分子作用位点。这些信息将有助于进一步表征全身麻醉药复杂体内药理学的多重靶点，并可能导致更安全药物的开发。

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.