remeglurant (MRZ-8456) / Merz Pharma - LARVOL DELTA

Detailed in vitro pharmacological characterization of clinically tested negative allosteric modulators of the metabotropic glutamate receptor 5 (mGlu5). (PubMed, Mol Pharmacol) - "k and k values varied greatly between the nine NAMs (34- and 139-fold, respectively) resulting in long receptor residence times (>400 min) for basimglurant and mavoglurant, medium residence times (10-30 min) for AZD2066, remeglurant, and (RS)-remeglurant, and low residence times (<10 mins) for dipraglurant, F169521, F1699611, and STX107. Negative allosteric modulators (NAMs) have shown promising results in preclinical models but have so far failed in human clinical trials. Here we provide the most comprehensive and comparative molecular pharmacological study to date of nine preclinical/clinical tested negative allosteric modulators (NAMs) at the mGlu5 receptor, which is also the first study to measure binding kinetics and negative allosteric modulation of mGlu5 receptor internalization."

Journal • CNS Disorders

Rescue of Fmr1 phenotypes with mGluR inhibitors: MRZ-8456 versus AFQ-056. (PubMed, Neurobiol Dis) - "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."

Biomarker • Journal