Anesth Analg 2004;99:91-96
© 2004 International Anesthesia Research Society
doi: 10.1213/01.ANE.0000120083.10269.54
ANESTHETIC PHARMACOLOGY
2,6 Di-tert-butylphenol, a Nonanesthetic Propofol Analog, Modulates 
1ß Glycine Receptor Function in a Manner Distinct from Propofol
Jörg Ahrens, MD*,
Gertrud Haeseler, MD*,
Martin Leuwer, MD
,
Bahram Mohammadi, MD
,
Klaus Krampfl, MD,
Reinhard Dengler, MD, and
Johannes Bufler, MD
Departments of *Anaesthesiology and
Neurology and Neurophysiology, Hannover Medical School, Hannover, Germany; and
University Department of Anaesthesia, The University of Liverpool, Liverpool, United Kingdom
Gertrud Haeseler, MD, Department of Anaesthesiology, OE 8050, Hannover Medical School, D-30623 Hannover, Germany. Address e-mail to Haeseler.Gertrud{at}MH-Hannover.de
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Abstract
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The anesthetic propofol (2,6 diisopropylphenol) mediates some of its effects by activating inhibitory chloride currents in the lower brainstem and spinal cord. The effects comprise direct activation of 
-aminobutyric acid-A and glycine receptors in the absence of the natural agonist, as well as potentiation of the effect of submaximal agonist concentrations. Replacement of propofol’s isopropyl groups by di-tert-butyl groups yields a compound without in vivo anesthetic effects. We have studied the effects of propofol and 2,6 di-tert-butylphenol on chloride inward currents via rat 
1ß glycine receptors heterologously expressed in human embryonic kidney cells. Propofol, but not 2,6 di-tert-butylphenol, directly activated glycine receptors; half-maximal current activation was observed with propofol 114 ± 27 µM. Both compounds potentiated the effect of a submaximal glycine concentration (10 µM) to a maximum value of 136% ± 71% (propofol) and 279% ± 109% (2,6 di-tert-butylphenol) of the response to glycine 10 µM. The 50% effective concentration for this effect was 12.5 ± 6.4 µM and 9.4 ± 10.2 µM for propofol and 2,6 di-tert-butylphenol, respectively. Propofol and its nonanesthetic structural analog do not differ in their ability to coactivate the glycine receptor but differ in their ability to directly activate the receptor in the absence of the natural agonist.
IMPLICATIONS: This in vitro study shows that, at the glycine receptor level, propofol does not differ from its nonanesthetic structural analog 2,6 di-tert-butylphenol in its ability to enhance the effect of small glycine concentrations but differs in its potential to directly activate chloride inward currents in the absence of the natural agonist.
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Introduction
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Like most other anesthetics, propofol acts on different molecular targets at different levels of the central nervous system (1). The effects comprise positive allosteric modulation of inhibitory synapses (2,3) and blockade of voltage-operated sodium channels (4). Whereas gamma-aminobutyric acid (GABA) is the most important inhibitory neurotransmitter in the brain, glycine plays a major role in the spinal cord and lower brainstem. Both GABAA and glycine receptors inhibit neuronal firing by opening chloride channels after agonist binding (5). The in vitro propofol effects on neocortical tissue are mediated almost exclusively via the GABAA receptor (6). There is experimental evidence that anesthetic-induced immobility, a cardinal aspect of general anesthesia, is produced—in the case of propofol, at least partly—by action on the spinal cord (7). Depression of spinal -motoneuron excitability (8,9) and depression of low-threshold sensory information processing within the spinal cord (10) have been shown during propofol anesthesia. However, in one study, this effect was observed only with very large propofol concentrations (11). Most spontaneous inhibitory postsynaptic currents in motor neurons are mediated by glycine receptors (12). The potential contribution of positive allosteric modulation of spinal glycine receptors in propofol anesthesia is currently under discussion (13).
