Stereoselective interaction of thiopentone enantiomers with the GABA_A receptor

Abstract

1 As pharmacokinetic di erences between the thiopentone enantiomers seem insu cient to explain the *2 fold greater potency for CNS e ects of (7)-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 e ects. 2 Two electrode voltage clamp recording was performed on Xenopus laevis oocytes expressing human GABA A receptor subtype a 1 b 2 g 2 to determine relative di erences in potentiation of the GABA response by rac-, (+)-R-and (7)-S-thiopentone, and rac-pentobarbitone. Changes in the cellular environment pH and in GABA concentrations were also evaluated. 3 With 3 mM GABA, the EC 50 values were (7)-S-thiopentone (mean 26.0+s.e.mean 3.2 mM, n=9 cells) 4rac-thiopentone (35.9+4.2 mM, n=6, P=0.1) 4(+)-R-thiopentone (52.5+5.0 mM, n=8, P50.02) 4rac-pentobarbitone (97.0+11.2 mM, n=11, P50.01). Adjustment of environment pH to 7.0 or 8.0 did not alter the EC 50 values for (+)-R-or (7)-S-thiopentone. 4 Uninjected oocytes responded to 4100 mM (7)-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 Ca 2+ chelating agent. With BAPTA, the EC 50 values were (7)-S-thiopentone (20.6+3.2 mM, n=8) 5(+)-R-thiopentone (36.2+3.2 mM, n=9, P50.005). 5 (7)-S-thiopentone was found to be *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 di erences in potency for CNS depressant e ects found in vivo.

Thiopentone and Methohexitone Enantiomers Do Not Act Stereoselectively on the Oxidative Response in Human Neutrophils in vitro

“…Plasma levels of thiopentone and methohexitone in patients were determined in several previous studies after the induction of anesthesia with a single bolus or after continuous infusion. For thiopentone, concentrations in the range 1-40 Ìg/ml and for methohexitone concentrations in the range 1-18 Ìg/ml (illustrated in figure 2A, B) are considered to be therapeutically effective plasma levels [6,[12][13][14][15]. This study confirms previous findings [3,16] that the effect of thiopentone is significant at therapeutic concentrations, but the effect of methohexitone becomes significant only at doses 5-50 times the therapeutic concentrations.…”

“…However, pharmacokinetic parameters of the single enantiomers during and following prolonged highdose therapy in ICU patients did not differ significantly [5]. S(-)-thiopentone was found to be more potent in the potentiation of GABA (Á-amino butyric acid) at GABA A receptors expressed in Xenopus oocytes, but in contrast to these results, some nAChRs (nicotinic acetylcholine receptors) do not differentiate between the two isomers [6,7].…”

Differential Effects of Thiopental and Pentobarbital on Spinal GABAA Receptors

“…The effects of different thiopental enantiomers on GABA A receptors expressed on Xenopus oocytes match well with their differences in hypnotic potency [2]. Thus, besides the differences in pharmacokinetics, it is possible that GABA A receptormediated mechanisms also partly underlie the different anesthetic properties between thiopental and pentobarbital.…”

“…It is generally agreed that barbitals primarily exert their sedative and anesthetic effects by enhancing the GABA A receptor-mediated responses [2][3][4][5]. The effects of different thiopental enantiomers on GABA A receptors expressed on Xenopus oocytes match well with their differences in hypnotic potency [2].…”

Enantioselectivity of α-Benzyl-α-methyl-γ-butyrolactone-Mediated Modulation of Anticonvulsant Activity and GABAA Receptor Function

“…The fact that the degree of enantioselectivity was the same in both the anticonvulsant and patch-clamp assays confirms the significance of the stereoselective effect. Although the overall magnitude of enantioselective preference seems relatively modest, this degree of enantioselectivity has been reported for other molecules and does result in distinct functional effects (Hall et al, 1994;Cordato et al, 1999;Covey et al, 2000).…”