Molecular Modelling Analysis of the Metabolism of Chlorpromazine

 Fazlul Huq^* and Zahed Hossain

School of Biomedical Sciences, Faculty of Health Sciences, The University of Sydney f.huq@fhs.usyd.edu.au.,  Australia

Abstract: Chlorpromazine (CPZ) is an antipsychotic drug that is said to have revolutionized the practice of psychiatry. Before its introduction in mid-1950s, there was no regularly efficacious treatment for the most common psychotic disorders. Neuroleptics also play an ill-defined and some times controversial role in the treatment of disturbed children. The most common side effects of CPZ are dry mouth, constipation, blurred vision and tachycardia. The two major routes for the metabolism of CPZ and other tricyclic antidepressants are through the cytochrome P450 mixed-function oxidase system. These include hydroxylation of either or both aromatic rings and N-demethylation of one or both of the methyl groups associated with amine side chain, N-oxidation and sulfoxidation. Hydroxylated and N-demethylated products are found to be pharmacologically active. Molecular modelling analyses show although CPZ and its metabolites have similar difference kinetic lability except CPZNOSO which is expected to be significantly more labile. That none of the compounds is extremely labile or highly inert may mean that a clear choice on the toxicity due to the drug cannot be made. The calculated dipole moment and the solvation energy values of CPZ and its metabolites differ widely, indicating a significant difference in their aqueous solubility. CPZ is expected to be least soluble in water whereas CPZNOSO which is found to be most kinetically labile is expected to be most soluble as it has the highest solvation energy and therefore more easily excreted.

Key words: Chlorpromazine, neuroleptic, chlorpromazine N-oxide, cytochrome P450, molecular modelling

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