2D-and 3D-QSAR of Tocainide and Mexiletine analogues acting as Nav1.4 channel blockers

Enantiomeric forms of Tocainide. Mexiletine, and structurally related local anaesthetic compounds, were analyzed with respect to their potency in blocking Na(v)1.4 channel. Structure-activity relationships based on in vitro pharmacological assays, suggested that an increase in terms of lipophilicity and/or molecular surface as well as the presence of specific polar spacers might be determinant for receptor interactions. QSAR and pharmacophore models were then used to support at 3D level this hypothesis. (C) 2008 Elsevier Masson SAS. All rights reserved.