Spatial requirements of the Na channel binding site for class I antiarrhythmics as derived from the crystal structures of 4-substituted 2,6-bis(1-pyrrolidinylmethyl)phenols.

The molecular structures of four class I antiarrhythmic agents containing a bis(1-pyrrolidinylmethyl)phenol framework were determined by X-ray diffraction methods and their conformations were analyzed by molecular mechanics. Each structure has an intramolecular hydrogen bond between the phenol OH group and one pyrrolidine N atom; this bond determines the orientation of the pyrrolidine ring. Only two distinct orientations are observed for the other pyrrolidine ring; the combination of the pyrrolidine ring positions produces molecular conformers that either have the two N atoms on the same side of the phenol ring plane or have the N atoms nearly coplanar with the phenol ring. Crystallographic conformations of benzamides as well as those calculated with molecular mechanics find a preferred conformation that has the three planar regions tilted by ca. 30 degrees with respect to one another. The combined restrictions of the hydrogen bond, the conformational preferences for the bis(pyrrolidinylmethyl)phenol moiety, and a consistent conformation for the central benzamide portion provide a suggestion of the active shape of class Ic antiarrhythmic drugs. The distance between two potential recognition groups--a phenyl ring (lipophilic group) separated by 3.8 A from an oxygen atom and a secondary or tertiary amine--is found to be unique for class Ic antiarrhythmics as compared to other class I antiarrhythmics, such as lidocaine, quinidine, procainamide, and disopyramide, and suggests a correlation between the molecular structures and the activity of class I antiarrhythmics.