Rescue of Fmr1 KO phenotypes with mGluR 5 inhibitors: MRZ-8456 versus AFQ-056

Neurobiol Dis. 2018 Nov;119:190-198. doi: 10.1016/j.nbd.2018.08.008. Epub 2018 Aug 17.


Metabotropic glutamate receptor 5 (mGluR5) is a drug target for central nervous system disorders such as fragile X syndrome that involve excessive glutamate-induced excitation. We tested the efficacy of a novel negative allosteric modulator of mGluR5 developed by Merz Pharmaceuticals, MRZ-8456, in comparison to MPEP and AFQ-056 (Novartis, a.k.a. mavoglurant) in both in vivo and in vitro assays in a mouse model of fragile X syndrome, Fmr1KO mice. The in vivo assays included susceptibility to audiogenic-induced seizures and pharmacokinetic measurements of drug availability. The in vitro assays included dose response assessments of biomarker expression and dendritic spine length and density in cultured primary neurons. Both MRZ-8456 and AFQ-056 attenuated wild running and audiogenic-induced seizures in Fmr1KO mice with similar pharmacokinetic profiles. Both drugs significantly reduced dendritic expression of amyloid-beta protein precursor (APP) and rescued the ratio of mature to immature dendritic spines. These findings demonstrate that MRZ-8456, a drug being developed for the treatment of motor complications of L-DOPA in Parkinson's disease and which completed a phase I clinical trial, is effective in attenuating both well-established (seizures and dendritic spine maturity) and exploratory biomarker (APP expression) phenotypes in a mouse model of fragile X syndrome.

Keywords: AFQ-056; Amyloid-beta precursor protein; Fmr1; MPEP; MRZ-8456; mGluR(5).

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • Excitatory Amino Acid Antagonists / chemistry
  • Excitatory Amino Acid Antagonists / pharmacology
  • Excitatory Amino Acid Antagonists / therapeutic use*
  • Female
  • Fragile X Mental Retardation Protein / genetics*
  • Fragile X Syndrome / drug therapy
  • Fragile X Syndrome / genetics*
  • Indoles / chemistry
  • Indoles / pharmacology
  • Indoles / therapeutic use*
  • Isoquinolines / chemistry
  • Isoquinolines / pharmacology
  • Isoquinolines / therapeutic use*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Phenotype*
  • Pregnancy
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology
  • Pyrazoles / therapeutic use*
  • Pyrimidines / chemistry
  • Pyrimidines / pharmacology
  • Pyrimidines / therapeutic use*
  • Random Allocation
  • Receptor, Metabotropic Glutamate 5 / antagonists & inhibitors*


  • Excitatory Amino Acid Antagonists
  • Fmr1 protein, mouse
  • Grm5 protein, mouse
  • Indoles
  • Isoquinolines
  • MRZ-8456
  • Pyrazoles
  • Pyrimidines
  • Receptor, Metabotropic Glutamate 5
  • Fragile X Mental Retardation Protein
  • mavoglurant