CIQUP-IMS/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, 4169-007, Porto, Portugal. Electronic address: fernando.fagin@fc.up.pt.
2 papers in the library · 17 citations · publishing 2023-2025
Adding an N-2-methoxybenzyl group to mescaline and related 2C phenethylamine drugs to create NBOMe compounds significantly increases their in vitro toxicity to both brain (SH-SY5Y) and liver (HepG2) cell lines. The NBOMe drugs had lower EC50 values, indicating greater potency, and were able to cross the blood–brain barrier. The increased toxicity was linked to higher lipophilicity, disruption of mitochondrial membrane potential, and depletion of glutathione and ATP levels. Inhibition of cytochrome P450 enzymes, particularly CYP3A4 and CYP2D6, influenced the drugs' toxicity, suggesting these enzymes play a role in detoxification or bioactivation. No reactive oxygen species overproduction was detected.
25I-NBOMe is significantly more cytotoxic than 2C-I in differentiated SH-SY5Y cells and primary rat cortical cultures, likely due to its higher lipophilicity. Both drugs cause severe mitochondrial dysfunction, including decreased ATP levels and mitochondrial membrane depolarization, without significant changes in reactive oxygen or nitrogen species. 25I-NBOMe also elevates intracellular calcium levels. Apoptosis occurs with both drugs, but 2C-I additionally induces autophagy and strong caspase-3 activation, suggesting caspase-3-dependent apoptosis, while 25I-NBOMe may trigger caspase-3-independent apoptosis through calcium dysregulation and direct mitochondrial damage. Mitochondrial dysfunction and calcium dysregulation are central to the neurotoxicity of these NPS.