Stereoselective interaction of thiopentone enantiomers with the GABA(A) receptor

1. As pharmacokinetic differences between the thiopentone enantiomers seem insufficient to explain the approximately 2 fold greater potency for CNS effects of (-)-S- over (+)-R-thiopentone, this study was performed to determine any enantioselectivity of thiopentone at the GABA(A) receptor, the prima...

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Bibliographic Details
Published in:British journal of pharmacology 1999-09, Vol.128 (1), p.77-82
Main Authors: Cordato, D J, Chebib, M, Mather, L E, Herkes, G K, Johnston, G A
Format: Article
Language:English
Subjects:
Animals
Binding Sites
Chelating Agents - metabolism
Dose-Response Relationship, Drug
Drug Synergism
Egtazic Acid - analogs & derivatives
Egtazic Acid - metabolism
Electric Conductivity
Female
GABA-A Receptor Agonists
gamma-Aminobutyric Acid - pharmacology
Humans
Hydrogen-Ion Concentration
Kinetics
Oocytes - drug effects
Oocytes - metabolism
Patch-Clamp Techniques
Pentobarbital - chemistry
Pentobarbital - metabolism
Pentobarbital - pharmacology
Receptors, GABA-A - genetics
Receptors, GABA-A - metabolism
Stereoisomerism
Substrate Specificity
Thiopental - chemistry
Thiopental - metabolism
Thiopental - pharmacology
Xenopus laevis
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Summary:1. As pharmacokinetic differences between the thiopentone enantiomers seem insufficient to explain the approximately 2 fold greater potency for CNS effects of (-)-S- over (+)-R-thiopentone, this study was performed to determine any enantioselectivity of thiopentone at the GABA(A) receptor, the primary receptor for barbiturate hypnotic effects. 2. Two electrode voltage clamp recording was performed on Xenopus laevis oocytes expressing human GABA(A) receptor subtype alpha1beta2gamma2 to determine relative differences in potentiation of the GABA response by rac-, (+)-R- and (-)-S-thiopentone, and rac-pentobarbitone. Changes in the cellular environment pH and in GABA concentrations were also evaluated. 3. With 3 microM GABA, the EC50 values were (-)-S-thiopentone (mean 26.0+/-s.e.mean 3.2 microM, n=9 cells) >rac-thiopentone (35.9+/-4.2 microM, n=6, P=0.1) >(+)-R-thiopentone (52.5+/-5.0 microM, n=8, Prac-pentobarbitone (97.0+/-11.2 microM, n=11, P100 microM (-)-S- and R-thiopentone. This direct response was abolished by intracellular oocyte injection of 1,2-bis(2-aminophenoxy)ethane-N, N,N1,N1-tetraacetic acid (BAPTA), a Ca2+ chelating agent. With BAPTA, the EC50 values were (-)-S-thiopentone (20.6+/-3.2 microM, n=8)
ISSN:0007-1188
1476-5381
DOI:10.1038/sj.bjp.0702744