Para-Halogenation Affects Monoamine Transporter Inhibition Properties and Hepatocellular Toxicity of Amphetamines and Methcathinones

Conclusion All investigated compounds inhibited norepinephrine uptake at submicromolar concentrations and dopamine uptake at low micromolar concentrations. In addition, para-fluorination and para-chlorination increased the potential to inhibit serotonin uptake, which could result in severe serotonergic neurotoxicity. In comparison to the non-halogenated compounds, para-halogenation of amphetamine and methcathinone furthermore increased the cytotoxicity of the respective derivatives in HepG2 cells. The results of this study suggest mitochondrial toxicity for amphetamine and its halogenated derivatives as well as for 4-chloromethcathinone. Methcathinone and 4-fluoromethcathinone may potentially disrupt mitochondrial function as well; however, this was not observed at investigated concentrations in this study (≤2 mM). The potent monoamine transporter inhibition potential of the substances indicates that adverse effects are most likely linked to sympathomimetic toxicity, which is consistent with clinical intoxication reports (Knippels et al., 2017; Wijers et al., 2017; Hondebrink et al., 2018). Direct cellular mechanisms, such as mitochondrial toxicity, may, however, additionally play a contributory role in susceptible users. Author Contributions DL, SK, and ML designed the research. DL, MW, XZ, and DR conducted the research. DL, DR, SK, and ML analyzed the data. DL, SK, and ML wrote the manuscript with significant input from all the ...
Source: Frontiers in Pharmacology - Category: Drugs & Pharmacology Source Type: research