The impact of methylphenidate and its enantiomers on dopamine synthesis and metabolism in vitro

Prog Neuropsychopharmacol Biol Psychiatry. 2017 Oct 3;79(Pt B):281-288. doi: 10.1016/j.pnpbp.2017.07.002. Epub 2017 Jul 8.

Abstract

Methylphenidate (MPH), a psychostimulant, is an effective first-line treatment for the symptoms associated with Attention-Deficit/Hyperactivity Disorder (ADHD). Although most MPH formulations are composed of the racemic 1:1 mixture of the two enantiomers (d- and l-threo), converging lines of evidence indicate that d-threo MPH seems to be superior to the l-isomer. We aimed to investigate whether MPH racemic mixture or pure enantiomers influence the enzyme activity of tyrosine hydroxylase (TH), monoamine oxidase B (MAO-B), catechol-O-methyltransferase (COMT), and aldehyde dehydrogenase (ALDH) in vitro in homogenates of rat PC12 cells incubated with racemic, d- and l-threo MPH (1nM up to 100μM), or a vehicle for control. We could observe dose dependent enhancement of TH activity with d-threo MPH, probably due to its higher affinity to the enzyme, which we could confirm for d-threo versus l-threo MPH via docking and molecular dynamic simulations analysis. MAO-B enzyme activity was found to be enhanced when incubated with both d- and l-isomers but not with the racemic mixture. This conflicting result was hypothesized to be due to possible aggregation of the two enantiomers or other molecular conformations. Such a possible interaction was observed indirectly, when TH was incubated with constant d-threo MPH while increasing l-isomer (increasing total MPH concentrations). Hence, TH activity was slightly decreased with increased l-isomer. In conclusion, the current in vitro investigation points to the stereoselectivity of the investigated enzymes and pharmacological effects of MPH enantiomers.

Keywords: Aldehyde dehydrogenase; Catechol-O-methyltransferase; Enantiomers; Methylphenidate; Monoamine oxidase B; Tyrosine hydroxylase.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldehyde Dehydrogenase / metabolism
  • Animals
  • Catalysis / drug effects
  • Catechol O-Methyltransferase / metabolism
  • Central Nervous System Stimulants / chemistry
  • Central Nervous System Stimulants / pharmacology*
  • Dopamine / metabolism*
  • Dopamine Agents / chemistry
  • Dopamine Agents / pharmacology*
  • Dose-Response Relationship, Drug
  • Methylphenidate / chemistry
  • Methylphenidate / pharmacology*
  • Molecular Docking Simulation
  • Molecular Dynamics Simulation
  • Monoamine Oxidase / metabolism
  • PC12 Cells
  • Rats
  • Stereoisomerism
  • Tyrosine 3-Monooxygenase / metabolism

Substances

  • Central Nervous System Stimulants
  • Dopamine Agents
  • Methylphenidate
  • Tyrosine 3-Monooxygenase
  • Aldehyde Dehydrogenase
  • Monoamine Oxidase
  • Catechol O-Methyltransferase
  • Dopamine