Synthesis and pharmacology of ethylphenidate enantiomers: the human transesterification metabolite of methylphenidate and ethanol

J Med Chem. 2005 Apr 21;48(8):2876-81. doi: 10.1021/jm0490989.

Abstract

Ethanol elevates methylphenidate (1) plasma concentrations and yields the metabolite ethylphenidate (2). The therapeutic implications are under investigation. The IC(50) for dopamine reuptake inhibition by (+)-2 was 27 nM compared to 367 nM for cocaine and 1730 nM for (-)-2. Binding selectivity for dopamine versus norepinephrine transporters was greater for (+)-2 than for cocaine. Intraperitoneal (+)-2 was approximately half as active as (+)-1 in stimulating mouse motor activity at 5 mg/kg, but (+)-2 was as active as (+)-1 at 10 mg/kg.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Cell Line
  • Cocaine / metabolism
  • Dopamine Plasma Membrane Transport Proteins
  • Esterification
  • Ethanol / metabolism*
  • Humans
  • Male
  • Membrane Glycoproteins / metabolism
  • Membrane Transport Proteins / metabolism
  • Methylphenidate / analogs & derivatives*
  • Methylphenidate / chemistry*
  • Methylphenidate / metabolism*
  • Methylphenidate / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Motor Activity / drug effects
  • Nerve Tissue Proteins / metabolism
  • Norepinephrine Plasma Membrane Transport Proteins
  • Protein Binding
  • Radioligand Assay
  • Receptors, Dopamine / metabolism
  • Receptors, Serotonin / metabolism
  • Stereoisomerism
  • Structure-Activity Relationship
  • Symporters / metabolism

Substances

  • Dopamine Plasma Membrane Transport Proteins
  • Membrane Glycoproteins
  • Membrane Transport Proteins
  • Nerve Tissue Proteins
  • Norepinephrine Plasma Membrane Transport Proteins
  • Receptors, Dopamine
  • Receptors, Serotonin
  • SLC6A2 protein, human
  • Slc6a2 protein, mouse
  • Symporters
  • Methylphenidate
  • Ethanol
  • ethylphenidate
  • Cocaine