Structure-activity relationships and electrophysiological effects of short-acting amiodarone homologs in guinea pig isolated heart.
Antiarrhythmic agents with amiodarone-like electrophysiological actions, but with a more favorable pharmacokinetic profile than amiodarone would be extremely useful for the treatment of many tachyarrhythmias. We designed a series of amiodarone homologs with an alkyl ester group at position 2 of the benzofurane moiety. It was hypothesized that the electrophysiological and pharmacokinetic properties of these compounds are closely related to the size and branching of the ester group. The magnitude and time course of electrophysiological effects caused by methyl (ATI-2001), ethyl (ATI-2010), isopropyl (ATI-2064), sec-butyl (ATI-2042), and neopentyl (ATI-2054) homologs, and their common metabolite (ATI-2000) were investigated in guinea pig isolated heart. In paced hearts (atrial cycle length = 300 ms), each homolog (1 microM) was infused for 90 min followed by a 90-min washout. The stimulus-to-atrium (St-A), atrium-to-His bundle (AH), His bundle-to-ventricle (HV), QRS, and QT intervals, and ventricular monophasic action potential duration at 90% repolarization (MAPD(90)) were measured every 10 min. ATI-2001 and ATI-2064 significantly lengthened the St-A, HV, and QRS intervals, whereas ATI-2042 and ATI-2054 prolonged only the St-A interval. All compounds except the metabolite prolonged the AH interval. The relative rank order for the homologs to lengthen ventricular repolarization (MAPD(90)) was ATI-2042 > or = 2001 = 2010 = 2064 > 2054 > or = 2000. The metabolite was electrophysiologically inactive. Thus, modification of the benzofurane moiety ester group size and branching markedly altered the magnitude and time course of the electrophysiological effects caused by the ATI compounds. The different structure-activity relationships among the amiodarone homologs may have important consequences for further development of amiodarone-like antiarrhythmic agents.
Morey
T E
TE
Department of Anesthesiology, Division of Cardiology, University of Florida, Gainesville, FL 32610-0254, USA.
Seubert
C N
CN
Raatikainen
M J
MJ
Martynyuk
A E
AE
Druzgala
P
P
Milner
P
P
Gonzalez
M D
MD
Dennis
D M
DM
D000200:Action Potentials / Q000187:drug effects; D000638:Amiodarone / Q000031:analogs & derivatives / Q000494:pharmacology*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D004562:Electrocardiography / Q000187:drug effects; D006168:Guinea Pigs; D006329:Heart Conduction System / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D013329:Structure-Activity Relationship
D000889:Anti-Arrhythmia Agents; D000638:Amiodarone