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

摘要: Abstract Cinnarizine (1-diphenylmethyl-4-(3-phenyl-2-propenyl)piperazine) and its di-fluorinated derivative flunarizine inhibit theMgATP-dependent generation of a transmembrane proton electrochemical gradient in chromaffine granule ghosts. The concentra-tions giving 50% inhibition (IC 50 ) the MgATP-dependent pH-gradient were 5.990.6 mM( n ˚6) 3.090.3mM( ˚5) for cinnarizine flunarizine, respectively. IC values inhibiting membrane potentialwere even lower, i.e. 0.1990.06 0.1590.01 ˚4) Cinnarizine(10 mM) also inhibited energy-dependent vesicular uptake [ 14 C]-dopamine (50 by 76%, from 2.190.9 to 0.5 90.6nmol:mg protein:min ( ˚5, P B0.002). (10 increased MgATPase activity ghosts 47926%( compatible with an uncoupling vacuolar H ˙ -ATPase activity. -values observed two compounds arein same range as their reported therapeutic plasma concentrations vivo, suggesting that may wellinhibit pumping catecholamine storage vesicles vivo. This mechanism action contribute tothe drug-induced parkinsonism seen side-effect drugs. © 1999 Elsevier Science Ltd. All rights reserved.