STRUCTURE/ACTIVITY STUDIES OF NEUROSTEROID ANALOGS

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Anesthetic steroids have been shown to act at the GABAa 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. Modulatory effects of anesthetic and other neuroactive steroids at additional ion channels are also known. The extent to which the actions of anesthetic steroids at these additional ion channels contributes to steroid-induced anesthesia is not yet clear. The specific aims of this proposal are focused on gaining new knowledge of the molecular details of the interactions of these steroids with the GABAA receptor complex and other ion channels. Synthetic chemistry will be performed to prepare novel steroid analogues and enantiomers of neuroactive steroids. Structure-activity relationships for GABAA receptor modulation will be analyzed using the computational method of Conformational Molecular Field Analysis. The steroid enantiomers will be used to distinguish between receptor-mediated effects and membrane perturbation effects. These compounds will be evaluated using electrophysiological, binding, and behavioral assays. Neuroactive steroids that increase GABA-mediated chloride current are known to have anesthetic, anticonvulsant, anxiolytic, and sedative hypnotic effects. The extent to which actions at other ion channels and/or to which membrane perturbing effects by these compounds contributes to the pharmacologic profile of neuroactive steroids is uncertain. The long term goals of this project are to use the methods of medicinal chemistry to obtain new pharmacological tools to investigate the effects of neuroactive steroids at GABAA receptors and other types of ion channels. Ultimately, this information could lead to the discovery of new anesthetic, anticonvulsant, anxiolytic, and sedative hypnotic drugs.