Sites of action and physiological impact of mGluR5 positive allosteric modulators

Abstract

Positive allosteric modulators (PAMs) of metabotropic glutamate receptor subtype 5 (mGluR5) may provide a novel approach that could be useful in the treatment of certain central nervous system disorders. However, their physiological effects and pharmacological properties, such as sites of action, are not fully understood. It has been suggested that two distinct mGluR5 PAMs, CDPPB and CPPHA, might act by binding to two distinct allosteric sites. We synthesized a series of CDPPB analogs and reported that these compounds bind to an allosteric antagonist (MPEP) site with affinities that are closely related to their potencies as mGluR5 PAMs. Furthermore, their allosteric potentiation is antagonized by a neutral ligand at the MPEP site called 5MPEP and reduced by a mutation that eliminates MPEP binding. Additionally, we have also reported that CPPHA potentiates mGluR5 responses by a mechanism that is distinct from that of VU-29, a CDPPB analog. CPPHA-induced potentiation of mGluR5 responses is also blocked by 5MPEP. However, 5MPEP and MPEP inhibit CPPHA in a non competitive manner compared with its competitive inhibition of the effect of VU-29. Consistent with this, the mutation that eliminates the effect of VU-29 has no effect on the response to CPPHA. Conversely, a distinct mutation that eliminates the effect of CPPHA does not alter the response to VU-29. Together, these data suggest that CPPHA and VU-29 act at two distinct sites. mGluR5 has been implicated as playing an important role in hippocampal synaptic plasticity. However, the precise roles of mGluR5 in different forms of hippocampal synaptic plasticity remain unclear. We found VU-29 significantly enhanced threshold theta burst stimulation (TBS)-induced long-term potentiation (LTP), which was completely blocked by 5MPEP and was mimicked by a structurally distinct mGluR5-selective PAM. In addition, VU-29 potentiated LTP was blocked by the NMDA receptor antagonist or src kinase inhibitor, suggesting that it shares a common mechanism with suprathreshold TBS-induced LTP. These raise the possibility that mGluR5 PAMs could be used as potential cognition enhancing agents.