Metabolites of the ring-substituted stimulants MDMA, methylone and MDPV differentially affect human monoaminergic systems

Amphetamine analogs with a 3,4-methylenedioxy ring-substitution are among the most popular illicit drugs of abuse, exerting stimulant and entactogenic effects. Enzymatic; N; -demethylation or opening of the 3,4-methylenedioxy ring via; O; -demethylenation gives rise to metabolites that may be pharmacologically active. Indeed, previous studies in rats show that specific metabolites of 3,4-methylenedioxymethamphetamine (MDMA), 3,4-methylenedioxymethcathinone (methylone) and 3,4-methylenedioxypyrovalerone (MDPV) can interact with monoaminergic systems.; Interactions of metabolites of MDMA, methylone and MDPV with human monoaminergic systems were assessed.; The ability of parent drugs and their metabolites to inhibit uptake of tritiated norepinephrine, dopamine and serotonin (5-HT) was assessed in human embryonic kidney 293 cells transfected with human monoamine transporters. Binding affinities and functional activity at monoamine transporters and various receptor subtypes were also determined.; MDMA and methylone displayed greater potency to inhibit norepinephrine uptake as compared to their effects on dopamine and 5-HT uptake.; N; -demethylation of MDMA failed to alter uptake inhibition profiles, whereas; N; -demethylation of methylone decreased overall transporter inhibition potencies.; O; -demethylenation of MDMA, methylone and MDPV resulted in catechol metabolites that maintained norepinephrine and dopamine uptake inhibition potencies, but markedly reduced activity at 5-HT uptake.; O; -methylation of the catechol metabolites significantly decreased norepinephrine uptake inhibition, resulting in metabolites lacking significant stimulant properties.; Several metabolites of MDMA, methylone and MDPV interact with human transporters and receptors at pharmacologically relevant concentrations. In particular,; N; -demethylated metabolites of MDMA and methylone circulate in unconjugated form and could contribute to the in vivo activity of the parent compounds in human users.