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Year: 2006 | Volume: 1 | Issue: 4 | Page No.: 369 - 375
Abstract
Modafinil (MDF) is a unique wake-promoting agent that may be used in a variety of conditions including narcolepsy, obstructive sleep apnea and shift work sleep disorder. The mechanism of action of MDF is believed to be different from those of CNS stimulants such as amphetamine or methylphenidate. The drug is primarily metabolized in the liver and eliminated mainly as metabolites in the urine. It is based largely on amide hydrolysis and to a smaller extent proceeds via cytochrome P450-mediated oxidative pathways. Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations show that MDF and all its metabolites have large LUMO-HOMO energy differences so that they would be kinetically inert. The molecular surfaces MDF and all its metabolites are found to have electron-deficient regions so that they may be subject to nucleophilic attacks such as those by glutathione and nucleobases in DNA. Reaction with glutathione induces cellular toxicity compromising the antioxidant status of the cell whereas oxidation of nucleobases in DNA causes DNA damage. The kinetic inertness of the molecules may however mean that the rates of such adverse reactions may not be significant.