Drug-induced parkinsonism: cinnarizine and flunarizine are potent uncouplers of the vacuolar H+-ATPase in catecholamine storage vesicles

Cinnarizine (1-diphenylmethyl-4-(3-phenyl-2-propenyl)piperazine and its di- fluorinated derivative flunarizine inhibit the MgATP-dependent generation o f a transmembrane proton electrochemical gradient in chromaffine granule gh osts. The concentrations giving 50% inhibition (IC50) of the MgATP-dependen t generation of the pH-gradient were 5.9 +/- 0.6 mu M (n = 6) and 3.0 +/- 0 .3 mu M (n = 5) for cinnarizine and flunarizine, respectively. The IC50 val ues for inhibiting the generation of the membrane potential were even lower , i.e. 0.19 +/- 0.06 mu M (n = 6) and 0.15 +/- 0.01 mu M (n = 4) for cinnar izine and flunarizine, respectively. Cinnarizine (10 mu M) also inhibited t he energy-dependent vesicular uptake of [C-14]-dopamine (50 mu M) by 76%, i .e. from 2.1 +/- 0.9 to 0.5 +/- 0.6 nmol/mg protein/min (n = 5, P < 0.002). Cinnarizine (10 mu M) increased the MgATPase activity of the granule ghost s by 47 +/- 26% (n = 4) compatible with an uncoupling of the vacuolar H+-AT Pase activity. The IC50-values observed for the two compounds are in the sa me range as their reported therapeutic plasma concentrations in vivo, sugge sting that cinnarizine and flunarizine may well inhibit proton pumping and catecholamine uptake in storage vesicles also in vivo. This mechanism of ac tion may contribute to the drug-induced parkinsonism seen as a side-effect of the two drugs. (C) 1999 Elsevier Science Ltd. All rights reserved.