Replacing the isopropyl groups in positions 2 and 6 of the propofol molecule by 2,6 di-tert-butyl groups yields 2,6 di-tert-butylphenol, a compound with an almost complete lack of in vivo anesthetic activity (14). The structures of propofol and 2,6 di-tert-butylphenol are given in Figure 1. The aim of our study was to compare the effects of propofol with the effects of its nonanesthetic analog at the glycine receptor level.
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Methods
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The glycine receptor complex consisting of 1ß subunits is considered a dominant receptor combination in the adult spinal cord (5). Rat 1ß glycine receptor subunits were transiently transfected into transformed human embryonic kidney cells (HEK 293). The kinetics of recombinant 1ß glycine receptors expressed in HEK 293 cells have recently been published (15). Cells were cultured in Dulbecco’s modified Eagle’s medium (Biochrom, Berlin, Germany) and supplemented with 10% fetal calf serum (Biochrom), penicillin 100 U/mL, and streptomycin 100 µg/mL at 37°C in a 5% CO2/air incubator. For transfection, cells were suspended in a buffer containing K2HPO4 50 mM and K-acetate 20 mM (pH 7.35). For co-transfection of rat 1 and ß glycine receptor subunits, the corresponding complementary DNA, each subcloned in the pCIS2 expression vector (Invitrogen, San Diego, CA), was added to the suspension. To visualize successful transfection, cells were co-transfected with complementary DNA of green fluorescent protein (10 µg/mL). For transfection, we used an electroporation device by EquiBio (Kent, UK). Transfected cells were replated on glass coverslips and incubated 15–24 h before recording.
2,6 Di-tert-butylphenol was purchased from Fluka (Deisenhofen, Germany). Purified 2,6 diisopropylphenol (propofol) was a gift from Braun (Melsungen, Germany). Propofol and 2,6 di-tert-butylphenol were prepared as 1 M stock solution in ethanol, light-protected, and stored in glass vessels at –20°C. Concentrations were calculated from the amount injected into the glass vials. Drug-containing vials were vigorously vortexed for 60 min. Glycine was dissolved directly in the bath solution. Patch electrodes contained (mM) KCl 140, MgCl2 2, EGTA 11, HEPES 10, and glucose 10; the bath solution contained (mM) NaCl 162, KCl 5.3, NaHPO4 0.6, KH2PO4 0.22, HEPES 15, and glucose 5.6.
Standard whole-cell experiments (16) were performed at –30 mV membrane potential. A tight electrical seal of several gigaohms formed between the cell membrane and a patch-clamp electrode allows inward currents due to agonist-induced channel activation to resolve in the picoampere range. An ultrafast liquid filament switch technique (17) was used for the application of the agonist in pulses of 2 s duration. The agonist and/or the drug under investigation was applied to the cells via a smooth liquid filament achieved with a single outflow (glass tubing with 0.15 mm inner diameter) connected to a piezo crystal. The cells were placed at the interface between this filament and the continuously flowing background solution. When a voltage pulse was applied to the piezo, the tube was moved up and down onto or away from the cell under investigation. Correct positioning of the cell with respect to the liquid filament was ensured by applying a saturating (1 mM) glycine pulse before and after each test experiment. Care was taken to ensure that the amplitude and the shape of the glycine-activated current had stabilized before proceeding with the experiment. Test solution and glycine (1 mM) were applied via the same glass-polytetrafluoroethylene perfusion system, but from separate reservoirs. The contents of these reservoirs were mixed at a junction immediately before entering the superfusion chamber.
Drugs were applied alone (to determine their direct agonistic effects), in combination with a subsaturating glycine concentration (10 µM) (to determine their coactivating effects), or together with a saturating (1 mM) concentration of glycine (to detect open channel block). A new cell was used for each drug and each protocol, and at least four different experiments were performed for each setting. The amount of the diluent ethanol that corresponded to the largest drug concentration used was tested separately.
For data acquisition and further analysis, we used the Axopatch 200B amplifier in combination with pClamp 6 software (Axon Instruments, Union City, CA). Currents were filtered at 2 kHz. Fitting procedures were performed by using a nonlinear least-squares Marquardt-Levenberg algorithm. Details are provided in the appropriate figure legends or in Results.
