Selective antagonism of 5alpha-reduced neurosteroid effects at GABA(A) receptors

Although neurosteroids have rapid effects on GABA(A) receptors, study of steroid actions at GABA receptors has been hampered by a lack of pharmacological antagonists. In this study, we report the synthesis and characterization of a steroid analog, (3alpha,5alpha)-17-phenylandrost-16-en-3-ol (17PA),...

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Bibliographic Details
Published in:Molecular pharmacology 2004-05, Vol.65 (5), p.1191
Main Authors: Mennerick, Steven, He, Yejun, Jiang, Xin, Manion, Brad D, Wang, Mingde, Shute, Amanda, Benz, Ann, Evers, Alex S, Covey, Douglas F, Zorumski, Charles F
Format: Article
Language:English
Subjects:
Androstenols - chemical synthesis
Androstenols - chemistry
Androstenols - pharmacology
Animals
Drug Synergism
GABA Antagonists - chemical synthesis
GABA Antagonists - chemistry
GABA Antagonists - pharmacology
GABA-A Receptor Antagonists
Hippocampus - cytology
Neurons - drug effects
Neurons - metabolism
Oocytes - drug effects
Oocytes - metabolism
Rats
Rats, Sprague-Dawley
Receptors, GABA-A - metabolism
Steroids - chemistry
Steroids - pharmacology
Xenopus laevis
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Summary:Although neurosteroids have rapid effects on GABA(A) receptors, study of steroid actions at GABA receptors has been hampered by a lack of pharmacological antagonists. In this study, we report the synthesis and characterization of a steroid analog, (3alpha,5alpha)-17-phenylandrost-16-en-3-ol (17PA), that selectively antagonized neurosteroid potentiation of GABA responses. We examined 17PA using the alpha1beta2gamma2 subunit combination expressed in Xenopus laevis oocytes. 17PA had little or no effect on baseline GABA responses but antagonized both the response augmentation and the direct gating of GABA receptors by 5alpha-reduced potentiating steroids. The effect was selective for 5alpha-reduced potentiating steroids; 5beta-reduced potentiators were only weakly affected. Likewise, 17PA did not affect barbiturate and benzodiazepine potentiation. 17PA acted primarily by shifting the concentration response for steroid potentiation to the right, suggesting the possibility of a competitive component to the antagonism. 17PA also antagonized 5alpha-reduced steroid potentiation and gating in hippocampal neurons and inhibited anesthetic actions in X. laevis tadpoles. Analogous to benzodiazepine site antagonists, the development of neurosteroid antagonists may help clarify the role of GABA-potentiating neurosteroids in health and disease.
ISSN:0026-895X
1521-0111
DOI:10.1124/mol.65.5.1191