Fig. 2
From: Targeting metabotropic glutamate receptors for novel treatments of schizophrenia
Emerging concepts in the development of mGlu receptor-targeting antipsychotic therapeutics. a mGlu5 PAMs have recently been developed that bias mGlu5 signaling away from NMDAR modulation but still mobilize intracellular Ca2+ and activate ERK1/2. The mechanism of this bias is still unclear but could involve G-protein dependent versus independent coupling of mGlu5 to NMDAR. The biased mGlu5 PAM VU0409551 retains antipsychotic-like efficacy in vivo but does not cause excitotoxicity or seizures observed with unbiased mGlu5 PAMs that enhance mGlu5-mediated modulation of NMDAR currents. This suggests that NMDAR modulation is not necessary for in vivo efficacy and that this signal bias may provide a means to overcome the NMDAR-mediated excitotoxicity that has stalled mGlu5 PAM development. b Recently, functional mGlu2/4 heterodimers with unique pharmacology have been identified. This suggests that actions at the mGlu2/4 heterodimer rather than at the mGlu4/4 homodimer might underlie the antipsychotic efficacy of mGlu4 PAMs, such as Lu AF21934, consistent with the antipsychotic-like effects of mGlu2-specific ligands. This remains to be tested experimentally but may provide an interesting alternative to failed mGlu2 clinical programs