The basic distinguishing feature of multidrug resistant (MDR) cells is
a decrease in steady-state drug levels as compared to drug-sensitive
controls. It is well-known that verapamil increases the sensitivity of
MDR cells to drugs, thus reverting drug resistance. A limiting factor
for its clinical use is the pronounced cardiovascular effects of the
calcium channel antagonist which occur at the high plasma concentratio
ns required to block P-glycoprotein transport efficiently. From a clin
ical point of view, it is important to find verapamil derivatives with
low calcium channel blocking activity and high reverting activity. Th
is was the aim of the present study. In this context we have investiga
ted the ability of 20 verapamil analogues with restricted molecular fl
exibility to increase cellular accumulation of anticancer drugs and ov
ercome resistance, and their inotropic, chronotropic, and slow calcium
channel antagonistic activity. In this study an anthracycline derivat
ive 4'-O-tetrahydropyranyl adriamycin, and an erythroleukaemia K562 ce
ll line were used. Three of the 20 derivatives checked were completely
devoid of calcium channel blocking activity while exhibiting MDR reve
rting ability comparable to that of verapamil. These derivatives could
be useful for the treatment of MDR in cancer patients and for the des
ign and development of other verapamil derivatives.