Alternative neuroactive steroid ring system scaffolds

Neuroactive steroids comprise a subset of bioactive steroids and have anxiolytic, anticonvulsant, anesthetic, and hypnotic properties. It is now widely accepted that these effects are mediated by modulation of gamma-aminobutyric acid type A (GABAA) receptors. Numerous structure-activity relationship studies of anesthetic steroids at GABAA receptors have established a pharmacophore for both positive and negative modulation of the receptor by steroids. The positive pharmacophore consists of a hydrogen-bond accepting group in a pseudoequatorial configuration at the 17beta position and a hydrogen-bond donating group in the axial 3alpha configuration. It appears that the relative orientation between these groups is more important than the precise distance between them. However, it is unclear whether the steroid ring system serves any role other than that of a scaffold.; The focus of this dissertation was to investigate the importance of the steroid framework for the activities of neuroactive steroids at GABA A receptors. To test the importance of the steroid tetracycle we have synthesized several optically-pure, rearranged steroid ring systems; systematically modifying both the number of carbocycles comprising the ring system and the relative positions of the steroid A and B rings. We prepared benz[ f]indenes, tricyclic compounds with a linear 6-6-5 fused carbocyclic ring system; cyclopenta[b]phenanthrenes, tetracyclic compounds with a non-linear ring system different from that of steroids; and cyclopenta[ b]anthracenes, tetracyclic molecules with a linear 6-6-6-5 carbocyclic ring system. We subsequently substituted these ring systems to satisfy the pharmacophore requirements of the critical hydrogen-bond donor and acceptor groups found in neuroactive steroids.; Through the use of several bioassays (oocyte electrophysiology, biochemical binding, and tadpole anesthetic response), we have evaluated the ability of these compounds to modulate GABAA receptor activity. Based on our studies, we have found alternatives to the steroid ring system that give neuroactive steroid analogues with potent activity. We have also gained insight into portions of the scaffold that provide necessary hydrophobic contacts, and regions of hydrophobic space that are disallowed by the receptor.