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Molecular modelling analysis of the metabolism of
scopolamine
Fazlul
Huq
Discipline of
Biomedical Science, Faculty of Medicine, The University of Sydney
Address reprint requests
and correspondences to:
Dr. Fazlul Huq, Discipline of Biomedical Science,
Faculty of Medicine, C42, The University of Sydney,
Lidcombe, NSW, Australia.
Abstract
Scopolamine
(SP) is a tropane alkaloid obtained from solanaceous species of plants
such as the roots of Anisodus tanguticus (maxim) Pascher used
in Chinese traditional medicine. It is the most effective single agent
to prevent nausea and vomiting associated with motion sickness.
Molecular modelling analyses based on molecular mechanics,
semi-empirical (PM3) and DFT (at
B3LYP/6-31G* level)
calculations
show that SP and its metabolites have moderately large LUMO-HOMO
energy differences ranging from
4.7 to 7.7 eV
from
DFT calculations,
indicating that the compounds would differ in their kinetic lability.
The molecular surfaces of M3, M7 and M11 appear to abound in
electron-deficient regions so they may react readily with glutathione
and nucleobases in DNA although the kinetic inertness of the molecules
may serve to reduce rates of the reactions. Reaction with glutathione
will induce cellular toxicity by compromising the antioxidant status
of the cell whereas that with nucleobases in DNA will cause DNA
damage. Since M3 is expected to be more labile than M7 and M11, such
adverse reactions may be more significant in the case of M3 than M7
and M11 even though the surface of M7 abounds more in
electron-deficient regions.
Key
words:
Scopolamine, tropane alkaloid, anaesthetic, ophthalmic effects,
molecular
modelling
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