title: 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.
authors.affiliation: Clinical Investigation Center CIC9302 and Department of Neurosciences and Clinical Pharmacology, INSERM UMR825, Toulouse University Hospital and University of Toulouse III, Toulouse, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Rascol
authors.affiliation: Movement Disorder Clinic, University of Toronto, Toronto Western Hospital, Toronto, Ontario, Canada.
authors.forename: Susan
authors.initials: S
authors.lastname: Fox
authors.affiliation: Novartis Institutes for Biomedical Research, Basel, Switzerland.
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Gasparini
authors.affiliation: Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Kenney
authors.affiliation: Neuroscience Research Unit, Centre Hospitalier Universitaire de Québec, Québec, Canada; Faculty of Pharmacy, Laval University, Québec, Canada.
authors.forename: Thérèse
authors.initials: T
authors.lastname: Di Paolo
authors.affiliation: Novartis Institutes for Biomedical Research, Basel, Switzerland; Department of Neurology and Neurosurgery, McGill University, Montreal, Québec, Canada. Electronic address: baltazar.gomezmancilla@novartis.com.
authors.forename: Baltazar
authors.initials: B
authors.lastname: Gomez-Mancilla
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects*; D004195:Disease Models, Animal; D020820:Dyskinesias / Q000188:drug therapy*; D006801:Humans; D007980:Levodopa / Q000009:adverse effects*; D010300:Parkinson Disease / Q000188:drug therapy*; D064529:Receptor, Metabotropic Glutamate 5 / Q000037:antagonists & inhibitors*
chemical_list: D000978:Antiparkinson Agents; D064529:Receptor, Metabotropic Glutamate 5; D007980:Levodopa
keywords: Dyskinesias; Levodopa; Metabotropic glutamate antagonists; Parkinsonism; l-Dopa