Novel quinolizidinyl derivatives as antiarrhythmic agents

Eighteen analogues of lidocaine, mexiletine, and procainamide were synthesized, replacing their aminoalkyl chains with the rigid and cumbersome quinolizidine nucleus. The target compounds were tested for antiarrhythmic, inotropic, and chronotropic effects on isolated guinea pig (gp) heart tissues and to assess calcium antagonist activity. Most compounds exhibited from moderate to high antiarrhythmic activity, and compounds 7, 9, and 19 were more active and potent than quinidine and lidocaine, while producing only modest inotropic, chronotropic, and vasorelaxant effects. These compounds were studied on spontaneously beating Langendorff-perfused gp heart. While quinidine and amiodarone produced a dose-dependent prolongation of all the ECG intervals, compounds 7, 9, and 19, even at concentrations 10-20 times higher than EC50 for the antiarrhythmic activity, only moderately prolonged the PR and QT intervals, leaving unchanged the QRS complex. Ether 7 deserves further investigations due to its interesting cardiovascular profile.