Use of metabotropic glutamate 5-receptor antagonists for treatment of levodopa-induced dyskinesias

Abstract

Background: Modulation of metabotropic glutamate receptors may be a novel therapeutic approach to manage L-Dopa-induced dyskinesias in patients with Parkinson's disease. This article reviews the rationale for use of metabotropic glutamate 5-receptor antagonists in experimental and clinical L-Dopa-induced dyskinesias.

Methods: Systematic literature searches were performed (between May 2012-March 2014) for relevant English language articles using PubMed. Additional articles of interest were identified from reference lists of included publications. Relevant clinical abstracts from Movement Disorder Society meetings were included.

Results: 16 preclinical studies of metabotropic glutamate 5-receptor antagonists in animal models of L-Dopa-induced dyskinesias and 7 clinical studies in patients with Parkinson's disease and L-Dopa-induced dyskinesias were included. Anti-dyskinetic effects of metabotropic glutamate 5-receptor blockade (MPEP, MTEP, fenobam, or MRZ-8676) were reported in dyskinetic 6-hydroxydopamine-lesioned rats. Studies in MPTP-lesioned non-human primates reported anti-dyskinetic effects of MPEP, MTEP, fenobam and mavoglurant (AFQ056). Three randomized, double-blind clinical trials reported anti-dyskinetic efficacy of mavoglurant, without effects on anti-parkinsonian therapy, with dizziness the most common adverse event. However, two further studies failed to demonstrate significant anti-dyskinetic efficacy. A randomized, double-blind, placebo-controlled safety study of dipraglurant (ADX48621) demonstrated tolerability and positive exploratory secondary outcomes of reduced dyskinesia.

Conclusions: Animal model studies provide evidence for anti-dyskinetic efficacy of metabotropic glutamate 5-receptor antagonists. Initial proof-of-concept clinical trials of mavoglurant and dipraglurant showed positive results; anti-dyskinetic efficacy was not supported by two recent mavoglurant trials. Further evaluations of optimal dosage and long-term efficacy and safety of metabotropic glutamate 5-receptor antagonists for management of L-Dopa-induced dyskinesias in Parkinson's disease are required.

Keywords: Dyskinesias; Levodopa; Metabotropic glutamate antagonists; Parkinsonism; l-Dopa.