Chirality in anesthesia II: stereoselective modulation of ion channel function by secondary alcohol enantiomers

Chirality has been proposed as a means for distinguishing relevant from irrelevant molecular targets of action, but the sensitivity and specificity of this test is unknown for volatile anesthetics. We applied enantiomers of two chiral anesthetic alcohols (2-butanol and 2-pentanol) that are enantioselective for the minimum alveolar concentration (MAC) preventing movement in 50% of animals and one (2-hexanol) that was not to frog oocytes. Each oocyte expressed one of three anesthetic-sensitive ion channels: a Twik-related-spinal cord K+ (TRESK) channel, a gamma-amino butyric acid type A (GABA(A)) receptor and an N-methyl-d-aspartate (NMDA) receptor. Using voltage-clamp techniques, we found that 2-butanol was not enantioselective for any channel (e.g., 16 mM 2-butanol R(-) and S(-) enantiomers decreased current through an NMDA receptors by 44% +/- 3% [mean +/- se] and 37% +/- 4%, respectively); 2-pentanol was enantioselective for one channel (the GABA(A) receptor, the enantiomers increasing current by 277% +/- 20% and 141% +/- 30%); 2-hexanol was enantioselective for both GABA(A) and NMDA receptors (e.g., decreasing current through the NMDA receptor by 19% +/- 3% and 43% +/- 5%). We calculated the sensitivity and specificity of chirality as a test of anesthetic relevance under two scenarios: 1) all three channels were relevant mediators of MAC and 2) no channel was a mediator of MAC. These sensitivities and specificities were poor because there is no consistent correspondence between receptor and whole animal results. We recommend that enantioselectivity not be used as a test of relevance for inhaled anesthetic targets.