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

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.

• Authors: Erwan Bezard, Elsa Y Pioli, Qin Li, Françoise Girard, Vincent Mutel, Charlotte Keywood, Francois Tison, Olivier Rascol, Sonia M Poli
• Journal: Movement disorders : official journal of the Movement Disorder Society (Mov Disord) Vol. 29 Issue 8 Pg. 1074-9 (Jul 2014) ISSN: 1531-8257 [Electronic] United States
• PMID: 24865335 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 International Parkinson and Movement Disorder Society.

Chemical References

• 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

Topics

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