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ANESTHETIC PHARMACOLOGY

Anesthetic Properties of Some Fluorinated Oxolanes and Oxetanes

Edmond I. Eger, II, MD^*, David Lemal, PhD, Michael J. Laster, DVM^*, Mark Liao, BS^*, Katarzyna Jankowska, DVM^*, Anilkumar Raghavanpillai, PhD, Anatoliy V. Popov, PhD, Yonghong Gan, PhD, and Yan Lou, MS

From the *Department of Anesthesia and Perioperative Care, University of California, San Francisco, California 94143-0464; and Department of Chemistry, Dartmouth College, Hanover, New Hampshire 03755-3564.

Address correspondence to Dr. Edmond I Eger, II, Department of Anesthesia, S-455, University of California, San Francisco, California 94143-0464. Address e-mail to egere{at}anesthesia.ucsf.edu.

	Abstract

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BACKGROUND: The search for new potent inhaled anesthetics has slowed, in large part because of the excellence of the two most recent additions, desflurane and sevoflurane. Nonetheless, neither desflurane nor sevoflurane are ideal anesthetics, desflurane causing cardiorespiratory stimulation, and sevoflurane having a slower (albeit rapid) recovery from anesthesia. Sevoflurane also can produce convulsions and postoperative agitation.

METHODS AND RESULTS: In the present report, we describe the physical and anesthetic properties of 31 cyclic ethers halogenated solely with fluorine. Although several produced anesthesia, none had solubilities that would make them better than sevoflurane. The remaining ethers were unstable or produced obvious central nervous system irritation, including convulsions.

CONCLUSIONS: We find that none of these cyclic ethers appear to provide advantages over desflurane or sevoflurane.

	Introduction

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Each of the several inhaled anesthetics released for clinical use in the last half century has improved the delivery and safety of anesthetic management. The modern inhaled anesthetics (those halogenated in part or whole with fluorine) began with fluroxene, a kinetic improvement over diethyl ether. But fluroxene had elements of toxicity and pungency, which often produced postoperative nausea and vomiting, and was flammable (1). By the 1960s, fluroxene and all other potent inhaled anesthetics were supplanted by halothane (1), which had the advantages of not being flammable, without pungency, and having low toxicity in nearly all patients. But halothane caused a rare, severe immune-based hepatotoxicity, and primarily for this reason, in anesthesia for adults it was displaced in the 1970s by enflurane, a much less hepatotoxic anesthetic. Isoflurane succeeded enflurane in the 1980s (1). Isoflurane was an incremental improvement over enflurane, having several modest advantages (lower solubility, greater resistance to metabolic degradation, no convulsive predisposition) (1). Desflurane and sevoflurane were released for use in the 1990s. Each had several, again incremental, advantages over isoflurane: still less hepatotoxicity because of the absence of any halogenation by chlorination, a lower solubility (particularly desflurane) and, in the case of sevoflurane, a markedly decreased pungency.

But desflurane and sevoflurane, good as they are, are still less than perfect. Desflurane's pungency at concentrations exceeding minimum alveolar concentration (MAC) limits its use as an induction agent (2), and sevoflurane's greater solubility produces a slower recovery from anesthesia (3). Sevoflurane can also produce convulsions (desflurane does not), and perhaps greater postoperative agitation, particularly in children (4). Desflurane can transiently increase heart rate and arterial blood pressure at concentrations exceeding MAC (5).

Thus, there is room for improvement. We asked whether a better anesthetic might be found in fluorinated cyclic ethers, both those with 4-membered rings (oxetanes) and 5-membered rings (oxolanes). (Henceforth, we will refer to oxetanes and oxolanes collectively as "ethers" or "cyclic ethers.") We chose ethers because the ether linkage decreases arrhythmogenicity (6), and we chose cyclic ethers because cyclic ethers had largely been ignored although at least one cyclic ether was a known anesthetic (7). We limited halogenation to fluorine because of the connection between chlorination and toxicity. The criteria we sought were: (a) stability in the presence of fresh soda lime at 40°C; (b) a solubility in normal saline at least as small as that for desflurane; (c) a good anesthetic "syndrome," no twitching or convulsions. We knew that increasing fluorination would decrease solubility in saline, but that too much fluorination would move towards a poor anesthetic syndrome (8). At least one and probably two or three hydrogen atoms would have to remain to produce anesthesia.

