Inhibition of [3H]dopamine uptake into striatal synaptosomes by isoquinoline derivatives structurally related to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

Biochem Pharmacol. 1996 Jul 12;52(1):29-34. doi: 10.1016/0006-2952(96)00133-5.


Isoquinoline derivatives structurally related to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or 1-methyl-4-phenylpyridinium (MPP+) may be endogenous neurotoxins causing nigral cell death in Parkinson's disease. These compounds inhibit mitochondrial function but, like MPP+, require accumulation in dopaminergic neurones via the dopamine reuptake system to exert toxicity. We, now, examine the substrate affinity of 14 neutral and quaternary isoquinoline derivatives (7 isoquinolines, 2 dihydroisoquinolines and 5 1,2,3,4-tetrahydroisoquinolines) for the dopamine reuptake system by their ability to inhibit the uptake of [3H]dopamine into rat striatal synaptosomes. Ten isoquinoline derivatives and MPP+ inhibited [3H]dopamine uptake in a concentration-dependent manner. Only 5 isoquinoline derivatives produced 50% inhibition of [3H]dopamine uptake (IC50 = 8.0-50.0 microM), none of which were as potent as MPP+ (IC50 = 0.33 microM). These findings suggest that isoquinoline derivatives are moderate to poor substrates for the dopamine reuptake system and that high concentrations of, or prolonged exposure to, isoquinoline derivatives may be necessary to cause neurodegeneration.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / chemistry*
  • Animals
  • Corpus Striatum / drug effects*
  • Corpus Striatum / metabolism
  • Dopamine Uptake Inhibitors / pharmacology*
  • Isoquinolines / chemistry
  • Isoquinolines / pharmacology*
  • Male
  • Rats
  • Rats, Wistar
  • Structure-Activity Relationship
  • Synaptosomes / drug effects*
  • Synaptosomes / metabolism
  • Tritium


  • Dopamine Uptake Inhibitors
  • Isoquinolines
  • Tritium
  • 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine