Dm. O'Leary et al., Selective mGluR5 antagonists MPEP and SIB-1893 decrease NMDA or glutamate-mediated neuronal toxicity through actions that reflect NMDA receptor antagonism, BR J PHARM, 131(7), 2000, pp. 1429-1437
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
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
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.