Neurosteroid analogues. 12. Potent enhancement of GABA-mediated chloride currents at GABAA receptors by ent-androgens.
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.
Katona
Bryson W
BW
Department of Molecular Biology and Pharmacology, Washington University in St. Louis, School of Medicine, St. Louis, MO 63110, USA. bkatona@wustl.edu
Krishnan
Kathiresan
K
Cai
Zu Yun
ZY
Manion
Brad D
BD
Benz
Ann
A
Taylor
Amanda
A
Evers
Alex S
AS
Zorumski
Charles F
CF
Mennerick
Steven
S
Covey
Douglas F
DF
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*
D000728:Androgens; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018118:Chloride Channels; D018757:GABA Modulators; D011963:Receptors, GABA-A; D013256:Steroids; C037476:tert-butylbicyclophosphorothionate