5- Molecular modelling analysis of the metabolism of loxapine

 Fazlul Huq

School of Medical Sciences, 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,

PO Box 170, Lidcombe, NSW 1825, Australia.

Telephone: +61 2 9351 9522 Fax: +61 2 9351 9520

E-mail : F.Huq@usyd.edu.au.

 Key words: Loxapine, Amoxapine, neuroleptic, psychiatric disorders, toxicity, molecular modelling

Abstract

Loxapine is a neuroleptic used in the treatment of patients with psychiatric disorders. Molecular modelling analyses based on molecular mechanics, semi-empirical (PM3) and DFT (at B3LYP/6-31G* level) calculations show that the metabolites 7-OH-Loxapine, 7-OH-amoxapine and loxapine-N-oxide have smaller LUMO-HOMO energy differences than loxapine or its other metabolites, so that they would be more reactive kinetically. The molecular surface of loxapine-N-oxide is also found to abound in electron-deficient regions so that the metabolite can react readily with cellular antioxidant glutathione and nucleobases in DNA, thus causing depletion of glutathione and damage to DNA. Depletion of reduced form of glutathione may induce cellular toxicity by compromising the antioxidant status of the cell whereas oxidation of nucleobases in DNA would cause DNA damage.

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