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. 1999 Sep;128(1):77–82. doi: 10.1038/sj.bjp.0702744

Stereoselective interaction of thiopentone enantiomers with the GABAA receptor

D J Cordato 1, M Chebib 2, L E Mather 3,*, G K Herkes 4, G A R Johnston 2
PMCID: PMC1571590  PMID: 10498837

Abstract

  1. As pharmacokinetic differences between the thiopentone enantiomers seem insufficient to explain the ∼2 fold greater potency for CNS effects of (−)-S- over (+)-R-thiopentone, this study was performed to determine any enantioselectivity of thiopentone at the GABAA receptor, the primary receptor for barbiturate hypnotic effects.

  2. Two electrode voltage clamp recording was performed on Xenopus laevis oocytes expressing human GABAA receptor subtype α1β2γ2 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 μM GABA, the EC50 values were (−)-S-thiopentone (mean 26.0±s.e.mean 3.2 μM, n=9 cells) >rac-thiopentone (35.9±4.2 μM, n=6, P=0.1) >(+)-R-thiopentone (52.5±5.0 μM, n=8, P<0.02) >rac-pentobarbitone (97.0±11.2 μM, 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-thiopentone.

  4. Uninjected oocytes responded to >100 μM (−)-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 μM, n=8) <(+)-R-thiopentone (36.2±3.2 μM, n=9, P<0.005).

  5. (−)-S-thiopentone was found to be ∼2 fold more potent than (+)-R-thiopentone in the potentiation of GABA at GABAA receptors expressed on Xenopus oocytes. This is consistent with the differences in potency for CNS depressant effects found in vivo.

Keywords: Thiopentone, enantiomers, GABAA receptor, Xenopus oocytes

Introduction

The main inhibitory neurotransmitter, γ-aminobutyric acid (GABA), activates the three major classes of GABA receptors: GABAA, GABAB and GABAC (Johnston, 1996). The GABAA receptor is a ligand-gated chloride channel assembled from 14 different glycoprotein subunits (α1–6, β1–3, γ1–3, δ and ε), in which 2α, 2β and one of either γ, δ or ε subunits combine to form a functional receptor complex (Tanelian et al., 1993). The majority of receptor subtypes found in most regions of the rat brain possess an α1 subunit (Mohler et al., 1992). The α1β2γ2 receptor complex is also considered a dominant human receptor subunit combination in vivo (Lambert et al., 1997). Barbiturates primarily exert their sedative and anaesthetic effects by potentiation of the GABA response at GABAA receptors (Huang & Barker 1980; Leeb-Lundberg & Olsen 1982; Akaike et al., 1985; 1987; Peters et al., 1988; Thompson et al., 1996; ffrench-Mullen et al., 1993). Electrophysiological studies have shown that this potentiation is due to a prolongation in duration of the chloride ion channel open-time (Mathers & Barker, 1980). Barbiturates are also capable of direct activation of GABAA receptors and, at high concentrations, may block the chloride channel (Peters et al., 1988; Thompson et al., 1996).

Thiopentone differs from pentobarbitone by the replacement of oxygen with sulphur at the C2 position of the barbiturate ring. This substitution confers upon thiopentone different pharmacological properties, particularly a more rapid onset of action and a reduction in the terminal elimination half-life from 30–50 h to 10–15 h (Chan et al., 1985), that convey clinical advantages. Recent studies also suggest that rac-thiopentone possesses neuroprotective advantages over pentobarbitone due to rac-thiopentone's ability to inhibit nitric oxide induced cytotoxicity, and over propofol by means of rac-thiopentone's attenuation of NMDA- and AMPA-mediated glutamate excitotoxicity (Shibuta et al., 1998; Zhu et al., 1997). Thiopentone has also been shown to impair astrocyte glutamate uptake at concentrations relevant to its clinical use (Swanson & Seid, 1998). Nevertheless, the utility of prolonged high-dose rac-thiopentone therapy for neurological and neurosurgical emergencies as well as prolonged anaesthesia is limited by its association with cardiac depression and by a prolonged duration of effect related to non-linear pharmacokinetics (Stanski et al., 1980; Turcant et al., 1985; Le Corre et al., 1993; Russo et al., 1996).

