Mechanism based neurotoxicity of mGlu5 positive allosteric modulators - Development challenges for a promising novel antipsychotic target

► We report the in vitro activity, in vivo efficacy and safety profile of novel mGlu5 PAMs. ► We identified several molecules that act as allosteric modulator with no agonist activity. ► Novel mGlu5 PAMs exhibit anti-psychotic like activity in rats. ► Safety studies revealed that novel mGlu5 PAMs produced similar neuronal death. ► Lack of neurotoxicity in mGlu5 KO mice supports a mechanism-dependent toxicity.