Rescue of Fmr1KO phenotypes with mGluR5 inhibitors: MRZ-8456 versus AFQ-056

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 c...

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Bibliographic Details
Published in:Neurobiology of disease 2018-11, Vol.119, p.190-198
Main Authors: Westmark, Pamela R., Dekundy, Andrzej, Gravius, Andreas, Danysz, Wojciech, Westmark, Cara J.
Format: Article
Language:English
Subjects:
AFQ-056
Amyloid-beta precursor protein
Fmr1
mGluR5
MPEP
MRZ-8456
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Summary: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. •Metabotropic glutamate receptor 5 antagonist MRZ-8456 attenuates seizures.•MRZ-8456 reduces dendritic expression of amyloid-beta protein precursor.•MRZ-8456 rescues the ratio of mature to immature dendritic spines in Fmr1KO neurons.
ISSN:0969-9961
1095-953X
DOI:10.1016/j.nbd.2018.08.008