Polyhalogenated methyl ethyl ethers: Solubilities and anesthetic properties

The several potent inhaled anesthetics released for clinical use in the pas t four decades have been halogenated ethers, and, with one exception, methy l ethyl ethers. In the present report, we detail some structural and physic al properties associated with anesthetic potency in 27 polyhalogenated meth yl ethyl ethers. We obtained new data for 22 compounds. We wed response/non response of rats to electrical stimulation of the tail as the anesthetic en d point (i.e., we measured the minimum alveolar anesthetic concentration [M AC]). For compounds that did not produce anesthesia when given alone (they only produced excitation/convulsions), we studied MAC by additivity studies with desflurane. We obtained MAC values for 20 of 22 of the studied ethers , which gave products of MAC x oil/gas partition coefficient ranging from 1 .27 to 18.8 atm, compared with a product of 1.82 +/- 0.56 atm for conventio nal inhaled anesthetics. Despite solubilities in olive oil and application of partial pressures predicted by the Meyer-Overton hypothesis to provide a nesthesia, 2 of 22 ethers (CCIF2OCCIFCF3 and CCIF2OCF2CCIF2) had no anesthe tic (immobilizing) effect when given alone, did not decrease the anesthetic requirement for desflurane, and had excitatory properties when administere d alone. As with other inhaled anesthetics, anesthetic potency seemed to co rrelate with both polar and nonpolar properties. These ethers, representing structural analogs of currently used clinical volatile anesthetics, may be useful in identifying and understanding the mechanisms by which inhaled an esthetics act. Implications: The several potent, inhaled, polyhalogenated m ethyl ethyl ether anesthetics released for clinical use in the past four de cades seem to have specific useful characteristics that set them apart from other methyl ethyl ethers. Properties of this class of compounds have impl ications for the future development of anesthetics and the mechanisms by wh ich they act.