A reassessment of the molecular structure-functional relationships of the inhaled general anaesthetics.

The importance of structure-activity relationships in the inhaled general anaesthetic agents may have been underestimated in the elucidation of the central and peripheral mechanisms of general anaesthesia. It is true that there is no single spatial arrangement of atoms in a molecule that is essential for anaesthetic activity; the "anesthesiophore", as it was termed, is a myth. However, the chemical structure of a compound is directly related to its physical properties which in turn are one of the major determinants in the molecular mechanisms. Second, chemical structures are the major factors in the physical, chemical and biological stability of the anaesthetics; in particular the electron distributions, bond densities and net atomic charges determine the extent and mode of biotransformation. Some of the evidence for the importance of structure in the anesthetic "side effects" on circulation, respiration and neuroelectric irritability is presented. An example of the detailed structural-molecular studies is provided by the nuclear magnetic resonance investigations of anaesthetic conformational perturbations of haemoglobin which we have used as a model system for elucidating the ground rules of anaesthetic-protein interactions.