Fipamezole (JP-1730) is a potent alpha2 adrenergic receptor antagonist that reduces levodopa-induced dyskinesia in the MPTP-lesioned primate model of Parkinson's disease

Mov Disord. 2003 Aug;18(8):872-83. doi: 10.1002/mds.10464.


Previous studies in the MPTP-lesioned primate model of Parkinson's disease have demonstrated that alpha(2) adrenergic receptor antagonists such as idazoxan, rauwolscine, and yohimbine can alleviate L-dopa-induced dyskinesia and, in the case of idazoxan, enhance the duration of anti-parkinsonian action of L-dopa. Here we describe a novel alpha(2) antagonist, fipamezole (JP-1730), which has high affinity at human alpha(2A) (K(i), 9.2 nM), alpha(2B) (17 nM), and alpha(2C) (55 nM) receptors. In functional assays, the potent antagonist properties of JP-1730 were demonstrated by its ability to reduce adrenaline-induced (35)S-GTPgammaS binding with K(B) values of 8.4 nM, 16 nM, 4.7 nM at human alpha(2A), alpha(2B), and alpha(2C) receptors, respectively. Assessment of the ability of JP-1730 to bind to a range of 30 other binding sites showed that JP-1730 also had moderate affinity at histamine H1 and H3 receptors and the serotonin (5-HT) transporter (IC(50) 100 nM to 1 microM). In the MPTP-lesioned marmoset, JP-1730 (10 mg/kg) significantly reduced L-dopa-induced dyskinesia without compromising the anti-parkinsonian action of L-dopa. The duration of action of the combination of L-dopa and JP-1730 (10 mg/kg) was 66% greater than that of L-dopa alone. These data suggest that JP-1730 is a potent alpha(2) adrenergic receptor antagonist with potential as an anti-dyskinetic agent in the treatment of Parkinson's disease.

MeSH terms

  • Adrenergic alpha-2 Receptor Antagonists*
  • Adrenergic alpha-Antagonists / pharmacology*
  • Adrenergic alpha-Antagonists / therapeutic use
  • Animals
  • Antiparkinson Agents / adverse effects*
  • Antiparkinson Agents / therapeutic use
  • Binding, Competitive / drug effects
  • Callithrix
  • Dyskinesia, Drug-Induced / drug therapy*
  • Dyskinesia, Drug-Induced / etiology
  • Female
  • Imidazoles / pharmacology*
  • Imidazoles / therapeutic use
  • Indans / pharmacology*
  • Indans / therapeutic use
  • Levodopa / adverse effects*
  • Levodopa / therapeutic use
  • Male
  • Parkinsonian Disorders / drug therapy*
  • Radioligand Assay
  • Rats
  • Receptors, AMPA / drug effects
  • Receptors, Adrenergic / drug effects
  • Receptors, Dopamine / drug effects
  • Receptors, GABA / drug effects
  • Receptors, Histamine / drug effects
  • Receptors, N-Methyl-D-Aspartate / drug effects
  • Receptors, Serotonin / drug effects


  • Adrenergic alpha-2 Receptor Antagonists
  • Adrenergic alpha-Antagonists
  • Antiparkinson Agents
  • Imidazoles
  • Indans
  • Receptors, AMPA
  • Receptors, Adrenergic
  • Receptors, Dopamine
  • Receptors, GABA
  • Receptors, Histamine
  • Receptors, N-Methyl-D-Aspartate
  • Receptors, Serotonin
  • Levodopa
  • fipamezole