1,5‐Disubstituted‐1,2,3‐triazoles as inhibitors of the mitochondrial Ca 2+ ‐activated F 1 F O ‐ATP(hydrol)ase and the permeability transition pore

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The mitochondrial permeability transition pore (mPTP), a high‐conductance channel triggered by a sudden Ca 2+ concentration increase, is composed of the F 1 F O ‐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. Compounds 3a and 3b were 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 Ca 2+ ‐activated F 1 F O ‐ATPase without affecting F‐ATPase activity sustained by the natural cofactor Mg 2+ . 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 ( K ʹ i ), but compound 3a has a doubled inactivation rate constant compared with compound 3b . Moreover, both compounds desensitize mPTP opening without altering mitochondrial respiration. The results strengthen the link between Ca 2+ ‐activated F 1 F O ‐ATPase and mPTP and suggest that these inhibitors can be pharmacologically exploited to counteract mPTP‐related diseases.