Positive Allosteric Modulators of Type 5 Metabotropic Glutamate Receptors (mGluR5) and Their Therapeutic Potential for the Treatment of CNS Disorders

Richard M Cleva,M Foster Olive

doi:10.3390/molecules16032097

Abstract

Studies utilizing selective pharmacological antagonists or targeted gene deletion have demonstrated that type 5 metabotropic glutamate receptors (mGluR5) are critical mediators and potential therapeutic targets for the treatment of numerous disorders of the central nervous system (CNS), including depression, anxiety, drug addiction, chronic pain, Fragile X syndrome, Parkinson’s disease, and gastroesophageal reflux disease. However, in recent years, the development of positive allosteric modulators (PAMs) of the mGluR5 receptor have revealed that allosteric activation of this receptor may also be of potential therapeutic benefit for the treatment of other CNS disorders, including schizophrenia, cognitive deficits associated with chronic drug use, and deficits in extinction learning. Here we summarize the discovery and characterization of various mGluR5 PAMs, with an emphasis on those that are systemically active. We will also review animal studies showing that these molecules have potential efficacy as novel antipsychotic agents. Finally, we will summarize findings that suggest that mGluR5 PAMs have pro-cognitive effects such as the ability to enhance synaptic plasticity, improve performance in various learning and memory tasks, including extinction of drug-seeking behavior, and reverse cognitive deficits produced by chronic drug use.

Highlights

Studies utilizing selective pharmacological antagonists or targeted gene deletion have demonstrated that type 5 metabotropic glutamate receptors are critical mediators and potential therapeutic targets for the treatment of numerous disorders of the central nervous system (CNS), including depression, anxiety, drug addiction, chronic pain, Fragile X syndrome, Parkinson’s disease, and gastroesophageal reflux disease
It appears that indirect enhancement of NMDA receptor function by allosteric potentiation of mGluR5 receptors enhances synaptic plasticity [18,25], performance on certain learning and memory tasks [25,26,27,28], and reverses cognitive and motivational deficits produced by drugs of abuse or NMDA antagonists [29,30,31]
Positive allosteric modulators (PAMs) of mGluR5 receptor function were originally developed with the intent of indirectly increasing NMDA receptor function toalleviate some of the cognitive deficits associated with schizophrenia, as there is a wealth of evidence suggesting that NMDA hypofunction contributes to cognitive deficits observed in this disorder [19,20,21,32,33,34]. mGluR5 positive allosteric modulators (PAMs) were hypothesized to be advantageous over orthosteric mGluR5 agonists such as CHPG because the latter compounds: (1) offer poor discrimination between metabotropic glutamate receptors (mGluRs) receptor subtypes due to the high degree of sequence homology of the glutamate binding site; (2) exhibit poor brain penetrance following systemic administration, and (3) cause rapid mGluR5 receptor desensitization

Summary

Glutamateric Neurotransmission

Glutamate is the most prevalent excitatory neurotransmitter within the central nervous system (CNS) and, upon its release into the synaptic cleft, can bind to one of three different ligand-gated ionotropic glutamate receptors (iGluRs): the N-methyl-D-aspartate (NMDA) receptor, the α-amino-3hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor, and the kainic acid (KA) receptor. As a result of this seemingly different molecular site of action, differing patterns of activation of intracellular signaling cascades, and a relatively shallow structure-activity relationship of CPPHA, recent attempts have been made to utilize the CPPHA chemical scaffold to develop mGluR5 PAMs that do not bind to the MPEP site on the receptor. Such ligands include N-(5-chloropyridin-2-yl)-4-propoxybenzamide (VU0001850), 4-butoxy-N-(2fluorophenyl)-benzamide (VU0040237). The systemic bioavailability of these compounds as well as their behavioral profiles has not yet been evaluated

Antipsychotic and Pro-Cognitive Effects of Systemically Active mGluR5 PAMs

Summary and Conclusions