	METHODS

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Synthesis of Fluorinated Cyclic Ethers
Fluoroether Compounds 1–8, 20–22, 24, 25, and 28–31 are new compounds, syntheses of which will be described elsewhere. All oxetanes were prepared by vapor phase photocycloaddition of hexafluoroacetone (Compounds 9–23, 28, 29) or trifluoroacetaldehyde (Compounds 24–27, 30, 31) to an alkene. For Compounds 9 and 10, see Barlow et al. (9); 9–12, see Tarrant and Bull (10); 13–17, see Cook and Landrum (11); and for 19, 26, 27 see Harris and Coffman (12). Nuclear magnetic resonance data for Compounds 9–19 and 23 are presented in Brey and Brey (13).

Compounds 5 and 6, 7 and 8, 26 and 27 were provided as cis/trans mixtures. After gas chromatographic separation, members of the first two pairs were assigned on the assumption that the cis isomers had the greater solubility; the third pair was assigned arbitrarily. Potency determinations were made with the mixtures. Because Compounds 18 and 19 cochromatographed, the data listed in Table 1 for 18 are actually for the mixture.

Solubility
We measured saline/gas (S/G) and olive oil/gas (O/G) partition coefficients using previously described techniques (8,15,16). S/G partition coefficients were determined at 37°C by equilibrating a known volume of gas containing the ether with a known volume of normal saline in a syringe capped with a 3-way stopcock. The ether concentration at equilibrium was determined using gas chromatography. The gas volume was then completely expelled and an equal volume of fresh gas drawn into the syringe and reequilibrated with the saline. The new concentration was determined and the process repeated. Regression analysis provided an estimate of the slope that, in turn, allowed calculation of the partition coefficient. In a subset of compounds, we also measured blood/gas (B/G) partition coefficients (hematocrit 45) using the technique described above for determination of S/G partition coefficients.

Olive O/G partition coefficients were determined at 37°C by first equilibrating the test ether with olive oil in a syringe capped with a 3-way stopcock and determining the resulting concentration in the gas phase using gas chromatography. A small (1–5 mL) aliquot of the equilibrated olive oil was then injected into a closed 600-mL flask at 37°C and the gas in the flask equilibrated with the injected oil. Analysis of the ether concentration in the gas phase and a knowledge of the volume of the injected oil and the volume of the gas phase inside the flask allowed calculation of the O/G partition coefficient.

Determinations of stability and solubility were done either in triplicate or quadruplicate. A mean ± sd was calculated for each of these variables.

Determination of MAC or convulsant properties of fluorinated cyclic ethers.
With approval of the Committee on Animal Research of the University of CA, San Francisco, we studied male (Crl:CD(SD)BR) rats weighing 250–450 g obtained from Charles River Laboratories (Hollister, CA). Rats were housed in rooms with daily cycles of 12 h light–dark and had water and standard rat chow ad libitum.

