Mechanistic Insights into the Neurotoxicity of 2,5-Dimethoxyphenethylamines (2C) and Corresponding N-(2-methoxybenzyl)phenethylamine (NBOMe) Drugs

• Type: Article in International Scientific Journal
• Date: 2024

Authors

Gil-Martins, E (Author) Other; Fernando Cagide (Author) FCUP; Martins, D (Author) Other; Borer, A (Author) Other; Barbosa, DJ (Author) Other; Fernandes, C (Author) Other; Chavarria, D (Author) Other; Fernando Remiao (Author) FFUP; Fernanda Borges (Author) FCUP; Silva, R (Author) Other

Journal

The Journal is awaiting validation by the Administrative Services.

Title: JOURNAL OF XENOBIOTICS

Vol. 14

Pages: 772-797

ISSN: 2039-4705

Indexing

ISI Web of Knowledge - 2 Citations

Scopus - 2 Citations

Other information

Authenticus ID: P-010-NPN

DOI: 10.3390/jox14020044

Abstract (EN): Substituted phenethylamines including 2C (2,5-dimethoxyphenethylamines) and NBOMe (N-(2-methoxybenzyl)phenethylamines) drugs are potent psychoactive substances with little to no knowledge available on their toxicity. In the present in vitro study, we explored the mechanisms underlying the neurotoxicity of six substituted phenethylamines: 2C-T-2, 2C-T-4, 2C-T-7 and their corresponding NBOMes. These drugs were synthesized and chemically characterized, and their cytotoxicity (0-1000 mu M) was evaluated in differentiated SH-SY5Y cells and primary rat cortical cultures, by the NR uptake and MTT reduction assays. In differentiated SH-SY5Y cells, mitochondrial membrane potential, intracellular ATP and calcium levels, reactive oxygen species production, and intracellular total glutathione levels were also evaluated. All the tested drugs exhibited concentration-dependent cytotoxic effects towards differentiated SH-SY5Y cells and primary rat cortical cultures. The NBOMe drugs presented higher cytotoxicity than their counterparts, which correlates with the drug's lipophilicity. These cytotoxic effects were associated with mitochondrial dysfunction, evident through mitochondrial membrane depolarization and lowered intracellular ATP levels. Intracellular calcium imbalance was observed for 2C-T-7 and 25T7-NBOMe, implying a disrupted calcium regulation. Although reactive species levels remained unchanged, a reduction in intracellular total GSH content was observed. Overall, these findings contribute to a deeper understanding of these drugs, shedding light on the mechanisms underpinning their neurotoxicity.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 26