Molecular modelling analysis of the metabolism of diazepam

Fazlul Huq^* and Zahed Hossain

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

Abstract: Diazepam (DZ) is used as a tranquilizer, anticonvulsant, muscle relaxant and psychostimulant. However, it has a number of side effects including abdominal cramps, dry mouth, increased heart beat, slurred speech, convulsions, hallucinations, memory loss, breathing problems, ataxia, headache, blurred vision, diplopia, confusion, venous thrombosis and phlebitis. It may also potentiate the effects of other drugs that cause drowsiness. DZ is metabolized by hepatic cytochrome P450 enzymes CYP3AP and CYP2C19 by N-demethylation and hydroxylation at C3 to produce three major pharmacologically active metabolites : N-desmethyldiazepam (NDZ), temazepam (TMZ), and oxazepam (OXZ) that are excreted in the urine. In addition, two minor metabolites may be produced by hydroxylation at the para-position of the not-fused aromatic ring. Molecular modelling analyses show that DZ and its metabolites have similar kinetic lability but differ in their thermodynamic stability and solubility in water. Based on the results of the analyses neither DZ nor any of its metabolites can be eliminated from being the cause of toxicity and side effects due to the drug. The results of the analyses also indicate that carbonyl oxygen atom and the two nitrogen centres are more likely to be subject to electrophilic attack. Also, commonness in surface locations of the negative regions may mean that DZ and its pharmacologically active metabolites interact with the positive centres of the receptor(s) via these positions leading to the formation of strong hydrogen bonds and may induce similar polarisation effects in receptor(s).

Key words: Diazepam, psychotic disorders, epilepsy, molecular modelling

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