Molecular-dynamics and NMR investigation of the property space of the zwitterionic antihistamine cetirizine

The zwitterionic antihistamine cetirizine and its parent drug hydroxyzine a s reference compound were examined for their 3D structures and dynamics. Af ter attributing, by NMR spectroscopy, the two basic pK(a) values. the most common conformations for each electrical species were determined by molecul ar-dynamics simulations and confirmed by NMR measurements. For cetirizine, the results demonstrate that the zwitterion, which is the predominant speci es at physiological pH, exists as folded conformers able to partly mask pol ar groups. Extended and folded conformers of similar energy were also found for neutral hydroxyzine. whereas its monocationic species displayed folded conformers stabilized by intramolecular H-bonds. These findings are in lul l agreement with previous results on the lipophilicity behavior of cetirizi ne in isotropic solvent systems and, taken together, could explain the favo rable pharmacokinetic properties of the drug.