1 As pharmacokinetic differences between the thiopentone enantiomers seem i
nsufficient to explain the similar to 2 fold greater potency for CNS effect
s of (-)-S- over (+)-R-thiopentone, this study was performed to determine a
ny enantioselectivity of thiopentone at the GABA(A) receptor, the primary r
eceptor for barbiturate hypnotic effects.
2 Two electrode voltage clamp recording was performed on Xenopus laevis ooc
ytes expressing human GABA(A) receptor subtype alpha(1)beta(2)gamma(2) to d
etermine relative differences in potentiation of the GABA response by rac-,
(+)-R- and (-)-S-thiopentone, and rac-pentobarbitone. Changes in the cellu
lar environment pH and in GABA concentrations were also evaluated.
3 With 3 mu M GABA, the EC50 values were (-)-S-thiopentone (mean 26.0 +/- s
.e.mean 3.2 mu M, n = 9 cells) >rac-thiopentone (35.9 +/- 4.2 mu M, n = 6,
P = 0.1) >(+)-R-thiopentone (52.5 +/- 5.0 mu M, n=8, P < 0.02) > rac-pentob
arbitone (97.0 +/- 11.2 mu M, n = 11, P < 0.01). Adjustment of environment
pH to 7.0 or 8.0 did not alter the EC50 values for (+)-R- or (-)-S-thiopent
one.
4 Uninjected oocytes responded to > 100 mu M (-)-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 mu
M, n = 8) <(+)-R-thiopentone (36.2 +/- 3.2 mu M, n = 9, P < 0.005).
5 (-)-S-thiopentone was found to be similar to 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 CN
S depressant effects found in vivo.