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Molecular-Dynamics and NMR Investigation of the Property Space of the Zwitterionic Antihistamine Cetirizine

✍ Scribed by Giuseppe Ermondi; Giulia Caron; Géraldine Bouchard; Georgette Plemper van Balen; Alessandra Pagliara; Teresa Grandi; Pierre-Alain Carrupt; Roberta Fruttero; Bernard Testa

Publisher
John Wiley and Sons
Year
2001
Tongue
German
Weight
197 KB
Volume
84
Category
Article
ISSN
0018-019X

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✦ Synopsis

The zwitterionic antihistamine cetirizine and its parent drug hydroxyzine as reference compound were examined for their 3D structures and dynamics. After attributing, by NMR spectroscopy, the two basic pK a values, the most common conformations for each electrical species were determined by molecular-dynamics simulations and confirmed by NMR measurements. For cetirizine, the results demonstrate that the zwitterion, which is the predominant species at physiological pH, exists as folded conformers able to partly mask polar 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 full agreement with previous results on the lipophilicity behavior of cetirizine in isotropic solvent systems and, taken together, could explain the favorable pharmacokinetic properties of the drug.

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