5. Molecular
Modelling Analysis of The Metabolism of Tacrine
Fazlul Huq
Discipline of Biomedical Science, Faculty of Medicine, The
University of Sydney
C42,
75 East Street, PO Box 170, Lidcombe, NSW
1825, Australia.
Phone: 061 2 9351 9522; Fax: 061 2 9351 9520
e-mail:
f.huq@fhs.usyd.edu.au
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.
Key words:
Tacrine, Alzheimer’s disease, CYP1A, hepatotoxicity,
molecular modelling
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