Kinetic and system bias as drivers of metabotropic glutamate receptor 5 allosteric modulator pharmacology

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mGluR5 Negative Allosteric Modulators (NAMs) at a glance

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Comprising both the brain and spinal cord, the Central Nervous System (CNS) is vulnerable to various disorders or damage caused by factors such as trauma, infections, degeneration (Alzheimer’s and Parkinson’s diseases, multiple sclerosis), structural defects, strokes, tumors, blood flow disruption, autoimmune disorders, and most certainly many others yet to be discovered. The field of research for CNS disorders also encompasses the study of symptoms such as epilepsy, migraines, psychiatric troubles, and addiction mechanisms.
According to recent reports issued by the World Health Organization and United Nations, more than 1 billion people around the world suffer from neurological disorders, with several million dying each year. A major challenge for pharmaceutical research is to identify new drugs and develop new pharmacological approaches for more specific and efficient treatments.
The potential of metabotropic glutamate receptor subtype 5 (mGluR5) as a key target for CNS disorder treatments has been well accepted by researchers for many years. It represents a classic case for studying new pharmacological approaches focusing on allosteric modulators.
In this article, Kathy Sengmany clearly highlights the mechanisms of action of mGluR5 Negative Allosteric Modulators (mGluR5 NAMs). Providing a massive set of very convincing data, she uses either HEK recombinant cell lines or mouse primary cortical neuron cultures to describe complex binding properties and affinities, subtle cooperativity mechanisms of several NAMs’ binding to mGluR5, and downstream signaling cascades triggered in the presence of NAMs.
Join the game with your NAMs and tackle Central Nervous System diseases directly with smart pharmacological approaches to design novel innovative therapeutics!


Allosteric modulators of the metabotropic glutamate receptor subtype 5 (mGlu5) have been proposed as potential therapies for various CNS disorders. These ligands bind to sites distinct from the orthosteric (or endogenous) ligand, often with improved subtype selectivity and spatio-temporal control over receptor responses. We recently revealed that mGlu5 allosteric agonists and positive allosteric modulators exhibit biased agonism and/or modulation. To establish whether negative allosteric modulators (NAMs) engender similar bias, we rigorously characterized the pharmacology of eight diverse mGlu5 NAMs. Radioligand inhibition binding studies revealed novel modes of interaction with mGlu5 for select NAMs, with biphasic or incomplete inhibition of the radiolabeled NAM, [3H]methoxy-PEPy. We assessed mGlu5-mediated intracellular Ca2+ (iCa2+) mobilization and inositol phosphate (IP1) accumulation in HEK293A cells stably expressing low levels of mGlu5 (HEK293A-rat mGlu5-low) and mouse embryonic cortical neurons. The apparent affinity of acetylenic NAMs, MPEP, MTEP and dipraglurant, was dependent on the signaling pathway measured, agonist used, and cell type (HEK293A-rat mGlu5-low versus mouse cortical neurons). In contrast, the acetylenic partial NAM, M-5MPEP, and structurally distinct NAMs (VU0366248, VU0366058, fenobam), had similar affinity estimates irrespective of the assay or cellular background. Biased modulation was evident for VU0366248 in mouse cortical neurons where it was a NAM for DHPG-mediated iCa2+ mobilization, but neutral with DHPG in IP1 accumulation assays. Overall, this study highlights the inherent complexity in mGlu5 NAM pharmacology that we hypothesize may influence interpretation when translating into preclinical models and beyond in the


Neuropharmacology. 2019 May 1; 149:83-96.

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