Positive Allosteric Modulation of Metabotropic Glutamate 5 (mGlu5) Receptors Reverses N-Methyl-D-Aspartate Antagonist-Induced Alteration of Neuronal Firing in Prefrontal Cortex

Abstract

Background-Several lines of evidence suggest that N-methyl-D-aspartate (NMDA) receptor hypofunction may be associated with schizophrenia. Activation of metabotropic glutamate 5 (mGlu5) receptors enhances NMDA receptor mediated currents in vitro, implying that allosteric modulation of mGlu5 receptors may have therapeutic efficacy for schizophrenia. The aim of this study was to determine if positive allosteric modulators of mGlu5 receptors are effective in reversing two cellular effects of NMDA receptor antagonists that are relevant to schizophrenia: increases in corticolimbic dopamine neurotransmission and disruption of neuronal activity in the prefrontal cortex (PFC).

Orbitofrontal cortex neurons as a common target for classic and glutamatergic antipsychotic drugs

“…Treatment with 4 compounds with distinct mechanisms of action that are either well-established antipsychotic compounds or novel candidates for treatment of schizophrenia ameliorated the impact of NMDA hypofunction on OFC neurons and on behavior. These compounds included (i) haloperidol, a D2 antagonist and a typical antipsychotic drug; (ii) clozapine, an atypical antipsy- chotic drug with a wide range of affinity at dopamine and serotonin receptors; (iii) LY354740, a selective mGlu2/3 agonist with no affinity for dopamine or serotonin receptors that has been suggested recently to have antipsychotic efficacy (5); and (iv) CDPPB, a novel mGlu5 receptor-positive allosteric modulator that has also been proposed as a potential antipsychotic agent (18,19). In a similar way, haloperidol and CDPPB reversed amphetamine-induced hyperactivation of OFC neurons.…”

“…Treatment with an NMDA antagonist increased the spontaneous activity of most pyramidal cells at the same time that it inhibited the activity of putative inhibitory GABA interneurons and increased behavioral stereotypy. We then examined the effects of pretreatment with haloperidol, a D2 antagonist and a typical antipsychotic drug; clozapine, an atypical antipsychotic drug with a wide range of affinity on dopamine and serotonin receptors; LY354740, a selective mGlu2/3 agonist (5, 17); and CDPPB, a novel mGlu5 receptor-positive allosteric modulator that has been proposed to have antipsychotic efficacy (18,19), on NMDA antagonist-induced disrupted OFC neuronal activity and behavior. To further establish the clinical utility of our results, we also examined whether normalization of activity by antipsychotic drugs is observed after the induction of NMDA receptor hypofunction.…”

Discovery of VU0409551/JNJ-46778212: An mGlu5 Positive Allosteric Modulator Clinical Candidate Targeting Schizophrenia

“…1 To effectively address this major unmet medical need, other neurotransmitter systems and circuits, such as those of the glutamatergic system, have emerged as high priority targets. 2,3 Of these, the metabotropic glutamate receptor subtype 5 (mGlu 5 ), due to its localization in brain regions implicated in schizophrenia and its colocalization with N-methyl-D-asparatate (NMDA) receptors, is of great interest in the context of the NMDA receptor hypofunction hypothesis of schizophrenia. 4−6 Positive allosteric modulation of mGlu 5 , pioneered by our laboratories 7,8 and now demonstrated by multiple chemotypes and laboratories ( Figure 1), has provided key target validation data in a diverse array of preclinical antipsychotic and cognition models.…”

“…2,3 Of these, the metabotropic glutamate receptor subtype 5 (mGlu 5 ), due to its localization in brain regions implicated in schizophrenia and its colocalization with N-methyl-D-asparatate (NMDA) receptors, is of great interest in the context of the NMDA receptor hypofunction hypothesis of schizophrenia. 4−6 Positive allosteric modulation of mGlu 5 , pioneered by our laboratories 7,8 and now demonstrated by multiple chemotypes and laboratories ( Figure 1), has provided key target validation data in a diverse array of preclinical antipsychotic and cognition models. 6 However, issues remain with potential target-based neurotoxicity and seizure liability due to ago-PAM activity, high fold-shift and/or efficacy, or other unknown mechanisms that have somewhat diminished enthusiasm for this novel mechanism.…”

“…6 However, issues remain with potential target-based neurotoxicity and seizure liability due to ago-PAM activity, high fold-shift and/or efficacy, or other unknown mechanisms that have somewhat diminished enthusiasm for this novel mechanism. 9,10 Previous target validation attributed the efficacy of mGlu 5 PAMs, as well as adverse effect liability, to the potentiation of NMDA receptor currents. Emerging data on stimulus bias within allosteric GPCR signaling, however, may offer an approach to potentially mitigate these undesired effects that reduce the therapeutic window and preclude development.…”