Abstract
Halogenated derivatives of amphetamine-type stimulants are appearing on the drug market, often with altered pharmacological profile and sometimes different legal status compared to the non-halogenated substances. The aim of the present study was to investigate the pharmacological profile and hepatocellular toxicity of para-halogenated amphetamines and cathinones. The potential of amphetamine, 4-fluoroamphetamine, 4-chloroamphetamine, methcathinone, 4-fluoromethcathinone, and 4-chloromethcathinone to inhibit the monoamine transporters for norepinephrine, dopamine, and serotonin was determined in transporter-transfected human embryonic kidney 293 cells. Cell membrane integrity, ATP content, oxygen consumption rate, and superoxide levels were measured in human hepatoma HepG2 cells after exposure to the substances for 24 h. All compounds inhibited the norepinephrine transporter at submicromolar concentrations and the dopamine transporter at low micromolar concentrations. The selectivity of the compounds to inhibit the dopamine versus serotonin transporter decreased with increasing size of the para-substituent, resulting in potent serotonin uptake inhibition for the halogenated derivatives. All substances depleted the cellular ATP content at lower concentrations (0.25–2 mM) than cell membrane integrity loss occurred (≥0.5 mM), suggesting mitochondrial toxicity. The amphetamines and 4-chloromethcathinone additionally impaired the mitochondrial respiratory chain, confirming mitochondrial toxicity. The following toxicity rank order for the para-substituents was observed: chloride > fluoride > hydrogen. In conclusion, para-halogenation of stimulants increases the risk for serotonergic neurotoxicity. Furthermore, para-halogenation may increase hepatic toxicity mediated by mitochondrial impairment in susceptible users.
Highlights
Halogenation of illicit amphetamine-type substances represents a tool to create novel designer drugs in clandestine chemistry
A significant and concentration-dependent depletion of ATP was observed at 0.1 mM for 4-chloroamphetamine; FIGURE 2 | Monoamine uptake inhibition in stably transfected human embryonic kidney (HEK) 293 cells that expressed the human NET, DAT, or SERT
In comparison to the non-halogenated compounds, para-halogenation of amphetamine and methcathinone increased the cytotoxicity of the respective derivatives in HepG2 cells
Summary
Halogenation of illicit amphetamine-type substances represents a tool to create novel designer drugs in clandestine chemistry. Other para-halogenated stimulants (Figure 1), such as 4-fluoroamphetamine (4-FA), 4-fluoromethcathinone (flephedrone), and 4-chloromethcathinone (clephedrone), have recently appeared on the recreational drug market (Brandt et al, 2010; Taschwer et al, 2014; Linsen et al, 2015; Odoardi et al, 2016; Grifell et al, 2017; Tomczak et al, 2018), but their pharmacological properties and toxicity are currently not well investigated. Considering the lack of knowledge about the pharmacological and toxicological properties of the halogenated amphetamine and methcathinone (β-keto N-methylamphetamine) derivatives, the current study had two principle aims. We wanted to determine the effect of para-halogenation of amphetamine and methcathinone on the stimulant-type pharmacological potency of these compounds. We investigated the impact of para-halogenation of amphetamine and methcathinone on the toxicological profile of these compounds. We aimed on the one hand to assess the hepatotoxic potential of these drugs and on the other hand to put this potential into perspective to their stimulant properties, which may put users at risk of sympathomimetic toxicity
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