Biased agonism and allosteric modulation of metabotropic glutamate receptor 5

Abstract

Metabotropic glutamate receptors belong to class C G-protein-coupled receptors and consist of eight subtypes that are ubiquitously expressed throughout the central nervous system. In recent years, the metabotropic glutamate receptor subtype 5 (mGlu5) has emerged as a promising target for a broad range of psychiatric and neurological disorders. Drug discovery programs targetting mGlu5 are primarily focused on development of allosteric modulators that interact with sites distinct from the endogenous agonist glutamate. Significant efforts have seen mGlu5 allosteric modulators progress into clinical trials; however, recent failures due to lack of efficacy or adverse effects indicate a need for a better understanding of the functional consequences of mGlu5 allosteric modulation. Biased agonism is an interrelated phenomenon to allosterism, describing how different ligands acting through the same receptor can differentially influence signaling to distinct transducers and pathways. Emerging evidence demonstrates that allosteric modulators can induce biased pharmacology at the level of intrinsic agonism as well as through differential modulation of orthosteric agonist-signaling pathways. Here, we present key considerations in the discovery and development of mGlu5 allosteric modulators and the opportunities and pitfalls offered by biased agonism and modulation.

Protein-protein interaction modulators: advances, successes and remaining challenges

“…Another indirect strategy for discovering small-molecule PPI modulators involves searching for allosteric modulators. An allosteric site is a region of a protein that lies outside the binding site for the protein natural ligand, but when modulated, changes the conformation of the protein in such a way that it affects the activity of the binding site (Hansen et al 2018;Trinh et al 2018). For example, the anti-HIV/AIDS drug maraviroc, an allosteric PPI inhibitor of the CCR5 chemokine receptor, was discovered via high-throughput screening (HTS) (Dorr et al 2005).…”

“…Another serendipitous discovery of small-molecule allosteric modulators of PPIs is the discovery of compounds that act at an allosteric site to inhibit the subunits of the heterodimeric transcription factor core binding factor (CBF) CBFβ and Runx1 (also known as CBFα) (Gorczynski et al 2007). Developing methods for identification of allosteric sites in proteins and discovering drugs that modulate the activity of these proteins by binding to these allosteric sites is now the focus of pharmaceutical studies (Hansen et al 2005;Hansen et al 2018;Trinh et al 2018).…”

Identification of monellin as the first naturally derived proteinaceous allosteric agonist of metabotropic glutamate receptor 5

“…Expression of mGlu 5 is found extensively in the brain, where it is involved in a myriad of functions, including synaptic transmission and plasticity . While it is unlikely for monellin to cross the blood‐brain barrier due to its large size and proteinaceous nature, the ability of monellin to activate mGlu 5 raises the potential of a yet undiscovered role of mGlu 5 in taste or taste perception, or other peripheral functions.…”

Allosteric Molecular Switches in Metabotropic Glutamate Receptors

“…The detection, validation and quantification of allosteric modulation is a permanent challenge in allosteric drug discovery. Binding and functional assays in various setups are used to explore the behavior of allosteric ligands [125,126] . Binding assays are able to directly validate of allosteric mode of action and unmask the site of interaction; however, they are not able to provide information about efficacy modulation.…”

“…In addition, they are also useful to study probe dependence and saturation effects. The former describes the direction and degree of cooperativity between the allosteric modulator and the orthosteric ligand (probe), which might be, however, probe dependent [126–129] . The latter expresses the limited influence of allosteric modulator caused by the cooperativity between orthosteric and allosteric sites.…”