Thiopentone is a racemate used as an equimolar mixture of (+)-R- and (−)-S-enantiomers; thus it should strictly be designated RS-, (±) or rac-thiopentone to designate its racemic nature. Pentobarbitone has the same configuration and signs of the optical rotations as thiopentone but was only used as the racemate. As the signs of the optical rotations are not of significance to this study, they have been deleted for simplicity. The potential for differences in the pharmacokinetics and pharmacodynamics of enantiomers of racemic drugs, including a number of barbiturates, is well known (Mather & Rutten, 1991). Despite its long history of clinical use, there has only been a limited study of the pharmacological differences between the thiopentone enantiomers. It has been reported that S-thiopentone is a more potent hypnotic than R-thiopentone in mice (Christensen & Lee 1973; Haley & Gidley 1976), humans (Mark et al., 1977) and rats (Mather et al., 1999a). Although recent studies have identified various pharmacokinetic differences between R- and S-thiopentone (Mather et al., 1996, 1999c,1999d; Nguyen et al., 1996; Cordato et al., 1997, 1999), the differences would seem too small to explain the pharmacodynamic differences.

In this study, we investigated the relative differences in potentiation of the GABA response at GABAA receptor subtype α1β2γ2, expressed in Xenopus laevis oocytes, by rac-thiopentone, its R- and S- enantiomers and rac-pentobarbitone. We also evaluated the effects of changes in the pH of the cellular environment, as this may influence drug receptor binding along with alterations to the degree of drug ionization, and compared the EC50 values of R- and S-thiopentone and rac-pentobarbitone in the presence of lower (3 μM) and higher (15 μM) GABA concentrations.

Methods

Human GABAA receptor cDNAs

Human α1, β2 and γ2 cDNA encapsulated in the pcDM8 vector (Stratogene, La Jolla, CA, U.S.A.) was obtained from Dr Paul Whiting (Department of Biochemistry and Molecular Biology, Neuroscience Research Centre, Merck, Sharp and Dohme Research Laboratories, Harlow, Essex, U.K.). The plasmids were linearized with NOT1 and mRNA were transcribed using T7 RNA Polymerase and capped with 5,7-methyl guanosine using the mMESSAGE mMACHINE kit from Ambion Inc. (Austin, TX, U.S.A.).

Drug preparations

Drugs used were: R- and S-thiopentone (Huang et al., 1996), rac-thiopentone sodium, rac-pentobarbitone sodium, γ-aminobutyric acid and 1,2-bis(2-aminophenoxy)ethane-N,N,N1,N1=tetraacetic acid [BAPTA] (Sigma Chemical Co, St Louis, MO, U.S.A.). R- and S-thiopentone (0.1 mmoles) were dissolved in 0.5 ml 4 M NaOH and 9.5 ml ND96 recording solution (mM) (NaCl 96, KCl 2, MgCl2.6H2O 1, CaCl2 1.8, HEPES 5, pH 7.5) to give 10 mM solutions. Further dilutions with the same recording solution were performed to make the final concentrations used in the electrophysiological studies. rac-Thiopentone was prepared from a 50 : 50 mixture of the R- and S-thiopentone solutions and the electrophysiological findings were comparable to those obtained from rac-thiopentone sodium (Sigma). The pH of higher concentrations (>50 μM) of R- and S-thiopentone, rac-thiopentone and pentobarbitone was adjusted to pH 7.5 using 0.5–10 μl 2 M HCl, where appropriate.

Electrophysiological recording

Female Xenopus laevis were anaesthetized with 0.17% 3-aminobenzoic acid ethyl ester. A lobe of the ovaries was removed, rinsed with OR2 buffer (mM) (NaCl 82.5, KCl 2, MgCl2.6H2O 1, HEPES 5, pH 7.5) and treated with collagenase A (2 mg ml−1 in OR-2, Boehringer Mannheim) for 2 h to separate oocytes from connective tissue and follicular cells. Released oocytes were then rinsed in ND96 storage solution (mM) (NaCl 96, KCl 2, MgCl2.6H2O 1, CaCl2 1.8, HEPES 5, pH 7.5 supplemented with 2.5 mM pyruvate, 0.5 mM theophylline and 50 μM ml−1 gentamicin). Stage V to V1 oocytes were collected and stored in ND96 solution with constant mixing on an orbital shaker.

