Quinolizidine derivatives as potent antiarrhythmic agents

Recently a number of lidocaine, mexiletine and procainamide analogues were synthesized, replacing their aminoalkyl chains with the rigid and cumbersome quinolizidine nucleus [I]. Most compounds exhibited from moderate to high antiarrhythmic activity, resulting in several cases more active and potent than quìnidìne and lidocaine. Moreover, while quinidine and amiodarone produced a dose dependent prolongation of all the ECC intervals, our best compounds, 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. These interesting characteristics seem Lo be connected with the presence of quinolizidine ring, and therefore we deemed worthy to investigate other derivatives of these peculiar bicyclic systems. At the moment, sixteen compounds corresponding to the general structures I-IV have been prepared and tested using isolated guinea pig left and right atria electrically driven%2