Where synthesis produced sufficient test compound, MAC or the lowest test concentration producing convulsions was determined concurrently in two rats restrained in individual clear plastic cylinders as described previously (17). Briefly, a rectal temperature probe was placed, and three pairs of electrodes were inserted into the tail of the awake rat. The tail was taped to an extension of the plastic cylinder, and the cylinder was inserted into a clear plastic hyperbaric chamber that had pass-throughs allowing monitoring of temperature and application of electrical currents to the tail. The chamber contained a freshly filled carbon dioxide absorbent canister and circulating fan. The chamber was sealed, flushed with oxygen, and tested for leaks. An aliquot of liquid ether was injected into the chamber and flushed into the chamber with a small amount of oxygen. After allowing 40 min for equilibration, each rat was stimulated as described (18), and the rat observed for movement (all rats moved at the initial partial pressure of the test ether). The pressure in the chamber was noted and a sample of gas was drawn from the chamber and analyzed using gas chromatography (see below). The partial pressure of ether was calculated from knowledge of the pressure and the concentration of the ether. Further aliquots of ether were added to the chamber, and after 20–30 min of equilibration after each injection, the rat was again stimulated and observed for movement or absence of movement. This process continued until one of four results was obtained: (a) the agent supply was exhausted; (b) the rat failed to move; (c) the rat convulsed; or (d) the rat died. MAC was defined as the partial pressure midway between the greatest partial pressure permitting movement and the lowest pressure preventing movement. A convulsant dose was taken as the average of the lowest partial pressures that produced convulsions.

When convulsions rather than anesthesia were obtained, if sufficient ether were available, we determined MAC by a study of additivity with isoflurane as described previously (16). Isoflurane was obtained from Baxter Healthcare Corp. (New Providence, NJ). MAC for isoflurane was determined in a pair of rats. One or more days later, the rats were prepared for study in the hyperbaric chamber as described above. An isoflurane concentration equal to approximately half the MAC previously determined was established and then the convulsant ether added. After allowing 40 min for equilibration of the rats with the mixture of gases, the tails of the rats were stimulated and the rats observed for movement. (They moved at these concentrations.) The partial pressures of isoflurane and the ether were analyzed by gas chromatography. An additional aliquot of isoflurane was added, equilibrium attained and the rats again stimulated and the gas within the chamber analyzed. This process continued until the MAC of isoflurane was determined. The difference between the MAC with and without a known concentration of the ether allowed calculation of the MAC of the ether.

Analyses of inhaled anesthetics.
We used a Gow-Mac gas chromatograph (Gow-Mac Instrument Corp., Bridgewater, NJ) equipped with a flame ionization detector to measure concentrations of inhaled anesthetics. The 4.6 m-long, 0.22 cm (ID) column was packed with SF-96. The column temperature was 100°C. The detector was maintained at temperatures approximately 50°C warmer than the column. The carrier gas flow was nitrogen at a flow of 15–20 mL/min. The detector received 35–38 mL/min hydrogen and 240–320 mL/min air.

Because of the limited availability of the test compounds, we made lecture bottles (438-mL internal volume) as follows. A volume of liquid ether was drawn into a gas-tight syringe capped with a three-way stopcock, the volume noted (including the dead-space), and the syringe weighed. The lecture bottle was evacuated to 0 psi, and the opening of the bottle attached to a gas-tight apparatus fitted with a leur-lock connection. The syringe was coupled to the luer-lock connection and the contents of the syringe drawn into the bottle by the vacuum it contained. An air chaser assured transfer of all of the contents into the bottle. The syringe was then reweighed and the density of the ether calculated. From the weight drawn into the bottle and knowledge of the molecular weight and the volume of the bottle, we calculated the ether concentration within the bottle at 1 atm. The bottle was then pressurized by transfilling with nitrogen to a precisely determined pressure, and the concentration reestimated from knowledge of the original concentration and the total atmospheres of pressure. Such bottles served both as a source of ether for studies of stability and solubility, and as a source of calibration gas for studies of MAC and/or the lowest test vapor concentration producing convulsions. Values for MAC or convulsant concentration were calculated as mean ± sd.

	RESULTS

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Table 1 summarizes the results of all studies, and Table 2 provides the names of each compound. Where no results are given for convulsions or MAC, insufficient compound was available for testing or the compound was unstable in the presence of soda lime. The first three compounds (1–3) were unstable in soda lime and were not studied further except for solubility studies. Of the remaining compounds, 14 and 27 were unstable, and 4 and 16 were slightly unstable. The remaining compounds were stable.

