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

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 (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 (rЈ ϭ 0.87; p Ͻ 0.05) between potencies to block V max (ki 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.

Optimization of Propafenone Analogues as Antimalarial Leads

“…With these parameters in mind, the initial medicinal chemistry plan incorporated two key elements: (1) incorporating fluorines at the 5- and 4′-positions of propafenone to modulate metabolism in order to increase and normalize the elimination half-life across species and within humans − and (2) exploring alkyl amines that have been shown in other lead series to modulate interaction with ion channels …”

Characterization of a novel class of antimalarials and its applicability to plasmodial target identification

“…Previous studies by our group, however, demonstrate that several of the analogues lack cardiac activity. For example the highly active compound GPV576 lacks cardiac activity as indicated by studies on cardiac action potential and mechanical twitch parameters of rat papillary muscle preparations [10]. In addition, IC50 values in the low nanomolar range compare favourably with therapeutically achievable plasma concentration of the parental drug propafenone.…”

Impact of the Recent Mouse P‐Glycoprotein Structure for Structure‐Based Ligand Design

“…Finally, there is experimental evidence that some of the compounds described as inhibitors are stimulating the ATPase activity of P‐gp, thus indicating that they are substrates (propafenones,95, 96 verapamil,97 cyclosporine98). This adds another layer of complexity, especially when considering the fact that within the structurally analogous series of propafenone analogs some compounds inhibited the ATPase activity, some stimulated it in low concentrations and inhibited it in high concentrations and some compounds showed only ATPase stimulation, but no inhibition 96. To explain these data on a structural basis, intense studies on the dynamics of the transporter combined with detailed investigations of the coupling of ATP‐binding to TMD movement need to be performed.…”

“…As outlined in the introductory section, P-gp inhibitors show clear SAR, but this is observed for numerous scaffolds. Finally, there is experimental evidence that some of the compounds described as inhibitors are stimulating the ATPase activity of P-gp, thus indicating that they are substrates (propafenones,[95, 96] verapamil,[97] cyclosporine[98]). This adds another layer of complexity, especially when considering the fact that within the structurally analogous series of propafenone analogs some compounds inhibited the ATPase activity, some stimulated it in low concentrations and inhibited it in high concentrations and some compounds showed only ATPase stimulation, but no inhibition.…”

“…This adds another layer of complexity, especially when considering the fact that within the structurally analogous series of propafenone analogs some compounds inhibited the ATPase activity, some stimulated it in low concentrations and inhibited it in high concentrations and some compounds showed only ATPase stimulation, but no inhibition. [96] To explain these data on a structural basis, intense studies on the dynamics of the transporter combined with detailed investigations of the coupling of ATP-binding to TMD movement need to be performed. Thus, there is definitely still a long way to go for full understanding of the structure and function of this important drug efflux pump and its 47 human homologues.…”