TY - JOUR
T1 - Neurosteroid analogues. 12. Potent enhancement of GABA-mediated chloride currents at GABAA receptors by ent-androgens
AU - Katona, Bryson W.
AU - Krishnan, Kathiresan
AU - Cai, Zu Yun
AU - Manion, Brad D.
AU - Benz, Ann
AU - Taylor, Amanda
AU - Evers, Alex S.
AU - Zorumski, Charles F.
AU - Mennerick, Steven
AU - Covey, Douglas F.
N1 - Funding Information:
This work was supported by NIH grants GM47969 (DFC, AES, CFZ), AA12952 (SM), a grant from the McDonnell Center for Cellular and Molecular Neurobiology (SM) and a grant from the Bantly Foundation (CFZ).
PY - 2008/1
Y1 - 2008/1
N2 - 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.
AB - 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.
KW - GABA receptors
KW - Neuroactive steroids
KW - Steroid enantiomers
KW - ent-Androgens
UR - http://www.scopus.com/inward/record.url?scp=38149081435&partnerID=8YFLogxK
U2 - 10.1016/j.ejmech.2007.02.017
DO - 10.1016/j.ejmech.2007.02.017
M3 - Article
C2 - 17434649
AN - SCOPUS:38149081435
SN - 0223-5234
VL - 43
SP - 107
EP - 113
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
IS - 1
ER -