Contributions of dipole moments, quadrupole moments, and molecular polarizabilities to the anesthetic potency of fluorobenzenes.
Previous studies have emphasized the role of molecular polarizability and electric moments, especially dipole and quadrupole moments, in binding of drugs to sites of action. A recent publication of ED50s that prevent response to a noxious stimulus for eight fluorobenzenes has made it possible to compare anesthetic potency with ab initio Hartree-Fock calculations of molecular polarizability as well as dipole and quadrupole moments. Fluorobenzenes provide a stringent test of the role of electric moments in anesthetic potency because individual dipole moments range from 0 to 2.84 debye (D) while the quadrupole moment of benzene is large and negative (-30 x 10(-40) C m(2)), that of hexafluorobenzene is large and positive (30 x 10(-40) C m(2)), and that of 1,3,5-trifluorobenzene is nearly zero. We found that anesthetic potency of fluorobenzenes was not affected by the presence of either dipole or quadrupole moments. This result is surprising because fluoroalkanes and fluorocycloalkanes are most potent when half fluorinated and are usually not anesthetics when perfluorinated. The results suggest that electrostatic interactions are not important for binding of fluorobenzenes at sites of anesthetic action and that these sites are different from those that bind conventional anesthetics.
Trudell
J R
JR
Department of Anesthesiology and Center for Molecular and Genetic Medicine, Stanford School of Medicine, Stanford, CA 94305-5117, USA. trudell@leland.stanford.edu