An amount of 50 ng 50 nl−1 of α1, β2 and γ2 cRNA in the ratio of 1 : 1 : 1 was injected into the cytoplasm of defolliculated Stage V Xenopus oocytes. Oocytes were stored at 9°C in ND96 storage solution; 2–8 days after mRNA injection, receptor activity was measured by two electrode voltage clamp recording using a Geneclamp 500 amplifier (Axon Instruments Inc., Foster City, CA, U.S.A.), MacLab 2e recorder (AD Instruments, Sydney, NSW, Australia) and Chart version 3.5.2 software on a Macintosh Quadra 605 computer. Oocytes were placed in a cell bath and voltage clamped using two micropipettes containing 3 M KCl. The membrane potential was clamped at −60 mV and the oocyte continually superfused with ND96 recording solution. Before any recording, oocytes were screened for functional receptor formation by the addition of 3 μM and 100 μM GABA to the cell bath. Different concentrations of drugs being tested were added to the buffer solution for receptor activation measurements. The drugs were applied until a peak response was observed, followed by a 3 min washout period to avoid receptor desensitization.

pH adjustments

The pH of the buffer solutions containing different concentrations of R- and S-thiopentone was adjusted to pH 7.0 or 8.0 using small amounts (<0.1% buffer volume) of 2 M HCl or NaOH to determine any effect on the degree of GABA potentiation in the presence of 3 μM GABA.

Analysis of electrophysiological data

Current (‘I ') dose-response relationships were measured from the recorded peak amplitude of I obtained for each drug concentration. The parameters of the relationship between ‘I ' and agonist concentration [A] were determined from the least squares fit of the Hill equation ‘I '=‘Imax' [A]nH/(EC50nH+[A]nH) to the data (where ‘Imax' is the maximal current, EC50 is the effective dose that activates 50% of the maximal current for n individual cells and nH is the Hill coefficient). The EC50 values, expressed as the mean±s.e.mean from a number of different cells (n), were calculated by fitting data from individual oocytes using Kaleidograph 2.1 software. The statistical significance of differences between mean EC50 values was determined by one-way analysis of variance (ANOVA).

Results

Expression of human α1β2γ2 mRNA in Xenopus oocytes generated GABAA receptors that showed a dose-dependent GABA-activated inward current when the cell was voltage clamped at −60 mV. The log dose-response curve gave an EC50 value of 32.1 μM (n=5 cells, s.e.mean 5.7) and a Hill coefficient of 1.3 (s.e.mean 0.1). The effects of R-thiopentone, S-thiopentone, rac-thiopentone and rac-pentobarbitone on the GABAA α1β2γ2 receptor subtype were studied in the presence of 3 and 15 μM GABA. The degree of potentiation was measured by subtracting the current (‘I ') produced by GABA, 3 or 15 μM respectively, in the absence of agonist drug from the absolute current (‘I ') value produced in the presence of agonist drug. The direct activation component of the agonist drug, however, was included in the potentiation response value. For R-thiopentone, S-thiopentone and rac-thiopentone, >90% of the maximal GABA potentiation response was achieved with 100 μM agonist drug concentrations. For rac-pentobarbitone, 300 μM concentrations were required to achieve >90% of the maximal GABA potentiation response. In contrast, direct activation of the GABAA receptor by 100 μM S-thiopentone and R-thiopentone produced responses that were 13 and 5%, respectively, of the maximal GABA potentiation response.

