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

Allopregnanolone (1) and pregnanolone (2), steroids containing a 17β-acetyl group, are potent enhancers of GABA (γ-aminobutyric acid) action at GABA_A 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 GABA_A receptors. Unexpectedly, their enantiomers (ent-3 and ent-4) have been found to have enhanced, not diminished, activity at GABA_A 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 GABA_A receptors and might have clinical potential as GABAergic drugs of the future.