The gastric proton pump, a target for neuroleptics and antidepressant drugs?

The antisecretory action of the antidepressant drugs trimipramine, doxepin and nortriptyline was studied in two different in-vitro test systems; the isolated and enriched guinea-pig parietal cell and the purified H+/K(+)-ATPase preparation. The effect of the antidepressants was compared with that of the neuroleptic agents chlorpromazine, triflupromazine, trifluperazine, haloperidol, fluspirilene and with that of the tricyclic anticholinergic agent pirenzepine. All neuroleptics and antidepressants inhibited acid formation in intact parietal cells with IC50 values in the nanomolar range. The inhibitory potency for each compound was identical regardless of whether histamine or db-cAMP was used as stimulant. Isolated H+/K(+)-ATPase, measured in the presence of 5 mmol litre-1 KCl, was inhibited by all psychotropic drugs with IC50 values in the micromolar range. EGTA did not affect the inhibitory potency at the H+/K(+)-ATPase, indicating that the action of the drugs does not depend on their calmodulin blocking activity. Pirenzepine was ineffective in both test systems. Kinetic studies done with nortriptyline, chlorpromazine and haloperidol showed a competitive type of inhibition with respect to K+ at low inhibitor concentrations. This competitive type was changed to a mixed type of inhibition with increasing inhibitor concentrations, demonstrating cooperative effects between drug binding and K+ activation of the enzyme. From these data it is suggested that antidepressants and neuroleptics act by an allosteric mechanism of action, and that the lipid solubility is a significant factor to establish enzyme inhibition.