Despite slight instability, Compound 4 was studied in two rats. At 0.0336 atm both appeared to be sedated and were not twitching. At 0.0526 atm, one rat convulsed, and at 0.0762 atm, the second rat convulsed.

Two rats were given a mixture of the isomers, Compounds 5 and 6. At 0.0297 atm both appeared sedated but had occasional twitching. Neither rat moved in response to 5 V; but both moved at 15 V. This exhausted the supply of these compounds. MAC probably equals approximately 0.035 atm.

Two rats were given a mixture of the isomers, Compounds 7 and 8. These caused somnolence. One rat convulsed at 0.0133 atm, and the other had twitches. Both moved in response to 2 or 5 V stimulation to the tail at this concentration. No compound remained for further testing (e.g. studies of additivity).

Compound 9 was tested alone in two rats. This compound was a mixture with one dominant peak on gas chromatography; the other may have been the isomer (Compound 10) and made up roughly 10% of the area of the peaks. At 0.0048 atm, one rat convulsed. Increasing concentrations did not evoke overt convulsions although minor "convulsive-like" movements occurred at 0.0293 atm but stopped at 0.0346 atm. MAC was 0.0320 atm in one rat and 0.0366 atm in the other. Both rats awoke rapidly, responding to stimulation in 2–3 min after beginning washout and moving spontaneously 4–6 min after beginning washout.

Compound 10 produced convulsions at 0.0158 atm in one rat and at 0.0247 atm in a second rat. Compound 10 was tested with isoflurane for additivity in two rats. At 0.0278 atm of Compound 10, MAC for isoflurane increased from 0.0138 to 0.0170 atm (23%) in one rat and 0.0153 to 0.0170 at (11%) in the second, indicating that Compound 10 has no anesthetic potency [is a nonimmobilizer (16)].

Compound 11 was tested alone in two rats, producing convulsions at 0.10 atm, the lowest concentration applied. When tested using additivity, the presence of 0.164 atm of Compound 11 decreased isoflurane MAC by 25.8% in one rat and 9.8% in another. Applying the average of these values (17.8%) indicates that the MAC of Compound 11 alone would be 0.92 atm. Compound 11 has an O/G partition coefficient of 10.1, which according to the Meyer-Overton relationship would correspond to a MAC of 0.179 atm (15). Thus, the experimental MAC is 5.1 times the predicted MAC, making Compound 11 a transitional compound (16).

Compound 13 produced somnolence in two rats. At 0.064 atm, one rat convulsed and the other had occasional twitches. Both rats moved spontaneously in response to 2 V stimulation to the tail at this concentration. No compound remained to test further effects (e.g. additivity).

Compound 15 was tested with four rats. Twitching and labored breathing occurred below and at anesthetizing concentrations. MAC was 0.0746 ± 0.0040 atm.

Despite slight instability, Compound 16 was tested with four rats. Occasional twitching and regular gasping occurred at 0.0245 atm to 0.0308 atm and greater. At 0.0350 atm, one rat died. MAC was 0.0306 ± 0.0021 atm in the remaining three rats. Gasping and twitching stopped within 1–2 min after commencing flush of the chamber, and rats moved spontaneously 3 min after commencing flush.

Compound 17 was tested in two rats. At 0.0229 atm, both rats moved slowly in response to 5 V stimulation. At 0.0311 atm they did not move in response to 5 V stimulation, but did move with 15 V. No more compound remained. MAC probably was approximately 0.035 atm.

Compound 25 was tested in two rats. Anesthesia was smoothly achieved. MAC was 0.0314 atm for both rats.

Except for one rat who died during anesthesia, all of the remaining 29 exposed rats survived for 24 h after anesthesia with no apparent problems.

