Abstract
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.
Footnotes
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This work was partly supported by Austrian Science Foundation (project ASF 13851), Austrian National Bank (“Jubiläumsfonds” project OENB 8525), and Medizinisch-Wissenschaftlicher Fonds des Bürgermeisters der Bundeshauptstadt Wien (project 2047).
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DOI: 10.1124/jpet.103.052993.
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ABBREVIATIONS: P-gp, P-glycoprotein; MDR, multidrug resistance; APD, action potential duration; BDM, butanedione monoxime; AF, active developed force; VI, virtual instrument; DMSO, dimethyl sulfoxide.
- Received April 14, 2003.
- Accepted July 8, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
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