Xenopus oocytes not injected with human α1β2γ2 mRNA were found also to respond to >100 μM concentrations of R- and S-thiopentone. This direct response was not seen with 1 mM rac-pentobarbitone. In uninjected oocytes, the respective median currents produced by 100 μM and 1 mM S-thiopentone were 15 nA (range 5–50 nA, n=5) and 150 nA (range 20–500 nA, n=7); the respective median currents produced by 100 μM and 1 mM R-thiopentone were 10 nA (range 2–20 nA, n=5) and 50 nA (range 20–200 nA, n=5). In Xenopus oocytes injected with human α1β2γ2 mRNA, the respective median currents produced by 100 μM and 1 mM R-thiopentone were 120 nA (range 5–260 nA, n=11) and 720 nA (range 140–1500 nA, n=5); the respective median currents produced by 100 μM and 1 mM R-thiopentone were 50 nA (range 2-115 nA, n = 10) and 250 nA (range 60–600 nA, n=5). Hence, a dose-related and enantioselective difference was apparent in the endogenous direct responses produced. Endogenous receptor responses, including muscarinic cholinergic and voltage-sensitive calcium-dependent chloride currents, have been previously described in Xenopus oocytes (Kusano et al., 1982; Miledi & Parker 1984). Atropine (1 mM) did not significantly alter the response of 1 mM R- or S-thiopentone on uninjected cells. Intracellular injection of 50 nl 50 mM BAPTA, a Ca2+ chelating agent that was injected into the Xenopus oocytes at least 30 min prior to electrophysiological recording, virtually completely abolished the direct response to 1 mM R- and S-thiopentone. Hence further electrophysiological experiments comparing the degree of potentiation of the 3 μM GABA response by R- and S-thiopentone were carried out in Xenopus oocytes injected intracellularly with 50 mM BAPTA.

Electrophysiological responses in the absence of intracellular BAPTA

The EC50 for potentiation of 3 μM GABA by R-thiopentone was significantly greater than the EC50 for rac-thiopentone and S-thiopentone (P=0.02 and P=0.0004, respectively). In contrast, the EC50 for rac-pentobarbitone was greater than that for R-thiopentone (P=0.007). The EC50 and Hill coefficient for rac-pentobarbitone in the presence of 15 μM GABA were both comparable to previously reported values (Thompson et al., 1996). The EC50 values for potentiation of 15 μM GABA by rac-pentobarbitone, R-thiopentone and S-thiopentone were significantly less than those for the potentiation of 3 μM GABA (P=0.004, P=0.002 and P=0.04, respectively) by each agonist. The ratios of ‘Imax'/1 mM GABA responses, however, were similar for both 3 and 15 μM GABA. Figures 1 and 2 illustrate the typical current responses of R- and S-thiopentone. The concentration-response curves for R-thiopentone, S-thiopentone, rac-thiopentone and rac-pentobarbitone, respectively, are shown in Figure 3. The EC50 values, Hill coefficients and ratios of ‘Imax'/1 mM GABA response are summarized in Table 1.

Figure 1.

Figure 1

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Illustrative recordings of current produced, in the absence and presence of S-thiopentone at increasing concentrations (as shown), by GABA at the GABAA receptor subtype α1β2γ2 expressed in Xenopus oocytes not injected with BAPTA.

Figure 2.

Figure 2

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Illustrative recordings of current produced, in the absence and presence of R-thiopentone at increasing concentrations (as shown), by GABA at the GABAA receptor subtype α1β2γ2 expressed in Xenopus oocytes not injected with BAPTA.

Figure 3.

Figure 3

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Dose-response relationships for rac-, R- and S-thiopentone and rac-pentobarbitone in the presence of 3 μM GABA at the GABAA receptor subtype α1β2γ2 expressed in Xenopus oocytes not injected with BAPTA.

Table 1.

Values of EC50, Hill coefficients (nH) and ratios of ‘Imax'/1  mM GABA at the GABAA receptor subtype α1β2γ2 expressed in Xenopus oocytes not injected with BAPTA

graphic file with name 128-0702744t1.jpg

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The results of an adjustment in the environment of the cell bath to pH 7.0 and to 8.0 are also shown in Table 1. Although the concentration-response curves showed a trend towards a shift to the left at the lower pH, the mean differences in EC50 values were not significantly different (P=0.08 and P=0.27 for R-thiopentone and S-thiopentone, respectively).