The maximum current response induced by a compound acting directly as an agonist was expressed as percentage of the maximum response to 1 mM glycine in the absence of drug immediately after the respective test experiment. The coactivating effect was expressed as the percentage of the current elicited by 10 µM glycine according to
where I0 is the current response to glycine 10 µM. Activated or coactivated currents were normalized to their own maximum response and were fitted according to
where Inorm is the current either induced directly by the respective concentration ([C]) of the agonist or coactivated (I – I0) by the agonist/glycine (10 µM) mixture, normalized to the maximum inward current or maximum coactivated current (Imax – I0); EC50 is the concentration required to evoke a response amounting to 50% of the maximal response; and nH is the Hill coefficient. All data are presented descriptively as means ± SD.
The experiments were performed in small cells lifted from the bottom of the dish. This technique allows stable whole-cell recordings over 30 min. However, with stepwise application of the agonist with an ultrafast application device, longer rise times in saturating glycine concentrations—compared with recordings from excised patches—may lead to a small underestimation of the peak current response induced by glycine 1 mM. As a consequence, the effect of glycine 10 µM, normalized to the 1 mM response, might be overestimated relative to recordings from outside-out patches.
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Results
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A total of 41 cells were included in the study. Expression of rat 1ß messenger RNA in HEK 293 cells generated glycine receptors that showed glycine-activated inward currents with amplitudes of 1.6 ± 0.9 nA after saturating (1 mM) concentrations of the agonist when the cells were voltage-clamped at –30 mV. The current transient showed a fast increase, followed by a monophasic decay. The time constant of desensitization was 986 ± 320 ms. Steady- state current that did not desensitize in the presence of 1 mM glycine during the 2 s of application was at 77.0% ± 11.0% of the peak current amplitude.
When applied without glycine, only propofol (n = 4 experiments), but not 2,6 di-tert-butylphenol (n = 4), directly activated receptor-mediated inward currents in a concentration-dependent manner. As illustrated by the tracings in Figure 2, desensitization of Cl– currents elicited by propofol showed a pattern that was different from that of glycine-activated currents. Whereas glycine-induced currents showed some desensitization during the 2-s application, propofol-induced currents did not desensitize.
Currents reached 71.0% ± 14% (n = 4) of the maximum glycine (1 mM) response in the presence of saturating concentrations of propofol 600 µM (n = 4). Hill fits to the dose-response curves depicted in Figure 2 gave an EC50 value of 114 ± 27 µM. The nH was 1.7 ± 0.6.
Glycine 10 µM evoked currents of 46% ± 12% and 19% ± 8% of the maximum response in 1 mM glycine in the propofol and 2,6 di-tert-butylphenol experiments, respectively. The response to 10 µM glycine was potentiated by 136% ± 71% and by 279% ± 109% in the presence of saturating concentrations of propofol (n = 5) and 2,6 di-tert-butylphenol (n = 6), amounting to 90% ± 4% and 57% ± 19% of the maximum response in 1 mM glycine. Coactivated currents in the presence of either propofol or 2,6 di-tert-butylphenol showed no desensitization. Figure 3 shows representative current traces and the respective concentration-response plots. Hill fits to the dose-response curves gave EC50 values of 12.5 ± 6.4 µM and 9.4 ± 10.2 µM for propofol and 2,6 di-tert-butylphenol, respectively. The nH values were 1.1 ± 0.6 and 1.3 ± 1.0.
