A Subset of Highly Effective Propafenone-Type Multidrug Resistance Modulators Lacks Effects on Cardiac Action Potential and Mechanical Twitch Parameters of Rat Papillary Muscles

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 307; no. 2; pp. 589 - 596
• Main Authors: Schmid, Diethart, Staudacher, Dawid L, Loew, Hans G, Spieckermann, Paul G, Ecker, Gerhard F, Kopp, Stephan, Chiba, Peter
• Format: Journal Article
• Language: English
• Published: United States American Society for Pharmacology and Experimental Therapeutics 01.11.2003
• Subjects: Action Potentials - drug effects; Action Potentials - physiology; Animals; Anti-Arrhythmia Agents - chemistry; Anti-Arrhythmia Agents - pharmacology; Biological Transport - drug effects; Drug Resistance, Multiple; Heart - drug effects; Heart - physiology; Kinetics; Male; Papillary Muscles - drug effects; Papillary Muscles - physiology; Propafenone - chemistry; Propafenone - pharmacology; Rats
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.103.052993

In this study, we tested a series of 12 previously identified, highly effective propafenone-type multidrug resistance (MDR) modulators for their possible undesirable effects on cardiac tissue. We used rat papillary muscle preparations and quantitatively determined the potency of these substances to block action potential (AP) upstroke velocity ( V max ) and to prolong APD 50 . Simultaneously, the effects on isometric twitch parameters were evaluated. Concentration-response curves were obtained for all parameters. Within a subset of the compounds, we found a significant rank correlation ( r ′ = 0.87; p < 0.05) between potencies to block V max ( k i Vmax ) and to inhibit daunomycin efflux in MDR cells (IC 50 ). Surprisingly, the most lipophilic compounds with additional aromatic side chains completely lacked effects on AP and mechanical twitch parameters, although they are the most effective MDR modulators. Additional structural modifications such as fluoride substitution of the aromatic ring, introduction of arylpiperazine or piperidine side chains, as well as modifying the hydrogen bond acceptor strength of the carbonyl group did not reestablish cardiac side effects. In contrast, when these substances were truncated at the phenylpropiophenone moiety of the propafenone core structure, cardiac effects reoccurred. We conclude that aromatic substituents in the vicinity of the nitrogen atom prevent interaction with ion channels, likely due to steric hindrance, and are thus a prerequisite for eliminating unwanted cardiac effects.