Energetic and conformational study of four benzylimidazole compounds with alpha 2 agonist profile: The mivazerol and three methylated derivatives

The mivazerol and three of its methylated derivatives are studied at the ab initio SCF level within the MINI-1 and 6-31G basis sets. This study aimed at determining some probable conformations, either neutral or protonated, that could interact with the alpha 2 adrenoceptors. The solvent effect was also studied within the Onsager's solvent model at the two dielectric constant (epsilon) values of 4 and 80. The interaction with the environment (either solvent or receptor) is schematically studied by positioning either two water molecules or one formamide or/and one formic add near the amide and the imidazole for few isomers. The medium polarization, through epsilon, and the solvation effect, through the interaction with the solvent molecules or the receptor side chains, stabilize the same isomers. Post-SCF calculations are performed at the CISD level, the first excited singlet and triplet states energies are determined, and the question of the wave-function stability is addressed. The results indicate the probability of a spin-orbit coupling with the first excited triplet state, thus opening the question of such a possibility within an enzyme active site. (C) 1996 John Wiley & Sons, Inc.