The metabotropic glutamate receptor subtype 5 (mGlu5) is a G protein-coupled receptor implicated in schizophrenia. JNJ-46778212 is a mGlu5 positive allosteric modulator with an EC50 value of 260nM and with 84% Glu Max. It is highly selective for mGlu5 relative to mGlu1–4,6–8 at 10μM. JNJ-46778212 showed excelled central nervous system penetration with Kps of 1.0 and 2.3 for mouse and rat, respectively. It was inactive in the hERG patch clamp (22% inhibition at 3μM) and was clean in a CV-relevant ion channel panel (hERG, Ca, Na channels, IC50s >10μM). JNJ-46778212 exhibited robust dose-responsive efficacy with a maximum reversal of ∼78% at 100mg/kg (p.o.) and a minimum effective dose of 10mg/kg (p.o.) with an ED50 value of 23mg/kg in a preclinical assay. In an investigational new drug-enabling study, chronic administration of JNJ-46778212 at a dose of 360mg/kg (p.o.) for 30 days induced neuronal death (indicated by Fluoro-Jade C staining) in rats.[1]
作用机制
JNJ-46778212 is a potent, selective, and orally bioavailable positive allosteric modulator of mGlu5.[1]
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