Stereoselective interaction of thiopentone enantiomers with the GABAA receptor
| Autor: | Cordato, D J, Chebib, M, Mather, L E, Herkes, G K, Johnston, G A R |
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| Jazyk: | angličtina |
| Rok vydání: | 1999 |
| Předmět: |
Binding Sites
Patch-Clamp Techniques Dose-Response Relationship Drug Electric Conductivity Drug Synergism Stereoisomerism Hydrogen-Ion Concentration Receptors GABA-A Substrate Specificity Kinetics Xenopus laevis Papers Oocytes Animals Humans Female GABA-A Receptor Agonists Thiopental Egtazic Acid Pentobarbital gamma-Aminobutyric Acid Chelating Agents |
| Popis: | 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, P0.02)rac-pentobarbitone (97.0+/-11.2 microM, n=11, P0.01). Adjustment of environment pH to 7.0 or 8.0 did not alter the EC50 values for (+)-R- or (-)-S-thiopentone. 4 Uninjected oocytes responded to100 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)(+)-R-thiopentone (36.2+/-3.2 microM, n=9, P0.005). 5 (-)-S-thiopentone was found to be approximately 2 fold more potent than (+)-R-thiopentone in the potentiation of GABA at GABA(A) receptors expressed on Xenopus oocytes. This is consistent with the differences in potency for CNS depressant effects found in vivo. |
| Databáze: | OpenAIRE |
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