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 GABA(A) 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 GABA(A) 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 GABA(A) receptors and as anesthetics. For all compounds studied, the effects on GABA(A) 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, and ent-3α5βP, but not ent-3α5αP, or with two different binding sites for steroid anesthetics.

Original languageEnglish
Pages (from-to)1009-1116
Number of pages108
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number3
StatePublished - Jun 2000


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