S-15176 and its methylated derivative suppress the CsA-insensitive mitochondrial permeability transition and subsequent cytochrome c release induced by silver ion, and show weak protonophoric activity

A recent report has described that S-15176 (N-[(3,5-di-tert-butyl-4-hydroxy-1-thiophenyl)]-3-propyl-N′-(2,3,4-trimethoxybenzyl) piperazine), an anti-ischemic agent, inhibits the mitochondrial permeability transition (PT) induced by not only Ca2+ and inorganic phosphate, but also by tert-butylhydroperoxide or phenylarsine oxide [Morin et al. (Biochem Pharmacol 72:911–918, 2006)]. In the present study, we tested the effects of S-15176 on the PT induced by Ag+, PT of which is not suppressed by cyclosporin A or oligomycin. S-15176 was effective in suppressing the PT and the subsequent cytochrome c release induced by Ag+, and hence, it was concluded to be a more universal PT inhibitor than cyclosporin A or oligomycin. In addition to the PT-suppression activity, S-15176 also showed weak protonophoric activity. Thus, we further tested to investigate whether the hydroxyl group of S-15176 was involved in its PT-suppression or weak protonophoric activities. The methylated derivative of S-15176 also showed both PT suppression and weak protonophoric activities; hence, the hydroxyl group of S-15176 was concluded not to be involved in these activities.