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 an...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2007-01, Vol.50 (2), p.334-343
Main Authors: Vazzana, Iana, Budriesi, Roberta, Terranova, Emanuela, Ioan, Pierfranco, Ugenti, Maria Paola, Tasso, Bruno, Chiarini, Alberto, Sparatore, Fabio
Format: Article
Language:English
Subjects:
Amiodarone - pharmacology
Animals
Anti-Arrhythmia Agents - chemical synthesis
Anti-Arrhythmia Agents - chemistry
Anti-Arrhythmia Agents - pharmacology
Antiarythmic agents
Aorta, Thoracic - drug effects
Aorta, Thoracic - physiology
Biological and medical sciences
Cardiovascular system
Electrocardiography
Female
Guinea Pigs
Heart Rate
In Vitro Techniques
Isometric Contraction - drug effects
Lidocaine - pharmacology
Medical sciences
Muscle, Smooth, Vascular - drug effects
Muscle, Smooth, Vascular - physiology
Myocardial Contraction - drug effects
Pharmacology. Drug treatments
Procainamide - pharmacology
Quinidine - pharmacology
Quinolizines - chemical synthesis
Quinolizines - chemistry
Quinolizines - pharmacology
Stimulation, Chemical
Structure-Activity Relationship
Vasodilation - drug effects
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm060878m