SEARCH

SEARCH BY CITATION

Keywords:

  • JP-1730;
  • α2-adrenergic;
  • dyskinesia;
  • marmoset

Abstract

Previous studies in the MPTP-lesioned primate model of Parkinson's disease have demonstrated that α2 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 α2 antagonist, fipamezole (JP-1730), which has high affinity at human α2A (Ki, 9.2 nM), α2B (17 nM), and α2C (55 nM) receptors. In functional assays, the potent antagonist properties of JP-1730 were demonstrated by its ability to reduce adrenaline-induced 35S-GTPγS binding with KB values of 8.4 nM, 16 nM, 4.7 nM at human α2A, α2B, and α2C 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 (IC50 100 nM to 1 μM). 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 α2 adrenergic receptor antagonist with potential as an anti-dyskinetic agent in the treatment of Parkinson's disease. © 2003 Movement Disorder Society