INTRODUCTION

Narcolepsy is a disorder of the Central Nervous System (CNS) characterized by symptoms that include Excessive Daytime Sleepiness (EDS) with involuntary sleep episodes, cataplexy, hypnagogic hallucinations and sleep paralysis (Wong et al., 1999b). It affects about 125,000 people in the United States and appears to have a genetic basis. Modafinil (MDF, 2-[diphenylmethyl)sulfinyl] acetamide) is a unique wake-promoting agent that facilitates wakefulness in a variety of clinical models including narcolepsy, obstructive sleep apnea and shift work sleep disorder (Arnulf et al., 1997). Pateinets who are treated with antiepileptic agents frequently complain of cognitive and sedative side-effects that may limit daily function and maximum dosage in seizure management (Smith, 2003). MDF can be used to reduce such side-effects. The daily dose of MDF in the treatment of excessive daytime sleepiness in patients with narcolepsy ranges from 200 to 300 mg. Taken orally, MDF is readily absorbed reaching peak plasma concentrations within 2 to 4 h after administration. Although the exact mechanism of action of MDF is not known, it is believed to be different from those of CNS stimulants such as amphetamine or methylphenidate (Wong et al., 1999a; Engber et al., 1998).

MDF is an optically molecule with a chiral center at the sulfur atom, with both the enantiomers being equally pharmacologically active. The elimination half-life of MDF is approximately 12-15 h, which is largely reflective of the long-lived l-enantiomer. The drug is metabolized predominantly in the liver and excreted mainly as metabolites via kidney (Hellriegel et al., 2002). Metabolism is largely via amide hydrolysis and to a smaller extent by cytochrome P450-mediated oxidative pathways. The major metabolite of MDF is modafinil acid (MDFA, 2-[(diphenylmethyl) sulfinyl] acetic acid) which is not pharmacologically active. Another circulating metabolite is modafinil sulfone (MDFS, 2-[(dimethyl) sulfinyl acetamide) and a minor metabolite is phenylthio-acetic acid (PTAA). MDF is found to produce a concentration-dependent induction of CYP3A4 and CYP3A5 activity (Hellriegel et al., 2002) suggesting that there is potential for metabolic drug-drug interactions between MDF and drugs or drug metabolites that act as substrates of CYP3A4 and CYP3A5.

In this study molecular modelling analyses have been carried of MDF and its metabolites in order to obtain a better understanding of toxicity due to MDF and its metabolites. The study was carried out in the School of Biomedical Sciences, The University of Sydney during February to June 2006.

Computational Methods

The geometries of MDF and its metabolites have been optimized based on molecular mechanics, (Fig. 1) semi-empirical and DFT calculations, using the molecular modelling program Spartan ’02 (2002). Molecular mechanics calculations were carried out using MMFF force field. Semi-empirical calculations were carried out using the routine PM3. DFT calculations were carried using the program Spartan ’02 (2002) at B3LYP/6-31G* level. In optimization calculations, a RMS gradient of 0.001 was set as the terminating condition. For the optimized structures, single point calculations were carried to give heat of formation, enthalpy, entropy, free energy, dipole moment, solvation energy, energies for HOMO and LUMO. The order of calculations: molecular mechanics followed by semi-empirical followed by DFT ensured that the structure was not embedded in a local minimum. To further check whether the global minimum was reached, some calculations were carried out with improvable structures. It was found that when the stated order was followed, structure corresponding to the global minimum or close to that could ultimately be reached in all cases. Although RMS gradient of 0.001 may not be sufficiently low for vibrational analysis, it is believed to be sufficient for calculations associated with electronic energy levels.

Fig. 1:	Metabolic pathways for MDF (Wong et al., 1999b)