Electrophysiological responses in the presence of intracellular BAPTA

The EC50 for potentiation of 3 μM GABA by S-thiopentone (20.6±3.2 μM, n=7 cells) was again significantly less than that for R-thiopentone (36.2±3.2 μM, n=8 cells, P<0.005). The EC50 for potentiation of 3 μM GABA by R-thiopentone in the presence of BAPTA was significantly less than that for potentiation of 3 μM GABA in the absence of BAPTA (P=0.02). The EC50 values, however, were not significantly different for S-thiopentone (P=0.20).

Adjustment of the pH environment to 7.0, in the presence of BAPTA, did not significantly alter the EC50 values for R- and S-thiopentone when compared to those at pH 7.5. The EC50 values, Hill coefficient and ratio of ‘Imax'/100 μM GABA responses at pH 7.0 and 7.5, in the presence of BAPTA, are summarized in Table 2.

Table 2.

Values of EC50, Hill coefficients (nH) and ratios of ‘Imax'/1  mM GABA at the GABAA receptor subtype α1β2γ2 expressed in Xenopus oocytes injected intracellularly with 50  mM BAPTA

graphic file with name 128-0702744t2.jpg

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Discussion

Intravenous rac-thiopentone remains the most widely used agent for the induction of anaesthesia after more than six decades of clinical use. During the last two decades, prolonged high dose rac-thiopentone aimed at achieving marked electroencephalographic (EEG) slowing or EEG burst-suppression activity has been introduced for treating acute neurological and neurosurgical emergencies, but is usually restricted to refractory cases due to haemodynamic side-effects and an unwanted and prolonged post-infusion duration of clinical unresponsiveness. We have been considering the question of whether enantiopure thiopentone might offer pharmacological advantages over the currently-used racemate. R-thiopentone is less potent than S-thiopentone in producing anaesthesia and lethality. It has been reported that the median anaesthetic and lethal doses for R-thiopentone in mice were approximately 2 fold greater than S-thiopentone (Christensen & Lee, 1973). Moreover, longer sleep duration times were found for S-thiopentone than R-thiopentone in three human subjects administered 300 mg of either enantiomer (Mark et al., 1977). It has also been found that R-thiopentone has a greater relative distribution into CNS tissues and lesser distribution into cardiac tissues in rats, and this probably contributes to its higher therapeutic index (Mather et al., 1999b). The present studies indicate that the lower potency of R-thiopentone may be related to its lesser activity at the GABAA receptor.

Barbiturates modulate the GABAA receptor to enhance GABA-mediated inhibition primarily by increasing the channel mean open duration. In vitro radioligand binding studies with [3H]-dihydropicrotoxinin, [35S]-t-butylbicyclophosphorothionate ([35S]-TBPT, a convulsant that binds to the picrotoxinin-binding site of the GABA-receptor complex), and [3H]-diazepam have revealed differences in efficacy among a number of barbiturate derivatives (Leeb-Lundberg & Olsen 1982; Johnston 1983; Lohse et al., 1987; Olsen et al., 1986; Richter & Holtman 1982). For example, it has been found that the relative potencies (IC50 values) for the inhibition of [35S]-TBPT binding increase in the order rac-methohexitone, rac-thiopentone, rac-pentobarbitone, rac-secobarbitone, rac-hexobarbitone, amobarbitone and phenobarbitone (Lohse et al., 1987). Stereoselective differences in potency for individual barbiturates are also known. The relative potencies for rac-pentobarbitone and its enantiomers in potentiation of GABA responses in frog sensory neurons and cultured mammalian neurons are S-pentobarbitone>rac-pentobarbitone>R-pentobarbitone (Huang & Barker 1980; Akaike et al., 1987).

The Hill slopes for both R- and S-thiopentone exceeded unity; this is consistent with the binding to the GABAA receptor of more than one agonist molecule to produce a GABA-evoked response (Colquhoun, 1998). The finding is similar to that previously reported for pentobarbitone (Thompson et al., 1996), and most probably reflects cooperativity of binding of agonist molecules to the GABAA receptor. Despite significant differences in EC50 values for R- and S-thiopentone, no enantiomeric differences in Hill coefficients were found.

