The Site of Anesthetic Action

Abstract

The mechanisms of general anesthesia constitute one of the great unsolved problems of classical neuropharmacology. Since the discovery of general anesthesia, hundreds of substances have been tested and found to possess anesthetic activity. Anesthetics differ tremendously in their chemical, physical, and pharmacological properties, greatly varying in size, in chemically active groups, and in the combinations of interactions and chemical reactions that they can undergo. The large spectrum of targets makes it obvious that dealing with anesthetics pharmacologically is different from dealing with most other drugs used in pharmacology. Anesthetic potency often correlates with the lipophilicity of anesthetic compounds, i.e., their preference for dissolving in lipophilic phases. This suggests as a main characteristic of anesthetic interactions that they are weak and that for many of them there is overall an approximate balance of nonspecific hydrophobic interactions and weak specific polar interactions. These include various electrostatic (ions, permanent and induced dipoles, quadrupoles), hydrogen bonding, and hydrophobic interactions. There are many molecular targets of anesthetic action within the central nervous system, but there are many more still to be discovered. Molecular interaction sites postulated from functional studies include protein binding sites, protein cavities, lipid/protein interfaces, and protein/protein interfaces.