Theoretical studies on local anesthetics: Procaine, lidocaine, tetracaine, bupivacaine, and dibucaine?neutral and monoprotonated

Abstract

The molecular basis of the pharmacological action of tertiary amine local anesthetics (LA) is still unclear. However, there is experimental evidence that the LA penetrates into the axon as a neutral form and acts in the charged form from the intracellular phase. In this work we report quantum chemical semiempirical results for the neutral and monoprotonated forms of procaine, lidocaine, tetracaine, bupivacaine, and dibucaine. All geometries have been fully optimized with the AM1 Hamiltonian. Solvent effects were included at the self-consistent reaction field (SCRF) approximation. We have found that the most stable conformers of positively charged LA agents are all characterized by intramolecular H-bond formation involving the protonated amine groups. INDO/S-CIS calculations have revealed that the gas-phase absorption spectra of LAs result from the superposition of the spectra of the ring π system and the carbonyl, in a large extent perturbed by intramolecular charge transfer (CT). For all studied LAs, the benzene B2u bands are very weak and the benzene B1u bands gain intensity due to symmetry breaking. Formation of intramolecular H bond strongly affects the carbonyl CT bands. On the other hand, the spectrum of dibucaine is dominated by the quinoline π system. © 1997 John Wiley & Sons, Inc.