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.
Vazzana
Iana
I
Dipartimento di Scienze Farmaceutiche, Università di Genova, Viale Benedetto XV 3, 16132 Genova, Italy.
Budriesi
Roberta
R
Terranova
Emanuela
E
Ioan
Pierfranco
P
Ugenti
Maria Paola
MP
Tasso
Bruno
B
Chiarini
Alberto
A
Sparatore
Fabio
F
D000638:Amiodarone / Q000494:pharmacology; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology; D004562:Electrocardiography; D005260:Female; D006168:Guinea Pigs; D006339:Heart Rate; D066298:In Vitro Techniques; D007537:Isometric Contraction / Q000187:drug effects; D008012:Lidocaine / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D009200:Myocardial Contraction / Q000187:drug effects; D011342:Procainamide / Q000494:pharmacology; D011802:Quinidine / Q000494:pharmacology; D011807:Quinolizines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013268:Stimulation, Chemical; D013329:Structure-Activity Relationship; D014664:Vasodilation / Q000187:drug effects
D000889:Anti-Arrhythmia Agents; D011807:Quinolizines; D008012:Lidocaine; D011802:Quinidine; D011342:Procainamide; D000638:Amiodarone