1. 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.
- Author
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Algieri V, Algieri C, Maiuolo L, De Nino A, Pagliarani A, Tallarida MA, Trombetti F, and Nesci S
- Subjects
- Animals, Mitochondria, Heart drug effects, Swine, Calcium metabolism, Membrane Potential, Mitochondrial drug effects, Mitochondria, Heart metabolism, Mitochondrial Permeability Transition Pore metabolism, Mitochondrial Proton-Translocating ATPases metabolism, Triazoles pharmacology
- Abstract
The mitochondrial permeability transition pore (mPTP), a high-conductance channel triggered by a sudden Ca
2+ concentration increase, is composed of the F1 FO -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 Ca2+ -activated F1 FO -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 (K'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 Ca2+ -activated F1 FO -ATPase and mPTP and suggest that these inhibitors can be pharmacologically exploited to counteract mPTP-related diseases., (© 2020 New York Academy of Sciences.)- Published
- 2021
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