Anesthetic steroids have been shown to act at the GABA receptor/chloride channel complex to facilitate hyperpolarization of GABAergic neurons. It is currently thought that this interaction is the molecular mechanism of action of anesthetic steroids.
The specific aims of this proposal are focused on gaining new knowledge of the molecular details of the interaction of steroids with this receptor complex. synthetic chemistry will be performed to prepare novel steroid analogs. These analogs will be evaluated electrophysiologically to provide new information about the molecular recognition of ligands acting at the steroid binding site associated with the GABA receptor channel complex present in rat hippocampal neurons. Dose/response curves will be generated to correlate structure with the ability of the analogs to activate a chloride current in the absence of GABA and to potentiate a chloride current in the presence of GABA. The identification of analogs having different dose/response curves for these two activities will make possible an evaluation of a hypothesis that correlates direct activation of a chloride current in the absence of GABA with anesthetic activity, and potentiation of a GABA-induced chloride current with anticonvulsant and anxiolytic activity. In addition, the specificity of the steroid analogs will be determined electrophysiologically by examining their effects in the presence of ligands known to modulate this receptor complex at the picrotoxin, benzodiazepine, and barbiturate binding sites. Clinically used drugs binding at the benzodiazepine and barbiturate binding sites of the GABA receptor channel complex can be used not only as anesthetics, but also as anticonvulsants, anxiolytics, and sedative hypnotics. Thus, it is clear that drugs acting at each of these binding sites can modulate the function of this receptor complex in multiple ways to produce different pharmacological effects. The structure of a particular benzodiazepine or barbiturate determines how it binds at its respective binding site and this molecular recognition process in turn influences the subsequent pharmacologic activity of the drug. The goals of this project are to synthesize steroid analogs that differentially modulate GABA receptor/chloride channel function and thereby define the structural features required of ligands to produce the different pharmacological responses. This knowledge could lead ultimately to the discovery of new anesthetic, anticonvulsant, anxiolytic, and sedative hypnotic drugs.
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