THEORETICAL-STUDIES ON LOCAL-ANESTHETICS - PROCAINE, LIDOCAINE, TETRACAINE, BUPIVACAINE, AND DIBUCAINE - NEUTRAL AND MONOPROTONATED

The molecular basis of the pharmacological action of tertiary amine lo cal anesthetics (LA) is still unclear. However, there is experimental evidence that the LA penetrates into the axon as a neutral form and ac ts in the charged form from the intracellular phase. In this work we r eport quantum chemical semiempirical results for the neutral and monop rotonated forms of procaine, lidocaine, tetracaine, bupivacaine, and d ibucaine. All geometries have been fully optimized with the AM1 Hamilt onian. Solvent effects were included at the self-consistent reaction f ield (SCRF) approximation. We have found that the most stable conforme rs of positively charged LA agents are all characterized by intramolec ular H-bond formation involving the protonated amine groups. INDO/S-CI S calculations have revealed that the gas-phase absorption spectra of LAs result from the superposition of the spectra of the ring pi system and the carbonyl, in a large extent perturbed by intramolecular charg e transfer (CT). For all studied LAs, the benzene B-2u bands are very weak and the benzene B-1u bands gain intensity due to symmetry breakin g. Formation of intramolecular H bond strongly affects the carbonyl CT bands. On the other hand, the spectrum of dibucaine is dominated by t he quinoline pi system. (C) 1997 John Wiley & Sons, Inc.