The mGluR5 negative allosteric modulator dipraglurant reduces dyskinesia in the MPTP macaque model

Mov Disord. 2014 Jul;29(8):1074-9. doi: 10.1002/mds.25920. Epub 2014 May 27.

Abstract

Background: Blocking metabotropic glutamate receptor type 5 (mGluR5) has been proposed as a target for levodopa-induced dyskinesias (LID) in Parkinson's disease (PD). We assessed the effect on LID of dipraglurant, a potent selective mGluR5 receptor negative allosteric modulator in the gold-standard LID macaque model.

Methods: Dipraglurant (3, 10, and 30 mg/kg, by mouth) was tested in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) macaque model of LID in a four-way crossover, single-dose, controlled study (n = 8).

Results: Dipraglurant inhibited dyskinesias in the LID macaque model, with best effect reached at 30 mg/kg dose with no alteration of levodopa efficacy.

Conclusion: Acute challenges of dipraglurant were efficacious on choreic and dystonic LID in the MPTP-macaque model. Dipraglurant pharmacokinetic variables were similar to those of levodopa, suggesting that both drugs can be co-administered simultaneously in further studies.

Keywords: MPTP; chorea; dystonia; macaque; on-time.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Antiparkinson Agents / adverse effects
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Dyskinesia, Drug-Induced / blood
  • Dyskinesia, Drug-Induced / drug therapy*
  • Excitatory Amino Acid Antagonists / blood
  • Excitatory Amino Acid Antagonists / chemistry*
  • Excitatory Amino Acid Antagonists / therapeutic use*
  • Imidazoles / pharmacology
  • Imidazoles / therapeutic use
  • Levodopa / adverse effects
  • MPTP Poisoning / drug therapy*
  • Macaca mulatta
  • Male
  • Motor Activity / drug effects
  • Pyridines / pharmacology
  • Pyridines / therapeutic use
  • Receptor, Metabotropic Glutamate 5 / metabolism
  • Severity of Illness Index
  • Time Factors

Substances

  • Antiparkinson Agents
  • Excitatory Amino Acid Antagonists
  • Imidazoles
  • Pyridines
  • Receptor, Metabotropic Glutamate 5
  • Levodopa
  • 6-fluoro-2-(4-(pyridin-2-yl)but-3-yn-1-yl)imidazo(1,2-a)pyridine