Bifunctional agents for reperfusion arrhythmias: novel hybrid vitamin E/class I antiarrhythmics.
We have synthesized a series of hybrid compounds combining the pharmacophoric redox moieties of vitamin E and key features responsible for the antiarrhythmic properties of the class I antiarrhythmics procainamide and lidocaine. Procainamide analogue (2a) and lidocaine analogues (14a) and (14b) are very strong inhibitors of lipid peroxidation. All analogues tested at 100 or 30 microM enhanced the post ischemic recovery without inducing ventricular fibrillations while there was no evidence in our experiments for drug-induced pro-arrhythmia. In addition, they induced a widening of the QRS intervals. Our data suggest that the efficacy of the new compounds in preventing reperfusion arrhythmias could be attributed to their combined effects involving inhibition of free radical mediated damage coupled with antiarrhythmic properties.
Koufaki
Maria
M
Institute of Organic and Pharmaceutical Chemistry, National Hellenic Research Foundation, 48 Vassileos Constantinou Ave., 116 35, Athens, Greece. mkoufa@eie.gr
Calogeropoulou
Theodora
T
Rekka
Eleni
E
Chryselis
Michael
M
Papazafiri
Panagiota
P
Gaitanaki
Catherine
C
Makriyannis
Alexandros
A
D000889:Anti-Arrhythmia Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D008012:Lidocaine / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D015227:Lipid Peroxidation; D009682:Magnetic Resonance Spectroscopy; D011342:Procainamide / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D015424:Reperfusion; D014810:Vitamin E / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*
D000889:Anti-Arrhythmia Agents; D000975:Antioxidants; D014810:Vitamin E; D008012:Lidocaine; D011342:Procainamide