Molecular Insights into Metabotropic Glutamate Receptor Allosteric Modulation

Abstract

The metabotropic glutamate (mGlu) receptors are a group of eight family C G protein-coupled receptors that are expressed throughout the central nervous system (CNS) and periphery. Within the CNS the different subtypes are found in neurons, both pre-and/or postsynaptically, where they mediate modulatory roles and in glial cells. The mGlu receptor family provides attractive targets for numerous psychiatric and neurologic disorders, with the majority of discovery programs focused on targeting allosteric sites, with allosteric ligands now available for all mGlu receptor subtypes. However, the development of allosteric ligands remains challenging. Biased modulation, probe dependence, and molecular switches all contribute to the complex molecular pharmacology exhibited by mGlu receptor allosteric ligands. In recent years we have made significant progress in our understanding of this molecular complexity coupled with an increased understanding of the structural basis of mGlu allosteric modulation.

Metabotropic glutamate receptor subtype 5: molecular pharmacology, allosteric modulation and stimulus bias

“…In both crystal structures, the allosteric ligand‐binding pocket is extracellularly accessible and resides between TM2, TM3, TM5, TM6 and TM7 (Dore et al ., ; Wu et al ., ). This pocket is consistent with extensive previous mutagenesis studies of the ‘2‐methyl‐6‐(phenylethynyl)pyridine (MPEP) binding site’ or the common allosteric site that is shared across multiple mGlu 5 receptor allosteric modulator chemotypes, including NAMs, PAMs and NALs (Gregory and Conn, ). Indeed, the crystal structures are also consistent with structure‐function studies of allosteric pockets across multiple family C GPCRs (Bennett et al ., ; Gregory and Conn, ), suggesting a common location for binding cavities in family C GPCRs that can be selectively targeted with small molecule allosteric ligands.…”

“…This pocket is consistent with extensive previous mutagenesis studies of the ‘2‐methyl‐6‐(phenylethynyl)pyridine (MPEP) binding site’ or the common allosteric site that is shared across multiple mGlu 5 receptor allosteric modulator chemotypes, including NAMs, PAMs and NALs (Gregory and Conn, ). Indeed, the crystal structures are also consistent with structure‐function studies of allosteric pockets across multiple family C GPCRs (Bennett et al ., ; Gregory and Conn, ), suggesting a common location for binding cavities in family C GPCRs that can be selectively targeted with small molecule allosteric ligands. Commensurate with this concept is the fact that some mGlu 5 receptor allosteric ligands have activity at other mGlu subtypes (Mathiesen et al ., ; O'Brien et al ., ; Sheffler et al ., ).…”

Novel Allosteric Modulators of G Protein-coupled Receptors

“…In particular, allosteric modulation of the mGlu 5 receptor has been of interest as a target for the treatment of schizophrenia and Alzheimer disease (65,66). As such, multiple small molecule PAMs have been developed for mGlu 5 (67)(68)(69)(70)(71)(72), with the bulk acting at a common site in the upper region of the 7TM domain often termed the "MPEP-binding site" after the prototypical mGlu 5 NAM, MPEP (65,66). However, several ligands have been identified that are non-competitive with the MPEP site, including the PAMs VU357121 and CPPHA, indicating the presence of at least two distinct allosteric sites (67,69,73,74).…”

Allosteric Modulation of GPCRs: New Insights and Potential Utility for Treatment of Schizophrenia and Other CNS Disorders

“…Given the vast number of possible allosteric binding sites there is reason to believe that many of these sites have not been identified or targeted from a medicinal chemistry perspective. Numerous examples have been detailed where multiple distinct allosteric binding sites have been found for a single GPCR subtype (Gregory and Conn, 2015), and the recent discovery of a cytoplasmic allosteric binding site in chemokine CCR9 represents one example of a previously unappreciated binding site that could allow therapeutic modulation of a previously intractable target (Oswald et al, 2016). As we continue to advance our understanding of the mechanisms underlying allosteric modulation of GPCRs, we have come to appreciate the immense number of conformations and higher-order complexes that these receptors can adopt (Changeux and Christopoulos, 2016; Latorraca et al, 2016), and are beginning to elucidate how these conformations differentially regulate various signaling pathways.…”