title: Neurosteroid analogues. 12. Potent enhancement of GABA-mediated chloride currents at GABAA receptors by ent-androgens.
abstract: Allopregnanolone (1) and pregnanolone (2), steroids containing a 17beta-acetyl group, are potent enhancers of GABA (gamma-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.
authors: Department of Molecular Biology and Pharmacology, Washington University in St. Louis, School of Medicine, St. Louis, MO 63110, USA. bkatona@wustl.edu
authors: Bryson W
authors: BW
authors: Katona
authors: Kathiresan
authors: K
authors: Krishnan
authors: Zu Yun
authors: ZY
authors: Cai
authors: Brad D
authors: BD
authors: Manion
authors: Ann
authors: A
authors: Benz
authors: Amanda
authors: A
authors: Taylor
authors: Alex S
authors: AS
authors: Evers
authors: Charles F
authors: CF
authors: Zorumski
authors: Steven
authors: S
authors: Mennerick
authors: Douglas F
authors: DF
authors: Covey
mesh_terms: D000728:Androgens / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000037:antagonists & inhibitors / Q000378:metabolism; D018118:Chloride Channels / Q000378:metabolism*; D018757:GABA Modulators / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D007814:Larva / Q000187:drug effects / Q000502:physiology; D051381:Rats; D011963:Receptors, GABA-A / Q000378:metabolism*; D013237:Stereoisomerism; D013256:Steroids / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000728:Androgens; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018118:Chloride Channels; D018757:GABA Modulators; D011963:Receptors, GABA-A; D013256:Steroids; C037476:tert-butylbicyclophosphorothionate