Correlation between antiarrhythmic activity of acyl derivatives of phenothiazine and their affinity for phospholipid membranes

Abstract

Binding constants for thirteen 10-acylaminopropionyl derivatives of phenothiazine possessing antiarrhythmic activity with model phospholipid membranes were determined by the fluorescent probe method. For ten of these substances significant correlation was observed between the binding constant and antiarrhythmic activity: Activity increased with an increase in the constant; three substances, those with the highest binding constants, however, possess low activity. The results are evidence that interaction between antiarrhythmic drugs and lipids of target membranes in vivo may be an important element in the molecular mechanism of their action. Meanwhile, very high affinity for lipids may evidently lead to delocalization of the drug in the body and to a reduction in its antiarrhythmic activity.