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Figure 3. A, Representative current traces elicited by 2-s coapplication of propofol (left row of traces) or 2,6 di-tert-butylphenol (right row of traces) and 10 µM glycine with respect to the current elicited by 1 mM glycine in the respective control experiment (upper trace). Both compounds increased the amplitude of the response to 10 µM glycine in the same concentration range, and currents in the presence of both compounds showed no desensitization. B, Normalized chloride currents coactivated in the presence of glycine 10 µM (mean ± SD) by propofol (upper diagram; n = 5) or 2,6 di-tert-butylphenol (lower diagram; n = 6), plotted against the concentration applied on a logarithmic scale. Coactivated currents were normalized to maximum value achieved by saturating concentrations of the compound and 10 µM glycine. Solid lines are Hill fits [I]norm = [1+(EC50/[C])nHto the data with the indicated variables. Data in the presence of 100 and 300 µM 2,6 di-tert-butylphenol could be obtained in only four experiments; two experiments had to be stopped after application of the 30 µM concentration because of a decline in the seal resistance. EC50 = concentration required to evoke a response amounting to 50% of the maximal response; nH = Hill coefficient; [C] = concentration; Inorm = current either induced directly by the respective concentration of the agonist or coactivated by the agonist/glycine (10 µM) mixture, normalized to the maximum inward current or maximum coactivated current.
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Propofol concentrations larger than 600 µM produced open channel block in the presence of 1 mM glycine, as revealed by a visible acceleration of the current decay after activation during coapplication of propofol and glycine (1 mM), followed by channel reopening when the application was stopped (Fig. 4A). The vehicle ethanol at a concentration of 34 mM, corresponding to a theoretical drug concentration of 2 mM, neither coactivated (n = 4 experiments) nor directly activated (n = 4) the receptor (see tracings in Fig. 4B).
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Figure 4. A, Open channel block induced by propofol at concentrations  600 µM, as revealed by a concentration-dependent acceleration of the current decay during coapplication of propofol and 1 mM glycine and channel reopening when the application was stopped (left row of traces). B, Representative tracings obtained with the vehicle ethanol at a concentration of 34 mM, corresponding to a drug concentration of 2 mM. Ethanol neither coactivated nor directly activated the receptor.
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Discussion
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In this in vitro study, we have shown that, at the glycine receptor level, the main difference between propofol and its nonanesthetic analog is the potential of propofol to directly activate the receptor in the absence of the natural agonist, producing a chloride inward current that does not desensitize as long as propofol is present. It has previously been reported by others that 2,6 di-tert-butylphenol neither directly activated nor coactivated GABAA receptors in vitro (18). In contrast, as revealed by our experiments, there is some interaction between 2,6 di-tert-butylphenol and glycine receptors. Coactivating effects in the presence of submaximal glycine concentrations were observed with both propofol and 2,6 di-tert-butylphenol in a similar small micromolar concentration range. These results suggest that either glycine receptor coactivation and direct activation are mediated via distinct binding sites, as has been proposed for propofol effects on GABAA receptors (19), or, alternatively, once the receptor is activated by small glycine concentrations, the propofol binding site undergoes a conformational change that leads to a loss of steric constraints imposed by the bulkier side chains of 2,6 di-tert-butylphenol. Mutagenesis studies on GABAA and glycine receptors have supported the idea of sequestered hydrophobic binding sites for small anesthetic molecules within these proteins acting as potential target sites (20). This idea of anesthetics binding to an amphiphilic pocket of circumscribed dimensions was originally proposed by Franks and Lieb (21) as an explanation for "cutoff" phenomena in the anesthetic activity of long-chain alcohols and alkanes as molecular volume is increased.
The nature of inhibitory control in the spinal cord is complex, and the relative contributions of GABA- versus glycine-mediated responses may differ between different classes of neurons in this area (22), precluding considerations about the relative contribution of molecular effects at either receptor to the entire anesthetic action. In vitro experiments in rat spinal horn neurons have shown that propofol directly induced chloride inward currents that were blocked to 90% by the GABAA antagonist bicuculline and to 12% by the glycine antagonist strychnine (13). Kinetics of propofol-induced currents differ from those of glycine-induced currents. Desensitization of propofol-induced currents was delayed during long pulses of agonist application (13) and was completely abolished in our experiments when propofol was applied in pulses of two seconds by using an ultrafast liquid filament switch technique. This distinct effect of propofol on desensitization has equally been described for GABAA receptors (23,24).
