Hypothesis: inhaled anesthetics produce immobility and amnesia by different mechanisms at different sites

E. I. Eger 2nd, D. D. Koblin, R. A. Harris, J. J. Kendig, A. Pohorille, M. J. Halsey and J. R. Trudell, Anesth. Analg 84 915-918 (1997).

Although the potency of conventional anesthetic molecules correlates with lipophilicity, we find that an affinity to water also is essential. Compounds with very low affinities to water do not produce anesthesia (are non-anesthetics) regardless of their lipophilicity. This finding implies that anesthetics act at a site having both hydrophilic and hydrophobic aspects, possibly a neural membrane interface with its aqueous environment. Accordingly, we postulate that anesthesia may require increased concentrations of molecules at a membrane interface. To test this hypothesis, we calculate in molecular dynamics simulations the free-energy profiles for the transfer of two pairs of anesthetic and non-anesthetic compounds across water-hexane and water-bilayer interfaces. The anesthetic but not the non-anesthetic compounds have a free-energy minimum at the interface. These result are consistent with the above hypothesis.