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

Kathy Sengmany, Shane D. Hellyer, Sabine Albold, Taide Wang, P. Jeffrey Conn, Lauren T. May, Arthur Christopoulos, Katie Leach, Karen J. Gregory

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5 Citations (Scopus)


Allosteric modulators of the metabotropic glutamate receptor subtype 5 (mGlu 5 ) 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 mGlu 5 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 mGlu 5 NAMs. Radioligand inhibition binding studies revealed novel modes of interaction with mGlu 5 for select NAMs, with biphasic or incomplete inhibition of the radiolabeled NAM, [ 3 H]methoxy-PEPy. We assessed mGlu 5 -mediated intracellular Ca 2+ (iCa 2+ ) mobilization and inositol phosphate (IP 1 ) accumulation in HEK293A cells stably expressing low levels of mGlu 5 (HEK293A-rat mGlu 5 -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 mGlu 5 -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 iCa 2+ mobilization, but neutral with DHPG in IP 1 accumulation assays. Overall, this study highlights the inherent complexity in mGlu 5 NAM pharmacology that we hypothesize may influence interpretation when translating into preclinical models and beyond in the design and development of novel therapeutics for neuropsychiatric and neurological disorders.

Original languageEnglish
Pages (from-to)83-96
Number of pages14
Publication statusPublished - 1 May 2019


  • (L-glutamic acid PubChem CID: 33032)
  • (PubChem CID: 108001)
  • (PubChem CID: 16036762)
  • (PubChem CID: 162834)
  • (PubChem CID: 3025961)
  • (PubChem CID: 44557636)
  • (PubChem CID: 57328392)
  • (PubChem CID: 9794218)
  • Biased modulation
  • DHPG
  • dipraglurant
  • fenobam
  • Glutamate
  • Kinetics
  • M-5MPEP
  • Metabotropic glutamate receptor 5
  • MPEP
  • MTEP
  • Negative allosteric modulator
  • VU0366058

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