Facilitatory effects of propofol on glycine-induced currents have previously been described at threshold concentrations between 1 and 5 µM (2,3,13,25), as has open channel block by propofol in large concentrations (13). These effects were confirmed in our study with heterologously expressed glycine receptors.
It is generally assumed that facilitatory effects at inhibitory synapses are the crucial mechanisms that mediate the effect of propofol and various other anesthetics, because the respective in vitro effects are observed at small concentrations considered to be relevant to anesthesia (1). Anesthetic concentrations of IV anesthetics are uncertain because it is still not possible to measure effector compartment concentrations. Under simplistic assumptions, the IV anesthetic concentration of propofol has been estimated as small as 0.4 µM (1). However, the propofol concentrations required for loss of righting reflex in tadpoles, a model used as a standard for anesthetic potency determinations in aqueous solution, are in the range of 1–10 µM (26). The fact that, in our experiments, both propofol and its nonanesthetic analog exerted facilitatory effects at the glycine receptor level in this concentration range suggests that this mechanism may not contribute substantially to propofol’s anesthetic effect in vivo. 2,6 Di-tert-butylphenol is ineffective as an anesthetic in mice after IV injection (14) and in tadpoles after bath application in the concentration range between 1 and 100 µM (18). It seems unlikely that the analog in vivo does not reach the anesthetic site of action in both preparations. The passage of drugs across the skin of tadpoles depends on the same physicochemical variables as does equilibration across the mammalian blood-brain barrier. 2,6 Di-sec-butylphenol, a compound with similar physicochemical properties compared with 2,6 di-tert-butylphenol, is highly potent as an anesthetic in tadpoles. This finding suggests that the tert-butyl groups crowd the phenolic hydroxyl group and interfere with a critical interaction between the phenolic hydroxyl group and a specific receptor site (18).
Glycine receptor activation in the absence of the natural agonist—an effect that, in our study, was caused by propofol but was not observed with the nonanesthetic structural analog—required very large propofol concentrations (>30 µM), much larger than the concentrations considered to be clinically relevant. This finding seems to indicate that direct glycine receptor activation does not contribute to propofol’s anesthetic effect in vivo either. However, propofol-induced currents show very little desensitization as long as the drug is present. Thus, even a small response might translate into long-lasting hyperpolarization in vivo, as it would be expected to occur continuously at all receptors.
In conclusion, our results obtained with a nonanesthetic propofol analog at the glycine receptor level in vitro suggest that glycine receptor coactivation by propofol, although observed in a concentration range potentially relevant to anesthesia, is not sufficient for anesthesia. This finding is consistent with recent in vivo studies—one with a propofol-resistant knock-in mouse—showing that not only the hypnotic response, but also the immobilizing response, to propofol is mediated largely via GABAA receptors (27). Injection of the GABA antagonists picrotoxin or gabazine increased the immobilizing EC50 of propofol in rats by almost 400%, whereas the glycine antagonist strychnine reached an increase of only 50% (28). These results provide further evidence for the hypothesis that glycine potentiation is not of great importance to the immobilizing action of propofol.
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Acknowledgments
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We are indebted to Professor Betz, Frankfurt, for providing us with cloned subunits and to Dr. Krüger, FA Braun, Melsungen, for providing us with propofol. We thank U. Jensen, Department of Neurology, Hannover, for transfection and cell culture; J. Kilian and A. Niesel, Department of Neurology, Hannover, for technical support; and W. Heyde, Clinical Pharmacy, Hannover, for preparing stock solutions of 2,6 di-tert-butylphenol.
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Accepted for publication January 16, 2004.
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Abstract
Introduction
. The solid line is a Hill fit [I]norm = [1 + (EC50/[C])nH to the data with the indicated variables. EC50 = concentration required to evoke a response amounting to 50% of the maximal response; nH = Hill coefficient; [C] = concentration; Inorm = current either induced directly by the respective concentration of the agonist or coactivated by the agonist/glycine (10 µM) mixture, normalized to the maximum inward current or maximum coactivated current.
