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Vol. 293, Issue 3, 1009-1016, June 2000
-Aminobutyric
AcidA Receptor Modulation and Anesthesia1
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 3
5P/ent-35P and
35
P/ent-35P as modulators of
-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 5-reduced
steroids, but not 5-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 35P, 35P, and ent-35P, but not ent-35P, or
with two different binding sites for steroid anesthetics.
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