Amphiphilic sites for general anesthetic action? Evidence from 129Xe-[1H] intermolecular nuclear Overhauser effects

Because a strong correlation exists between the potency of general anesthetics and their ability to dissolve in oil, a lipophilic site of action is often assumed. We show here that a lipophilic molecule may preferentially target less lipophilic sites after interaction with a membrane takes place. Xenon, a chemically inert and structureless general anesthetic, was chosen as an unbiased molecular probe for assessment of its dynamic distribution. Site-selective intermolecular 129Xe-[1H] nuclear Overhauser effects were used to measure the specific interaction between xenon and protons in different regions in a phosphatidylcholine lipid membrane. It was evident that xenon-membrane interaction was directed toward the amphiphilic head region, with significant involvement of interfacial water, despite xenon's apolar and highly lipophilic nature in the gas phase. This result may suggest the importance of amphiphilicity in association with anesthetic action.