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Research ArticleNEUROPHARMACOLOGY

Enantioselectivity of Pregnanolone-Induced γ-Aminobutyric AcidA Receptor Modulation and Anesthesia

Douglas F. Covey, Devi Nathan, Melissa Kalkbrenner, Kent R. Nilsson, Yuefei Hu, Charles F. Zorumski and Alex S. Evers
Journal of Pharmacology and Experimental Therapeutics June 2000, 293 (3) 1009-1016;
Douglas F. Covey
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Devi Nathan
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Melissa Kalkbrenner
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Kent R. Nilsson
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Yuefei Hu
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Charles F. Zorumski
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Alex S. Evers
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Abstract

This study reports the actions of enantiomer pairs of anesthetic steroids 3α5αP/ent-3α5αP and 3α5βP/ent-3α5βP as modulators of γ-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 5α-reduced steroids, but not 5β-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 3α5αP, 3α5βP, andent-3α5βP, but not ent-3α5αP, or with two different binding sites for steroid anesthetics.

Footnotes

  • Send reprint requests to: Douglas F. Covey, Ph.D., Department of Molecular Biology and Pharmacology, Box 8103, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110. E-mail: dcovey{at}molecool.wustl.edu

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

  • Abbreviations:
    3α5αP
    (3α,5α)-3-hydroxypregnan-20-one
    3α5βP
    (3α,5β)-3-hydroxypregnan-20-one
    GABA
    γ-aminobutyric acid
    TBPS
    t-butylbicyclophosphorothionate
    ent-3α5αP
    (3β,5β,8α,9β,10α,13β,14α,17α)-3-hydroxypregnan-20-one
    ent-3α5βP
    (3β,5α,8α,9β,10α,13β, 14α,17α)-3-hydroxypregnan-20-one
    3α5αACN
    (3α,5α,17β)-3-hydroxyandrostane-17-carbonitrile
    3α5βACN
    (3α,5β,17β)-3-hydroxyandrostane-17-carbonitrile
    ent-3α5αACN
    (3β,5β,8α,9β,10α,13β,14α,17α)-3-hydroxyandrostane-17-carbonitrile
    ent-3α5βACN
    (3β,5α,8α,9β, 10α,13β,14α,17α)-3-hydroxyandrostane-17-carbonitrile
    DMSO
    dimethylsulfoxide
    LRR
    loss of righting reflex
    • Received November 17, 1999.
    • Accepted February 22, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 293 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 293, Issue 3
1 Jun 2000
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Research ArticleNEUROPHARMACOLOGY

Enantioselectivity of Pregnanolone-Induced γ-Aminobutyric AcidA Receptor Modulation and Anesthesia

Douglas F. Covey, Devi Nathan, Melissa Kalkbrenner, Kent R. Nilsson, Yuefei Hu, Charles F. Zorumski and Alex S. Evers
Journal of Pharmacology and Experimental Therapeutics June 1, 2000, 293 (3) 1009-1016;

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Research ArticleNEUROPHARMACOLOGY

Enantioselectivity of Pregnanolone-Induced γ-Aminobutyric AcidA Receptor Modulation and Anesthesia

Douglas F. Covey, Devi Nathan, Melissa Kalkbrenner, Kent R. Nilsson, Yuefei Hu, Charles F. Zorumski and Alex S. Evers
Journal of Pharmacology and Experimental Therapeutics June 1, 2000, 293 (3) 1009-1016;
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