Albuquerque Bárbara
| Evaluation of mitochondrial toxicity induced by a novel COMT inhibitor |
| Bárbara Albuquerque1, Carla Lima2, Sofia Benfeito1, Daniel Chavarria1, Carlos Fernandes1, Paula Serrão1, Fernanda Borges1,2, Patrício Soares-da-Silva1 1 RISE-Health, Department of Biomedicine, Pharmacology and Therapeutics Unit, Faculty of Medicine, University of Porto, Alameda Prof. Hernâni Monteiro, 4200-319 Porto, Portugal 2 RISE-Health, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Rua do Campo Alegre s/n, 4169-007 Porto, Portugal |
| Abstract Catechol-O-methyltransferase (COMT) inhibitors are commonly used for treating Parkinson’s disease (PD) and potentially useful in other neuropsychiatric pathologies characterized by low dopamine levels in the brain. Currently available COMT inhibitors face limitations such as adverse reactions and low bioavailability [1], such as tolcapone (here used as reference compound), a COMT inhibitor that acts in the central nervous system, but with reported hepatocellular injury and acute liver failure. Compound 9 is a novel, brain-selective, non-nitrocatechol COMT inhibitor developed to overcome these issues [2]. In this study, the toxicological profile of compound 9 was evaluated by assessing its effect on cell mass, oxidative stress, ATP production, and mitochondrial membrane potential (Δψm). Human neuroblastoma (SK-N-SH) and hepatocarcinoma (HepG2) cells were treated with compound 9 or tolcapone (0.3–30 µM) for 24 or 48h. Tolcapone decreased cellular viability in both cell lines, characterized by a marked reduction in cell mass and severe ATP depletion, particularly at concentrations above 10 µM. These effects were accompanied by increased oxidative stress and a biphasic Δψm response-initial depolarization followed by hyperpolarization-consistent with mitochondrial uncoupling and hepatotoxicity [3]. In contrast, compound 9 exhibited a higher safety profile. Both cell mass and ATP homeostasis were not significantly affected across the tested concentration range, with oxidative responses suggestive of cellular adaptation rather than cytotoxic damage. Furthermore, Δψm remained largely stable, indicating minimal interference with mitochondrial function. To conclude, the novel brain-selective COMT inhibitor displayed a safer mitochondrial profile than tolcapone, supporting its potential as a promising candidate for further development. |
| References [1] Silva, TB. et al. Liver says no: the ongoing search for safe catechol O-methyltransferase inhibitors to replace tolcapone. Drug discov. today. 2020, 25(10), 1846–1854. doi: 10.1016/j.drudis.2020.07.015 [2] Benfeito, S. et al. Discovery of a Potent, Selective, and Blood-Brain Barrier Permeable Non-nitrocatechol Inhibitor of Catechol-O-methyltransferase. J. Med. Chem. 2024, 67(20), 18384–18399. doi: 10.1021/acs.jmedchem.4c01682 [3] Pinto, M. et al. Cellular and Mitochondrial Toxicity of Tolcapone, Entacapone, and New Nitrocatechol Derivatives. ACS Pharmacol. Transl. Sci. 2024, 7(5), 1637–1649. doi: 10.1021/acsptsci.4c00124 Acknowledgments: This work was funded by FEDER funds through the Operational Program Competitiveness Factors COMPETE and national funds by the FCT-Foundation for Science and Technology under research grants for RISE-Health (UID/06397/2025, https://doi.org/10.54499/UID/06397/2025) and RESTORE (COMPETE2030-FEDER-00776500 and 2023.17955.ICDT; https://doi.org/10.54499/2023.17955.ICDT). B.A. (UIDB/04308/2020), C.L. (UI/BD/154557/2023 – https://doi.org/10.54499/UI/BD/154557/2023) grants and S.B. (2023.06106.CEECIND/CP2833/CT0003 – https://doi.org/10.54499/2023.06106.CEECIND/CP2833/CT0003), D.C. (2024.07926.CEECIND) and C.F (10.54499/2021.04016.CEECIND/CP1655/CT0004) contracts were also supported by FCT and FEDER/COMPETE funds. |