RT Journal Article SR Electronic T1 A Subset of Highly Effective Propafenone-Type Multidrug Resistance Modulators Lacks Effects on Cardiac Action Potential and Mechanical Twitch Parameters of Rat Papillary Muscles JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 589 OP 596 DO 10.1124/jpet.103.052993 VO 307 IS 2 A1 Diethart Schmid A1 Dawid L. Staudacher A1 Hans G. Loew A1 Paul G. Spieckermann A1 Gerhard F. Ecker A1 Stephan Kopp A1 Peter Chiba YR 2003 UL http://jpet.aspetjournals.org/content/307/2/589.abstract AB 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 (Vmax) and to prolong APD50. 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 Vmax (kiVmax) and to inhibit daunomycin efflux in MDR cells (IC50). 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. The American Society for Pharmacology and Experimental Therapeutics