Molecular Pharmacology, Vol 13, 216-223, Copyright © 1977 by the American Society for Pharmacology and Experimental Therapeutics

Mechanism of Inhibition of Sodium- and Potassium-Dependent Adenosine Triphosphatase by Tricyclic Antipsychotics

¹ Institute of Pharmacology, University of Padova, 35100 Padova, Italy

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 Mg·ATP 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 difference was recorded between the thioxanthene and the phenothiazine derivative.

Note:
ACKNOWLEDGMENTS I wish to express my gratitude to Dr. A. Bruni for helpful discussion and criticism of the manuscript. I also thank Drs. S. Lorenzi and C. Scarpa for help in carrying out these experiments.