Structure/Activity Studies of Neurosteroid Analogues

Washington University, Saint Louis MO

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Abstract

Modulation of GABA-A or NMDA receptors underlie the anesthetic actions of most clinically used general anesthetics. In the central nervous system, enhancement of GABA-A receptor function increases inhibitory neurotransmission and inhibition of NMDA receptor function decreases excitatory neurotranmission. Anesthetic steroids enhance the actions of GABA and GABA-A receptors. Other steroids containing negatively charged groups (e.g., pregnenolone sulfate and pregnanolone sulfate) inhibit GABAergic neurotransmission. NMDA receptors are modulated, either positively or negatively., by steroids containing negatively charged groups. Thus, understanding the actions of steroids at these receptors is important for understanding the clinical effects of the clinical effects of the steroid class of anesthetics. The five specific aims of this proposal are focused on gaining new knowledge of the molecular details of the interactions of steroids with GABA-A and NMDA receptors. For three specific aims, synthetic chemistry will be performed to prepare novel analogues of anesthetic steroids so that new structure/activity relationships for steroid modulation of GABA-A and NMDA receptors can be investigated. Electrophysiological, binding, and behavioral assays will be used for evaluation of the compounds. For the fourth specific aims, photoaffinity labeling analogues of anesthetic steroids will be synthesized for use in the identification of steroid binding sites on GABA-A receptors. For the fifth specific aim, Langmuir-Blodgett monolayer and NMR methods will be used to provide data on the enantioselectively for anesthetic steroid effects on membrane properties. The behavior of other neuroactive steroid analogues in membranes will also be investigated. The long term goals of this project are to use the methods of medicinal chemistry to obtain new pharmacological tools for investigation of the effects of steroids at GABA-A and NMDA receptors. Ultimately, this information could lead to the discovery of new anesthetic, anti-convulsant, anxiolytic, and sedative hypnotic drugs.