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Vol. 293, Issue 3, 1009-1016, June 2000

Enantioselectivity of Pregnanolone-Induced gamma -Aminobutyric AcidA Receptor Modulation and Anesthesia1

Douglas F. Covey, Devi Nathan, Melissa Kalkbrenner, Kent R. Nilsson, Yuefei Hu, Charles F. Zorumski and Alex S. Evers

Departments of Molecular Biology and Pharmacology (D.F.C., Y.H., K.R.N., A.S.E.), Anesthesiology (D.N., M.K., A.S.E.), and Psychiatry (C.F.Z.), Washington University School of Medicine, St. Louis, Missouri

This study reports the actions of enantiomer pairs of anesthetic steroids 3alpha 5alpha P/ent-3alpha 5alpha P and 3alpha 5beta P/ent-3alpha 5beta P as modulators of gamma -aminobutyric acid (GABA)A receptors and as anesthetics. The enantiomers of structurally related 17-carbonitrile analogs also are examined. These studies were aimed at 1) determining whether the steroid recognition site could distinguish between molecules differing in shape, but not other physical properties (enantioselectivity); 2) providing further insight into the structure-activity relationships of anesthetic steroids; and 3) determining whether modulation of GABAA receptor function correlates with anesthetic potency for anesthetic steroid enantiomers. Stereoselective actions of the compounds were evaluated in four different bioassays: 1) noncompetitive displacement of [35S]t-butylbicyclophosphorothionate from the picrotoxin site of GABAA receptors present in rat brain membrane preparations; 2) modulation of GABA currents in cultured rat hippocampal neurons; 3) loss of righting reflex in tadpoles; and 4) loss of righting reflex in mice. The data indicate that 5alpha -reduced steroids, but not 5beta -reduced steroids, show a high degree of enantioselectivity/enantiospecificity in their actions as modulators of GABAA receptors and as anesthetics. For all compounds studied, the effects on GABAA receptor function closely tracked with anesthetic effects. These data show that the anesthetic steroid recognition site is capable of distinguishing enantiomers, suggesting a protein-binding site of specific dimensions and shape. The results are compatible either with a structural model of the binding site that can accommodate 3alpha 5alpha P, 3alpha 5beta P, and ent-3alpha 5beta P, but not ent-3alpha 5alpha P, or with two different binding sites for steroid anesthetics.

1 This study was supported by U.S. Public Health Service Grant GM47969, Research Scientist Development Award MH00964, and the Bantly Foundation.

0022-3565/00/2933-1009$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


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