Structural requirements for activity of propafenone-type modulators in P-glycoprotein-mediated multidrug resistance

The sodium channel blocker propafenone and a series of analogs have been identified as effective modulators of P-glycoprotein-mediated multidrug resistance in human tumor cells. A series of closely related structural homologues showed a highly significant correlation between lipophilicity and pharmacological effect. Reduction of the carbonyl group as well as conversion to a methylether led to a remarkable decrease in activity, whereby lipophilicity lost its predictive character as the main determinant for modulator potency. Similarly, the relative positioning of the acyl- and propanolamine side chains also influences activity, so the distance between carbonyl group and nitrogen atom seems important.