5 beta-pregnan-3 beta-ol-20-one, a specific antagonist at the neurosteroid site of the GABAA receptor-complex.
Studies were made on the potentiation of [3H]flunitrazepam binding to rat brain membranes by gamma-aminobutyric acid (GABA), pentobarbitone and pregnanolone (5 beta-pregnan-3 alpha-ol-20-one). Epipregnanolone, the 3 beta isomer of pregnanolone, inhibited competitively the potentiation by pregnanolone with a Ki of 10.5 microM without affecting that of GABA. The potentiation by pentobarbitone was slightly enhanced. Epipregnanolone alone showed only slight potentiation of benzodiazepine binding. These findings demonstrate that epipregnanolone is a specific antagonist of the neurosteroid site of the GABAA receptor and raise the possibility of a physiological role for 3 beta-hydroxysteroids in modulating this receptor.
Prince
R J
RJ
Department of Pharmacology, School of Pharmacy, University of London, U.K.
Simmonds
M A
MA
D000818:Animals; D001569:Benzodiazepines / Q000378:metabolism; D001667:Binding, Competitive / Q000187:drug effects; D005445:Flunitrazepam / Q000494:pharmacology; D058787:GABA-A Receptor Antagonists; D066298:In Vitro Techniques; D008297:Male; D010424:Pentobarbital / Q000494:pharmacology; D011280:Pregnanolone / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D058787:GABA-A Receptor Antagonists; D001569:Benzodiazepines; D005680:gamma-Aminobutyric Acid; D005445:Flunitrazepam; D011280:Pregnanolone; D010424:Pentobarbital