Activation of metabotropic glutamate receptors as a novel approach for the treatment of schizophrenia

Abstract

In recent years, the metabotropic glutamate (mGlu) receptors have emerged as potential new drug targets for treatment of a range of CNS disorders. Some of the most compelling advances have been made in targeting specific mGlu receptor subtypes as a fundamentally new approach to the treatment of schizophrenia. Recent animal and clinical studies provide strong evidence that agonists of group II mGlu receptors (mGluR2 and mGluR3) are effective in the treatment of the positive symptoms of schizophrenia, and animal studies suggest that mGluR5 agonists could provide a novel approach for the treatment of all major symptom domains (positive, negative, and cognitive) of this disorder. Although the discovery of selective agonists of these receptors is a challenge, there have been recent advances in the discovery of highly selective positive allosteric modulators (PAMs) of mGluR2 and mGluR5. These mGlu receptor-selective PAMs have properties needed for optimization as clinical candidates and have robust effects in animal models that predict efficacy in treatment of schizophrenia.

Figure 1

A Model of microcircuitry underlying the NMDA receptor hypofunction hypothesis of schizophrenia. (a) Under normal conditions, activation of NMDA receptors localized on GABAergic projection neurons (as shown in orange) in subcortical regions, such as the nucleus accumbens, provides inhibitory control on excitatory glutamatergic thalamocortical neurons (as shown in green) that project to pyramidal neurons in the PFC. (b) Hypofunction or blockade of these NMDA receptors on midbrain inhibitory GABAergic neurons, which are normally under excitatory control from glutamatergic afferents, results in decreased excitation of GABAergic inhibitory neurons. (c) This decreased excitation of GABAergic inhibitory neurons leads to disinhibition of thalamocortical glutamatergic neurons that normally provide excitatory input to pyramidal neurons in the PFC. (d) This disinhibition of glutamatergic neurons in the thalamus results in an enhanced release of glutamate, excessive activation of non-NMDA glutamate receptors, and enhanced excitability in postsynaptic structures in the PFC, including pyramidal neurons. mGluR5 and mGluR2/3 receptors are expressed in key regions for the potential modulation of this altered circuitry.

Figure 2

Schematic Illustration of metabotropic glutamate receptor structure. mGlu receptors share no sequence homology with any other GPCRs. As shown, mGlu receptors possess a large N-terminal extracellular domain that contains the orthosteric binding site of the endogenous ligand glutamate, seven putative transmembrane domains separated by short intra- and extracellular loops, and a cytoplasmic carboxyl-terminal domain variable in length.

Figure 3

Representative positive allosteric modulators of mGluR5 and their activities on responses to glutamate. (a) Representative chemical structures of four different series of mGluR5 PAMs, including DFB, CPPHA, CDPPB, and ADX47273. (b) Schematic representation of effect of a representative allosteric potentiator on the mGluR5 calcium mobilization response to an EC₂₀ concentration of glutamate. The responses to an EC₂₀ concentration of glutamate in the presence of vehicle (blue trace) and PAM (green trace) are shown. Also shown is the response to a maximally effective concentration of glutamate (red trace). (c) In the presence of an mGluR5 PAM, the concentration response curve of the group I mGluR5 orthosteric agonist DHPG for activation of mGluR5 is shifted to left.

Figure 4

Representative chemical structures of Group II mGlu receptor agonist LY354740 and mGluR2 PAMs LY487379 and BINA.