Fazlul Huq

Abstract

Tacrine (TAC) is a potent, centrally active, reversible, cholinesterase inhibitor, used for the treatment of mild to moderate Alzheimer’s disease. However, the use of TAC is associated with a number of adverse effects including gastrointestinal disturbances such as nausea and vomiting and hepatotoxicity. TAC is known to undergo extensive oxidative metabolism in rat and humans producing a number of mono- and di-hydroxylated metabolites catalyzed by CYP1A. Some of the hydroxylated metabolites can be further oxidized to produce corresponding ketone derivatives although no such metabolite has been detected. Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations show that TAC and all its metabolites have moderately large to large LUMO-HOMO energy differences so that none would be highly inert or extremely labile kinetically except the hypothetical metabolite 1,2-DK-TAC which is expected to be much more labile. Presence of some electron-deficient regions on the molecular surfaces means that TAC and its metabolites can react with glutathione and nucleobases in DNA, although the rates of such adverse reactions are expected to be low except in the case of 1,2-DK-TAC.