It has also been recently shown that differences in GABAA subunits influence the degree of drug efficacy obtained. The human GABAA α1β2γ2 subunit combination, as used in the present study, is thought to be a dominant combination in vivo (Lambert et al., 1997). The GABAA receptor complex, however, is a multigene family. Thompson et al. (1996) described the influence of various α and β subunits on the effects of rac-pentobarbitone. They found that GABAA receptors containing α6 subunits, that are believed to be primarily located on cerebellar granule cells, had a higher affinity and efficacy for the direct activation from rac-pentobarbitone than did other α subunits. In addition, the direct action of rac-pentobarbitone was not influenced by differences in β subunits to the same extent as the types of α subunits.

We found the relative potencies (EC50 values) to be S-thiopentone<rac-thiopentone<R-thiopentone. The finding of a ≃2 fold higher EC50 for R-thiopentone than S-thiopentone supports other studies describing a similar difference in hypnotic potency (vide supra). Our study also showed that rac-thiopentone is ⩾2-fold more potent than rac-pentobarbitone in its potentiation of the GABA response, a finding that is consistent with previous receptor binding studies. It is of interest that the EC50 for the GABA response of rac-thiopentone (35 μM) in our study is comparable to the free fraction associated with a serum concentration of 200 μmol.l−1 with the degree of protein binding at ∼80% (Morgan et al., 1981). This serum concentration clinically is associated with marked EEG slowing as well as a loss of motor activity to profound noxious stimuli (Hung et al., 1992).

A dose-dependent response to different GABA concentrations in the presence of a fixed concentration of pentobarbitone has been previously reported (Parker et al., 1986; Levitan et al., 1988). Our findings similarly demonstrate a leftward shift of the agonist dose-response curves for R- and S-thiopentone, as well as of rac-pentobarbitone, in the presence of a higher GABA concentration. A thiopentone enantiomeric difference in potency, however, is still apparent under these conditions. The introduction of vigabatrin, a GABA transaminase inhibitor, and of tiagabine, a GABA transport reuptake inhibitor, has resulted in the clinical availability of anticonvulsants that primarily act by increasing brain GABA levels. Free cerebrospinal fluid GABA concentrations in humans, for example, have been shown to increase 2–4 fold after a 2 month treatment period of oral vigabatrin (Ben-Menachem 1989). Hence it is conceivable that R- and S-thiopentone could exert a greater hypnotic effect if administered in the clinical setting of refractory status epilepticus to patients who are concurrently taking vigabatrin or tiagabine.

The effect of acidosis on the disposition of thiopentone has been studied previously. Brodie et al. (1950) reported that a pH of 6.8, induced by hypercarbia, resulted in decreased plasma thiopentone concentrations in dogs, and this was postulated have been caused by increased transfer of nonionized thiopentone into tissues. Hence, by increasing the uptake of thiopentone into brain and/or cerebrospinal fluid, decreased pH could enhance the anaesthetic effect by a pharmacokinetic mechanism. However, it was previously unknown if a change in nonionized drug concentrations could also influence the pharmacodynamic effect at a receptor level. Our study failed to demonstrate a significant change in EC50 values for either R- or S-thiopentone following a change in the cellular environment from pH 7.5 to 8.0 or pH 7.5 to 7.0.

In conclusion, S-thiopentone was found to be ∼2 fold more potent than R-thiopentone at potentiating the effects of GABA on GABAA receptors expressed on Xenopus oocytes. This difference is comparable to differences in hypnotic potency found previously in a small number of laboratory and clinical studies, most of which were performed over 20 years ago. Recent studies, however, have also indicated that relative lethal potential of S-thiopentone is increased disproportionately to R-thiopentone (Mather et al., unpublished observations). Further studies may be of value in determining whether enantiopure thiopentone has a clinical pharmacological advantage over rac-thiopentone.

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