Partitioning of four modern volatile general anesthetics into solvents that model buried amino acid side-chains

Partitioning of four modern inhalational anesthetics (halothane, isoflurane, enflurane, and sevoflurane) between the gas phase and nine organic solvents that model different amino acid side-chains and lipid membrane domains was performed in an effort to define which microenvironments present in proteins and lipid bilayers might be favored. Compared to a purely aliphatic environment (hexane), the presence of an aromatic-, alcohol-, thiol- or sulfide group on the solvent improved anesthetic partitioning, by factors of 1.3-5.2 for halothane, 1.7-5.6 for isoflurane, 1.7-7.6 for enflurane, and 1.5-7.3 for sevoflurane. The most favorable solvent for halothane partitioning was ethyl methyl sulfide, a model for methionine. Enflurane and isoflurane partitioned most extensively into methanol, a model for serine, and sevoflurane into ethanol, a model for threonine. Isoflurane also partitioned favorably into ethyl methyl sulfide. The results suggest that volatile general anesthetics interact better with partly polar groups, which are present on amino acids frequently found buried in the hydrophobic core of proteins, compared to purely aliphatic side-chains. Furthermore, if an anesthetic molecule was located in a saturated region of a phospholipid bilayer membrane, there would be an energetically favorable driving force for it to move into several higher dielectric microenvironments present on membrane proteins. The results provide evidence that proteins rather than lipids are the likely targets of volatile general anesthetics in biological membranes.