Neurosteroid analogues. 12. Potent enhancement of GABA-mediated chloride currents at GABAA receptors by ent-androgens

Bryson W. Katona, Kathiresan Krishnan, Zu Yun Cai, Brad D. Manion, Ann Benz, Amanda Taylor, Alex S. Evers, Charles F. Zorumski, Steven Mennerick, Douglas F. Covey

Research output: Contribution to journalArticlepeer-review

28 Scopus citations

Abstract

Allopregnanolone (1) and pregnanolone (2), steroids containing a 17β-acetyl group, are potent enhancers of GABA (γ-aminobutyric acid) action at GABAA receptors. Their effects are enantioselective with the non-naturally occurring enantiomers (ent-1 and ent-2) being less potent. Androsterone (3) and etiocholanolone (4), steroids with a C-17 carbonyl group, are weak enhancers of GABA action at GABAA receptors. Unexpectedly, their enantiomers (ent-3 and ent-4) have been found to have enhanced, not diminished, activity at GABAA receptors. Furthermore, the C-17 spiro-epoxide analogues (ent-5 and ent-6) of ent-3 and ent-4, respectively, have activities comparable to those of steroids 1 and 2. The results indicate that some ent-steroids are potent modulators of GABAA receptors and might have clinical potential as GABAergic drugs of the future.

Original languageEnglish
Pages (from-to)107-113
Number of pages7
JournalEuropean Journal of Medicinal Chemistry
Volume43
Issue number1
DOIs
StatePublished - Jan 2008

Keywords

  • GABA receptors
  • Neuroactive steroids
  • Steroid enantiomers
  • ent-Androgens

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