Polyamine analogue antiarrhythmics.
A group of polyamine analogues was assessed for their ability to prevent isoproterenol-induced ventricular fibrillation and death in a desoxycorticosterone acetate (DOCA)/saline rodent model. The compounds tested included polyamine antimetabolites and putrescine mimics. A structure-activity analysis revealed that tetraamines that are dicationic at physiological pH with their terminal nitrogens incorporated into pyridine rings are the most active analogues. It is clear from this study that there was no correlation between the compounds' ability to diminish polyamine metabolism and their effects on the electrical properties of the heart. In fact, the most potent polyamine antimetabolites were among the least effective antiarrhythmics. The most active of the compounds investigated, N1, N3-bis(4-pyridyl)-1,3-diaminopropane, PYR(3,3,3), was shown to both prevent isoproterenol-induced arrhythmias in DOCA/saline-treated rodents and reverse the progression of arrhythmic events that would otherwise culminate in ventricular fibrillation and death. Electrocardiographic tracings demonstrated that PYR(3,3,3) and propranolol both protect from and reverse the progression of arrhythmic events to ventricular fibrillation. In addition, cardiac pathologies from rats treated with both drugs are similar, but are substantially different from the control (isoproterenol)-treated animals. (c) 1998 The Italian Pharmacological Society.
Bergeron
R J
RJ
Department of Medicinal Chemistry, College of Pharmacy, Gainesville, FL, 32610-0485, USA.
Wiegand
J
J
Weimar
W R
WR
Snyder
P S
PS
D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use*; D004562:Electrocardiography / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D007473:Ion Channels / Q000187:drug effects*; D007545:Isoproterenol; D008297:Male; D065108:Ornithine Decarboxylase Inhibitors; D011073:Polyamines / Q000378:metabolism / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D014693:Ventricular Fibrillation / Q000139:chemically induced / Q000517:prevention & control*
D000889:Anti-Arrhythmia Agents; D004791:Enzyme Inhibitors; D007473:Ion Channels; D065108:Ornithine Decarboxylase Inhibitors; D011073:Polyamines; D007545:Isoproterenol