Clomipramine and related structures as inhibitors of the skeletal sarcoplasmic reticulum Ca2+ pump.

The Ca2+-pumping activity of skeletal sarcoplasmic reticulum vesicles is half-maximally inhibited by 120 microM clomipramine, 250 microM desipramine, and 500 microM imipramine or trimipramine. The inhibition is attributed to the dihydrodibenzazepine moiety, since 3-(dimethylamino)propionitrile, reproducing the aliphatic amine chain, has no inhibitory action. The inhibition is shown as a marked decrease of Ca2+ binding at equilibrium in the absence of ATP and as a reduction of phosphorylation of the Ca2+-free conformation by inorganic phosphate. Therefore, the drug effect is consistent with preferential interaction of tricyclic antidepressants with the Ca2+-free conformation of the nonphosphorylated enzyme. An additional decrease in the apparent rate constant of enzyme dephosphorylation, i.e., in the release of phosphate from ATP during enzyme cycling was also noticed.