7th International Drug Chemistry Congress, Antalya, Turkey, 14 - 17 March 2019, pp.8
General anesthesia is one of the most important advances in medical history allowing the execution of medical procedures that would be too painful to tolerate for conscious patients. Despite over 170 years of general clinical practice in Western medicine, neither the mechanism of general anesthesia nor the specific target(s) of general anesthetics are known. While it would seem obvious that anesthetic agents perturb membrane-bound signaling proteins, it is unclear whether the primary target of anesthetic agents are actually the proteins or the surrounding lipid membrane. To further understand how anesthetic agents affect lipid membranes, the effect of inhalation anesthetics chloroform, halothane, and isoflurane on phospholipid-cholesterol interaction energies was investigated. Interactions of these agents with model membranes consisting of cholesterol and 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), in both the liquid-ordered (lo) and liquid-disordered (ld) phases, were studied and phospholipid-cholesterol interaction energies were measured using the nearest-neighbor recognition technique.1-3 All three anesthetic agents caused a weakening of phospholipid-cholesterol interactions in the lo phase by about 30 kcal/mol at clinically-relevant concentrations (2 mM). Conversely, the same anesthetics caused a strengthening of phospholipid-cholesterol interactions by a similar magnitude in the ld phase. Furthermore, through binding studies, evidence for 1:1 complex formation between phospholipids and chloroform and halothane has been obtained. The relevance of these findings within the context of current theories of mechanism of general anesthesia will be discussed.