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

J Psychopharmacol. 2019 Jul;33(7):831-841. doi: 10.1177/0269881119844185. Epub 2019 Apr 30.

Abstract

Background: 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.

Aim: Interactions of metabolites of MDMA, methylone and MDPV with human monoaminergic systems were assessed.

Methods: 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.

Results: 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.

Conclusions: 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.

Keywords: MDMA; MDPV; metabolite; methylone; transporter.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Benzodioxoles / pharmacology*
  • Central Nervous System Stimulants / pharmacology*
  • Dopamine / metabolism
  • HEK293 Cells
  • Humans
  • Membrane Transport Proteins / metabolism
  • Methamphetamine / analogs & derivatives*
  • Methamphetamine / pharmacology
  • N-Methyl-3,4-methylenedioxyamphetamine / metabolism*
  • Norepinephrine / metabolism
  • Pyrrolidines / pharmacology*
  • Serotonin / metabolism
  • Synthetic Cathinone

Substances

  • Benzodioxoles
  • Central Nervous System Stimulants
  • Membrane Transport Proteins
  • Pyrrolidines
  • Serotonin
  • Methamphetamine
  • N-Methyl-3,4-methylenedioxyamphetamine
  • methylone
  • Dopamine
  • Norepinephrine
  • Synthetic Cathinone