	DISCUSSION

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The present series of compounds displayed various properties (Table 1). Some compounds produced somnolence or anesthesia, others produced a combination of anesthesia and central nervous system irritability, and still others simply produced convulsions. Of the six compounds that produced anesthesia, only three (17 and 25) did so without evidence of central nervous system irritability. The effects correlated with two physical properties, lipophilicity (O/G partition coefficient) and hydrophilicity (S/G partition coefficient). Anesthesia required sufficient lipophilicity. It also required sufficient hydrophilicity. Low S/G partition coefficients were associated either with no anesthesia or with tremors and convulsions. These observations parallel observations we have made previously (8).

We determined the B/G partition coefficients for six compounds (Table 1). If one assumes that the B/G value is determined by contributions of S/G and O/G partition coefficients, then the fractional contribution (X) of the S/G portion may be calculated as:

For the six compounds, X equaled 0.9960 ± 0.0004 (mean ± sd). That is, the B/G partition coefficient could be calculated by assuming that it was composed of 99.6% S/G and 0.4% O/G partition coefficients. Assuming this relationship applies to all the fluorinated ethers, none of the ethers that produced anesthesia would have B/G partition coefficients less than those for desflurane (0.45) and sevoflurane (0.65). Several compounds were not tested for anesthetic properties because of the limited supplies of test compounds. Most of these would probably have been nonimmobilizers or transitional compounds because they had S/G partition coefficients <0.1 (e.g., see Compounds 4, 10, and 11.) Even greater S/G partition coefficients were sometimes associated with evidence of central nervous system irritability (e.g., Compounds 5, 6, 15, and 16). The one compound we regret having insufficient material to test for anesthetic properties was 30 with a predicted B/G partition coefficient of 0.23.

None of the compounds that produced anesthesia would be useful clinically. Those that caused anesthesia engendered central nervous system irritability (Compounds 5, 6, 9, 15, 16) or were too soluble (Compounds 17, 25) to compete with presently available anesthetics such as sevoflurane or desflurane. We might have found a competitive compound among those for which we had too little material, but the only potential candidate would have been 30, and even this probably would have had solubilities no better than those of desflurane. Indeed, this compound resembles desflurane, substituting a —CF₂— link for the —F on the methyl carbon of desflurane. The remaining untested compounds had S/G partition coefficients (<0.1) that predicted central nervous system irritation or convulsions or were unstable (Compounds 1–3, 14, 27).

Instability in the presence of base at 40°C occurred in all 5-membered ring ethers (Compounds 1–8 in Table 1). Dehydrofluorination leading to both endo- and exocyclic double bonds must be considered. Regarding the former, both syn- and antielimination are readily achieved in 5-membered rings (19), but antielimination is more difficult in 4-rings because of their greater rigidity, and antistereochemistry is favored over syn in general (20). Formation of an exocyclic double bond on a 5-ring is more favorable thermodynamically than on a 4-ring (21). These considerations may explain the experimental observations, but the situation is complicated by the structural diversity among the fluoroethers.

A single previous report noted that various unhalogenated oxetanes can produce anesthesia (22). However, all compounds in this series were lethal. In contrast, although one rat in 30 died from exposure to the present fluorinated cyclic ethers, most survived both immediately and for 24 h after exposure. It would appear that fluorination markedly decreased toxicity, perhaps by decreasing metabolic degradation.

We conclude that although some fluorinated cyclic ethers can produce an acceptable anesthetic state, most do not, and/or have solubilities that indicate no particular advantage. Fluorinated cyclic ethers do not provide a challenge to the presently available conventional potent inhaled anesthetics.

	Footnotes

 
Accepted for publication January 19, 2007.

Supported by NIH Grant 1PO1GM47818 (UCSF).

Dr. Eger is a paid consultant to Baxter Healthcare Corp. Baxter Healthcare Corp. donated the isoflurane used in these studies.

	REFERENCES

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