Physicochemical, quantum chemical, and other theoretical studies of the mechanism of action of cns agents: Anesthetics, narcotics and narcotic antagonists, and psychotropic drugs

Abstract

Pharmacological effectivity of CNS agents is governed both by lipophilicity and by topographical and electronic structure of pharmacophores. Three different classes of drugs investigated (anesthetics, narcotics and narcotic antagonists, and psychotropic drugs) depend differently on these various factors. lsonarcotic pressures of most anesthetics are proportional to &(the van der Waals' constant). This has been verified by theoretical thermodynamical derivation. Narcotic and narcotic antagonist effectivities are governed both by their lipophilicities and by electronic and topographical properties. pK,,'s, partition coefficients, and drug distribution coefficients of these drugs have been measured accurately by a microtitrimetric titration technique as a smooth function of pH and these results have been related to their clinical significance. Calculated quantum chemical electron densities and molecular orbital energies have been verified by experimental ESCA and PES measurements. Neuroleptics require not only high partition coefficients but also very specific topography. Quantum chemical calculations on a hitherto unknown series indicate that these should be effective neuroleptics; this was confirmed by subsequent report of their synthesis and testing.