1,5-Disubstituted-1,2,3-triazoles as inhibitors of the mitochondrial Ca2+-activated F1FO-ATP(hydrol)ase and the permeability transition pore

The mitochondrial permeability transition pore (mPTP), a high-conductance channel triggered by a sudden Ca(2+)concentration increase, is composed of the F1FO-ATPase. Since mPTP opening leads to mitochondrial dysfunction, which is a feature of many diseases, a great pharmacological challenge is to find mPTP modulators. In our study, the effects of two 1,5-disubstituted 1,2,3-triazole derivatives, five-membered heterocycles with three nitrogen atoms in the ring and capable of forming secondary interactions with proteins, were investigated. Compounds3aand3bwere selected among a wide range of structurally related compounds because of their chemical properties and effectiveness in preliminary studies. In swine heart mitochondria, both compounds inhibit Ca2+-activated F1FO-ATPase without affecting F-ATPase activity sustained by the natural cofactor Mg2+. The inhibition is mutually exclusive, probably because of their shared enzyme site, and uncompetitive with respect to the ATP substrate, since they only bind to the enzyme-ATP complex. Both compounds show the same inhibition constant (KMODIFIER LETTER PRIMEi), but compound3ahas a doubled inactivation rate constant compared with compound3b. Moreover, both compounds desensitize mPTP opening without altering mitochondrial respiration. The results strengthen the link between Ca2+-activated F1FO-ATPase and mPTP and suggest that these inhibitors can be pharmacologically exploited to counteract mPTP-related diseases.