Mechanism of inhibition of sodium- and potassium-dependent adenosine triphosphatase by tricyclic antipsychotics

The interaction of the thioxanthene derivative flupenthixol and its phenothiazine analogue, fluphenazine, with brain (Na+ + K+)-ATPase [Mg++-dependent, (Na+-K+)-activated ATP phosphohydrolase, EC. 3.6.1.3] and the associated potassium-dependent p-nitrophenyl phosphatase (EC. 9.6.1.7) was studied under conditions preventing formation of semiquinone free radicals of the drugs. Inhibition of (Na+ + K+)-ATPase is enhanced by MgxATP and antagonized by both sodium and potassium. The influence of pH indicates that both drugs are more effective in the unprotonated, lipophilic form. The data on formation of 32P-labeled enzyme suggest that phosphorylation of the enzymatic protein is affected by the two drugs. Inhibition of K+-dependent p-nitrophenyl phosphatase is competitively antagonized by potassium. It is proposed that flupenthixol and fluphenazine bind to the enzyme-substrate complex, preventing subsequent activation by sodium and potassium. No differemce was recorded between the thioxanthene and the phenothiazine derivative.