Neurosteroid analogues. 11. Alternative ring system scaffolds: γ-aminobutyric acid receptor modulation and anesthetic actions of benz[f]indenes

Jamie B. Scaglione, Brad D. Manion, Ann Benz, Amanda Taylor, Gregory T. DeKoster, Nigam P. Rath, Alex S. Evers, Charles F. Zorumski, Steven Mennerick, Douglas F. Covey

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

Benz[f]indenes are tricyclic compounds with a linear 6-6-5 fused carbocyclic ring system. When properly substituted, benz[f]indenes can satisfy the pharmacophore requirements of the critical hydrogen-bond donor and acceptor groups found in neuroactive steroids that modulate γ-aminobutyric acidA (GABAA) receptor function. Thus, the benz[f]indene ring system provides an opportunity to extend the previously well-studied GABAA receptor structure-activity relationships (SAR) of neuroactive steroids to a different ring system. Depending on whether the stereochemistry of the 6-6-5 ring fusions are trans-trans or cis-trans, either planar or nonplanar benz[f]indenes are obtained. We found that the planar trans-trans benz[f]indenes are active, but less active than the steroids they were designed to mimic, whereas the nonplanar cis-trans compounds have little, if any, activity. The results provide new insight into the importance of the steroid framework for the actions of neuroactive steroids at GABAA receptors.

Original languageEnglish
Pages (from-to)4595-4605
Number of pages11
JournalJournal of Medicinal Chemistry
Volume49
Issue number15
DOIs
StatePublished - Jul 27 2006

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