Neuropharmacological Insight from Allosteric Modulation of mGlu Receptors

Abstract

The metabotropic glutamate (mGlu) receptors are a family of G protein-coupled receptors that regulate cell physiology throughout the nervous system. The potential of mGlu receptors as therapeutic targets has been bolstered by current research that has provided insight into the diverse modes of mGlu activation and signaling. Particularly, the allosteric modulation of mGlu receptors represents a major area of focus in studies of basic pharmacology as well as drug development, largely due to the high subtype specificity achievable by targeting allosteric sites on mGlu receptors. These provide sophisticated regulation of neuronal excitability and synaptic transmission to influence behavioral output. Here, we review how these allosteric mechanisms have been leveraged preclinically to demonstrate the therapeutic potential of allosteric modulators for neurological and neuropsychiatric disorders such as autism, cognitive impairment, Parkinson's disease, stress, and schizophrenia.

Family C G-Protein-Coupled Receptors in Alzheimer’s Disease and Therapeutic Implications

“…More recent studies using PAMs or NAMs, which are receptor subtype-specific, brought to light a somewhat different picture (see for references: Gregory and Conn, 2015). Indeed, the allosteric modulation of mGluRs is a major area of interest for Basic and Clinical Pharmacology (Stansley and Conn, 2019). In the CNS, mGluRs are involved in the regulation of glutamate uptake, cell proliferation, neurotrophic support, and proinflammatory responses.…”

Metabotropic glutamate receptor 5 in bulimia nervosa

“…The metabotropic glutamate receptor subtype 5 (mGlu5) plays an important role in glutamate signalling. mGlu5 is a G-protein-coupled seven transmembrane protein with two binding sites and a structural connection to NMDA receptors through a chain of scaffold proteins 1,2 . Glutamate activates mGlu5 by binding to its orthosteric binding site 1 .…”

“…mGlu5 is a G-protein-coupled seven transmembrane protein with two binding sites and a structural connection to NMDA receptors through a chain of scaffold proteins 1,2 . Glutamate activates mGlu5 by binding to its orthosteric binding site 1 . mGlu5 modulates NMDA receptor excitability and contributes to structural changes involved in adaptive synaptic plasticity, long-term potentiation, and learning [2][3][4] .…”

The cognitive cost of reducing relapse to cocaine-seeking with mGlu5 allosteric modulators

“…Allosteric modulators typically regulate functional receptor activity specifically in brain areas where the endogenous agonist exerts its physiological effects (Stansley and Conn 2019).…”

“…MTEP may be decreasing the ability of drug-associated cues to drive PrL brain activation and behavior (Martin-Fardon et al 2009;Kumaresan et al 2009;Keck et al 2014) via an mGlu5-mediated inhibition of neuronal excitability within this region (Timmer and Steketee 2012) or the NA core (Wang et al 2013), but not infralimbic cortex (IL, (Ben-Shahar et al 2013), whereas CDPPB may be facilitating within-session extinction learning via an mGlu5-mediated activation within the IL (Ben-Shahar et al 2013). Furthermore, the efficacy of these modulators in enhancing mGlu5 activity depends on the concentration of endogenous/orthostatic agonist (extracellular glutamate) and on mGlu5 agonist-modulator cooperativity factor (Stansley and Conn 2019). As such, region-specific dysregulation of mGlu5 signaling (Gobin et al 2019), mGlu5 function (Ben-Shahar et al 2013) and glutamate homeostasis (Knackstedt & Kalivas, 2009) after chronic cocaine may further determine circuit-specific effects of systemic MTEP and CDPPB administration.…”