Pharmacologically active conformation of disopyramide: evidence from apparent pKa measurements.

We have found evidence that an intramolecular hydrogen bond exists between the amido and pyridine groups of disopyramide in aqueous solutions. This conclusion was reached by a comparison of the pKa values for the basic nitrogen atoms of certain analogues of disopyramide. By comparing the pharmacological actions of disopyramide with those of pheniramine, which lacks an amido group, we have concluded that the constraint on the rotation of the pyridine ring which is imposed by the hydrogen bond is a major determinant of the antiarrhythmic activity. That constraint is, at the same time, a suppressor of the anticholinergic activity. We then concluded that a covalent link would hold the pyridine ring, and the amido group, in the desirable conformation permanently, which would lead to better antiarrhythmic activity and a lower degree of anticholinergic activity. Pharmacological studies on such new molecules are in general agreement with these concepts.