(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.
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