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 solven ts that model different amino acid side-chains and lipid membrane domains w as performed in an effort to define which microenvironments present in prot eins and lipid bilayers might be favored. Compared to a purely aliphatic en vironment (hexane), the presence of an aromatic-, alcohol-, thiol- or sulfi de 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 sevoflu rane into ethanol, a model for threonine. Isoflurane also partitioned favor ably into ethyl methyl sulfide. The results suggest that volatile general a nesthetics interact better with partly polar groups, which are present on a mino acids frequently found buried in the hydrophobic core of proteins, com pared to purely aliphatic side-chains. Furthermore, if an anesthetic molecu le was located in a saturated region of a phospholipid bilayer membrane, th ere would be an energetically favorable driving force for it to move into s everal higher dielectric microenvironments present on membrane proteins. Th e results provide evidence that proteins rather than lipids are the likely targets of volatile general anesthetics in biological membranes. (C) 1999 E lsevier Science B.V. All rights reserved.