Anesthetic activity and the electrostatic potential (revisited).

A survey of the fascinating history of anesthetics and the many critical findings that have improved our understanding of anesthetic activity is followed by an expanded analysis of the electrostatic potentials of 27 molecules and two noble gases with anesthetic activities ranging from high to totally inactive. We again find that an intermediate value for the internal charge separation (polarity) Π appears to be an important factor in anesthetic activity. Other electrostatic potential features that favor high anesthetic activity include the presence of at least one strongly positive site on the molecule and regions of weakly to moderately negative electrostatic potential. For 14 molecules with consistent anesthetic activity data, we find a reasonable multivariable correlation that reflects the above features and also includes a measure of molecular size, reflecting the polarizability. The commonalities found in the electrostatic potential data for the active anesthetics suggest that anesthetics interact via their positive and/or negative sites in noncovalent reversible interactions with target sites, perhaps in brain proteins.