Different distribution of fluorinated anesthetics and nonanesthetics in model membrane: a 19F NMR study

Abstract

Despite their structural resemblance, a pair of cyclic halogenated compounds, 1-chloro-1 ,2,2-trifluorocyclobutane (F3) and 1,2-dichlorohexafluorocyclobutane (F6), exhibit completely different anesthetic properties. Whereas the former is a potent general anesthetic, the latter produces no anesthesia. Two linear compounds, isoflurane and 2,3-dichlorooctofluorobutane (F8), although not a structural pair, also show the same anesthetic discrepancy. Using 19F nuclear magnetic spectroscopy, we investigated the time-averaged submolecular distribution of these compounds in a vesicle suspension of phosphatidylcholine lipids. A two-site exchange model was used to interpret the observed changes in resonance frequencies as a function of the solubilization of these compounds in membrane and in water. At clinically relevant concentrations, the anesthetics F3 and isoflurane distributed preferentially to regions of the membrane that permit easy contact with water. The frequency changes of these two anesthetics can be well characterized by the two-site exchange model. In contrast, the nonanesthetics F6 and F8 solubilized deeply into the lipid core, and their frequency change significantly deviated from the prediction of the model. It is concluded that although anesthetics and nonanesthetics may show similar hydrophobicity in bulk solvents such as olive oil, their distributions in various regions in biomembranes, and hence their effective concentrations at different submolecular sites, may differ significantly.

Large-scale molecular dynamics simulations of general anesthetic effects on the ion channel in the fully hydrated membrane: The implication of molecular mechanisms of general anesthesia

“…Three halothane molecules (3, 4, and 5) placed in the channel-lipid-water interface had relatively small overall displacements, suggesting that halothane molecules populate more favorably in these regions. Taken together, the results of halothane distribution over the 2.2-ns all-atom simulation are in excellent agreement with our NMR finding that volatile anesthetics are accessible to the aqueous phase and preferentially target the membrane interface (39)(40)(41).…”

“…Three halothane molecules (halothane 8-10) are placed in the water phase near the lipid head groups. These initial halothane arrangements also conform with the large lipidwater partition coefficient for halothane and qualitatively agree with the NMR prediction of volatile anesthetic distribution in the lipid bilayers (14,15,39). Redistribution of halothane occurred over the 2.2-ns simulation, despite the near equilibrating state of the initial setup.…”

“…Molecules that are nonanesthetics (nonimmobilizers) but are structurally similar to their anesthetic counterparts often have virtually zero dipole moment. We learned in our previous NMR experiments that nonanesthetic molecules prefer the lipid tail region to the lipid-water interface (39). The different tendency in the distribution of halothane 1 and 2 from that of other halothane molecules seems to suggest that the pairing of two anesthetics can render them indistinguishable from a nonanesthetic molecule.…”

First-passage-time analysis of atomic-resolution simulations of the ionic transport in a bacterial porin

“…(1) and (2) are solved self-consistently in combination with Poisson's equation of electrostatics, forming the so-called Poisson-Nernst-Planck (PNP) equations. This approach allows the analysis of electrically charged nanochannels in a consistent fashion [7][8][9][10][11]. In all cases, a continuous mean-field approximation is assumed, i.e., ions are treated not as discrete entities but as continuous charged densities that represent the space-time average of the microscopic motion of the ions.…”

“…The diffusion coefficient of ions, D, characterizes their motion within the channel, representing a spatial average over the region considered. In analyzing experiments, diffusion coefficients are often given bulk values when the comparison with experiment is qualitative or are treated as free parameters to adjust by fitting experimental data [8][9][10]12].…”