Structural requirements for activity of propafenone-type modulators in P-glycoprotein-mediated multidrug resistance
Chiba, P.; Ecker, G.; Schmid, D.; Drach, J.; Tell, B.; Goldenberg, S.; Gekeler, V.
Molecular Pharmacology 49(6): 1122-1130
1996
ISSN/ISBN: 0026-895X PMID: 8649352 Document Number: 462528
The sodium channel blocker propafenone and a series of analogs have been identified as effective modulators of P-glyco-protein-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.