DIFFERENT DISTRIBUTION OF FLUORINATED ANESTHETICS AND NONANESTHETICS IN MODEL MEMBRANE - A F-19 NMR-STUDY

Despite their structural resemblance, a pair of cyclic halogenated com pounds, 1-chloro-1,2,2-trifluorocyclobutane (F3) and 1,2-dichlorohexaf luorocyclobutane (F6), exhibit completely different anesthetic propert ies. Whereas the former is a potent general anesthetic, the latter pro duces no anesthesia. Two linear compounds, isoflurane and 2,3-dichloro octofluorobutane (F8), although not a structural pair, also show the s ame anesthetic discrepancy. Using F-19 nuclear magnetic spectroscopy, we investigated the time-averaged submolecular distribution of these c ompounds in a vesicle suspension of phosphatidylcholine lipids. A two- site exchange model was used to interpret the observed changes in reso nance frequencies as a function of the solubilization of these compoun ds in membrane and in water, At clinically relevant concentrations, th e anesthetics F3 and isoflurane distributed preferentially to regions of the membrane that permit easy contact with water. The frequency cha nges of these two anesthetics can be well characterized by the two-sit e exchange model. In contrast, the nonanesthetics F6 and F8 solubilize d deeply into the lipid core, and their frequency change significantly deviated from the prediction of the model. It is concluded that altho ugh anesthetics and nonanesthetics may show similar hydrophobicity in bulk solvents such as olive oil, their distributions in various region s in biomembranes, and hence their effective concentrations at differe nt submolecular sites, may differ significantly.