Inhibition of cellular ATP-hydrolyzing activity by tricyclic antidepressants and phenothiazine tranquilizers

Abstract

In a variety of cellular and subcellular preparations, total ATP-hydrolyzing activity was potently inhibited by tricyclic antidepressants (TA) and phenothiazine tranquilizers (PT). In leukocytes, preincubation of the cells with 5 x 10-4 M TA and 1 x 10-4 M PT resulted in up to 87% and 94% inhibition of the ATPase activity. Among TA, dibenzocycloheptadienes were somewhat more potent inhibitors than were derivatives of dibenzazepine. Substitution, at the position 2 of the phenothiazine nucleus, by a halogen and particularly by the CF3 group, increased the inhibitory strength of PT. However, most effective in inhibiting ATPase was thioridazine, structurally differing from mesoridazine, the weakest inhibitor in this study, by a methylmercapto group instead of a methylsulfinyl substituent. The inhibition by the drugs was markedly reduced in the presence of millimolar ATP. The results indicate a possible adverse effect of these drugs on the cellular energy-yielding capacity.