Vol. 297, Issue 1, 260-266, April 2001

Structure-Activity Relationships and Electrophysiological Effects of Short-Acting Amiodarone Homologs in Guinea Pig Isolated Heart

Timothy E. Morey, Christoph N. Seubert, M. J. Pekka Raatikainen, Anatoly E. Martynyuk, Pascal Druzgala, Peter Milner, Mario D. Gonzalez and Donn M. Dennis

Departments of Anesthesiology (T.E.M., C.N.S., A.E.M., D.M.D.), Pharmacology and Experimental Therapeutics (D.M.D.), and Medicine, Division of Cardiology (M.D.G.), University of Florida, Gainesville, Florida; Department of Internal Medicine, Division of Cardiology, University of Oulu, Oulu, Finland (M.J.P.R.); and ARYx Therapeutics Inc., Los Altos Hills, California (P.D., P.M.)

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 µM) 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 (MAPD₉₀) 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 (MAPD₉₀) was ATI-2042  2001 = 2010 = 2064 > 2054  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.