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.

Satoshi Kawashima, Takenori Yamamoto, Yuka Horiuchi, Kengo Fujiwara, Shunichi Gouda, Yuya Yoshimura, Atsushi Yamamoto, Yuki Inotani, Kikuji Yamashita, Seiichiro Kitamura, Hiroshi Terada, Makoto Kanematsu, Kozo Shishido, Yasuo Shinohara

Index: Mol. Cell Biochem. 358(1-2) , 45-51, (2011)

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Abstract

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 Ca(2+) 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.