6- Molecular modelling analysis of the metabolism of mirtazapine

 Fazlul Huq

School of Biomedical Sciences, Faculty of Health Sciences, C42, The University of Sydney, Lidcombe, NSW, Australia. Phone: 061 2 9351 9522; Fax: 061 2 9351 9520Email: f.huq@fhs.usyd.edu.au

Mirtazapine (MIR) is a second-generation antidepressant that differs in structure and mode of action from other compounds of its class. It is a nonadrenergic and specific serotonergic antidepressant that acts as an antagonist of a₂-autoreceptors and heteroreceptors, resulting in increased release of norephrine and serotonin. Dry mouth, sedation, and increase in appetite and body weight are the most common adverse side effects of the drug. However, MIR is not found to affect glucose homeostasis. MIR and its metabolites have large LUMO-HOMO energy differences so that they would be kinetically inert. Thus, although the molecular surfaces of MIR and a number of its metabolites are found to abound in electron-deficient regions so that they could potentially react with glutathione and nucleobases in DNA, the kinetic inertness of the molecules means the rates of such adverse reactions would be low. The metabolite MIR-NO has the smallest LUMO-HOMO energy difference so that it would least inert kinetically. MIR-NO also abounds most in electron-deficient regions so that its reaction with glutathione and nucleobases in DNA may be most significant. Hence the metabolite is more likely to cause oxidative stress by compromising the anti-oxidant status of the cell and more likely to cause DNA damage. 

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