Metabolites of the popular illicit drugs MDMA, methylone, and MDPV can interact with human monoamine transporters and receptors at concentrations relevant to their pharmacological effects. MDMA and methylone inhibited norepinephrine uptake more potently than dopamine or serotonin uptake. N-demethylation of MDMA did not change its uptake inhibition profile, but N-demethylation of methylone reduced overall potency. Opening the methylenedioxy ring produced catechol metabolites that maintained norepinephrine and dopamine uptake inhibition but had much weaker effects on serotonin uptake. Further O-methylation of these catechols reduced norepinephrine uptake inhibition, yielding metabolites without significant stimulant properties. N-demethylated metabolites of MDMA and methylone circulate unconjugated and may contribute to the drugs' effects in human users.
Halogenated derivatives of amphetamine-type stimulants, such as 4-fluoroamphetamine and 4-chloroamphetamine, inhibit the norepinephrine transporter at submicromolar concentrations and the dopamine transporter at low micromolar concentrations. As the size of the para-substituent increases, selectivity shifts from dopamine to serotonin transporter inhibition, resulting in potent serotonin uptake inhibition. All tested compounds deplete cellular ATP at lower concentrations (0.25–2 mM) than they cause cell membrane integrity loss (≥0.5 mM), indicating mitochondrial toxicity. The toxicity rank order for para-substituents is chloride > fluoride > hydrogen. Para-halogenation increases the risk of serotonergic neurotoxicity and may heighten hepatic toxicity through mitochondrial impairment.