Discovery of Positive Allosteric Modulators for the Metabotropic Glutamate Receptor Subtype 5 from a Series of N-(1,3-Diphenyl-1H- pyrazol-5-yl)benzamides That Potentiate Receptor Function in Vivo

Abstract

This report describes the discovery of the first centrally active allosteric modulators of the metabotropic glutamate receptor subtype 5 (mGluR5). Appropriately substituted N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamides (e.g., 8) have been identified as a novel class of potent positive allosteric modulators of mGluR5 that potentiate the response to glutamate. An iterative analogue library synthesis approach provided potentiators with excellent potency and selectivity for mGluR5 (vs mGluRs 1-4, 7, 8). Compound 8q demonstrated in vivo proof of concept in an animal behavior model where known antipsychotics are active, supporting the development of new antipsychotics based on the NMDA hypofunction model for schizophrenia.

Metabotropic Glutamate Receptors: Potential Drug Targets for Psychiatric Disorders

“…These modu-lators do not affect ligand binding to the orthosteric glutamate binding site, but potentiate its response to glutamate. DFB and CDPPB bind to the MPEP site and displace binding of radioligand to a well-characterized binding site for MPEP [155,156]. Thus, some reports indicate that these compounds have antipsychotic-like effects [156,157].…”

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

“…The compound CDPPB was synthesized in-house (Lindsley et al 2004) and dissolved in a vehicle composed of 10% dimethyl sulfoxide (DMSO) + 90% ethylene glycol. The MK801 (Sigma-RBI, St. Louis, Missouri) was dissolved in saline (.9% sodium chloride [NaCl]).…”

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

“…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.…”