Selective mGluR5 antagonists MPEP and SIB-1893 decrease NMDA or glutamate-mediated neuronal toxicity through actions that reflect NMDA receptor antagonism

1 The metabotropic glutamate receptors (mGluRs) are a family of G-protein l inked receptors that can be divided into three groups (group I, II and III) . A number of studies have implicated group I mGluR activation in acute neu ronal injury, but until recently it was not possible to pharmacologically d ifferentiate the roles of the two individual subunits (mGluR1 and mGluR5) i n this group. 2 We investigated the role of mGluR5 in acute NMDA and glutamate mediated n eurodegeneration in cultured rat cortical cells using the mGluR5 antagonist s MPEP and SIB-1893, and found that they provide significant protection at concentrations of 20 or 200 muM. 3 These compounds act as effective mGluR5 antagonists in our cell culture s ystem, as indicated by the ability of STB-1893 to prevent phosphoinositol h ydrolysis induced by the specific mGluR5 agonist, (RS)-2-chloro-5-hydroxyph enylglycine (CHPG). 4 However. they also significantly reduce NMDA evoked current recorded from whole cells voltage clamped at -60 mV, and significantly decrease the dura tion of opening of NMDA channels recorded in the outside out patch configur ation. 5 This suggests that although MPEP and SIB-1893 are effective mGluR5 antago nists, they also act as noncompetitive NMDA receptor antagonists. Therefore . the neuroprotective effects of these compounds are most likely mediated t hrough their NMDA receptor antagonist action, and caution should be exercis ed when drawing conclusions about the roles of mGluR5 based on their use.