1. Molecular modelling analysis of the metabolism of quazepam

Fazlul Huq

School of Biomedical Sciences, Faculty of Health Sciences, The University of Sydney,

E-mail: f.huq@fhs.usyd.edu.au Australia.

(Received 30 October 2005 ; accepted 13 January 2006)

Abstract: Quazepam (Q) is a trifluoroethyl benzodiazepine hypnotic that is used in the treatment of insomnia. The main side effect of Q is daytime drowsiness. It may also potentiate the effects of other drugs that cause drowsiness or dizziness including antidepressants, alcohol, sedatives, pain relievers, anxiety medications, muscle relaxants and antihistamines. Q is rapidly and extensively metabolized in humans. First it is metabolized by substitution of sulfur with oxygen to produce 2-oxoquazepm (OQ) which is N-dealkylated to produce N-desalkyl-2-oxoquazepam (DOQ) and hydroxylated to produce 3-hydroxy-2-oxoquazepam (HOQ). DOQ is further hydroxylated to form 3-hydroxy-N-desalkyl-2-oxoquazepm (HDOQ). CYP3A4 and CYP2C9 are believed to be the main enzymes involved in the metabolism of quazepam. Molecular modelling analyses show that Q is more labile kinetically and has a lower solvation energy than any of its metabolites. Q and its metabolites differ significantly in their heats of formation and thermodynamic stability. The locations of negative electrostatic potential close to a number of atoms including the two ring nitrogen atoms and the thionyl sulfur or the carbonyl oxygen atom indicate that the positions may be subject to electrophilic attack. The overlap of the regions of negative electrostatic potential and the HOMOs with high electron density at some of the positions including the thionyl sulfur atom or the carbonyl oxygen atom give further support to the idea.

 Key words: Quazepam, CYP, 2-Oxoquazepam, N-desalkyl-2-oxoquazepam, molecular modelling

<<<