Biased allosteric agonism and modulation of metabotropic glutamate receptor 5: Implications for optimizing preclinical neuroscience drug discovery

Neuropharmacology. 2017 Mar 15:115:60-72. doi: 10.1016/j.neuropharm.2016.07.001. Epub 2016 Jul 5.


Allosteric modulators, that exhibit no intrinsic agonist activity, offer the advantage of spatial and temporal fine-tuning of endogenous agonist activity, allowing the potential for increased selectivity, reduced adverse effects and improved clinical outcomes. Some allosteric ligands can differentially activate and/or modulate distinct signaling pathways arising from the same receptor, phenomena referred to as 'biased agonism' and 'biased modulation'. Emerging evidence for CNS disorders with glutamatergic dysfunction suggests the metabotropic glutamate receptor subtype 5 (mGlu5) is a promising target. Current mGlu5 allosteric modulators have largely been classified based on modulation of intracellular calcium (iCa2+) responses to orthosteric agonists alone. We assessed eight mGlu5 allosteric modulators previously classified as mGlu5 PAMs or PAM-agonists representing four distinct chemotypes across multiple measures of receptor activity, to explore their potential for engendering biased agonism and/or modulation. Relative to the reference orthosteric agonist, DHPG, the eight allosteric ligands exhibited distinct biased agonism fingerprints for iCa2+ mobilization, IP1 accumulation and ERK1/2 phosphorylation in HEK293A cells stably expressing mGlu5 and in cortical neuron cultures. VU0424465, DPFE and VU0409551 displayed the most disparate biased signaling fingerprints in both HEK293A cells and cortical neurons that may account for the marked differences observed previously for these ligands in vivo. Select mGlu5 allosteric ligands also showed 'probe dependence' with respect to their cooperativity with different orthosteric agonists, as well as biased modulation for the magnitude of positive cooperativity observed. Unappreciated biased agonism and modulation may contribute to unanticipated effects (both therapeutic and adverse) when translating from recombinant systems to preclinical models. This article is part of the Special Issue entitled 'Metabotropic Glutamate Receptors, 5 years on'.

Keywords: Biased agonism; CDPPB (PubChem CID: 11245456); DHPG (PubChem CID: 108001); DPFE (PubChem CID: 16663278); Glutamate (L-glutamic acid PubChem CID: 33032); Metabotropic glutamate receptor 5; Positive allosteric modulator; Stimulus bias; VU0360172 (PubChem CID: 53318624); VU0403602 (PubChem CID: 53384878); VU0405398 (PubChem CID: 70789303); VU0424465 (PubChem CID: 53384864); VU29 (PubChem CID: 11610682).

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Allosteric Regulation / drug effects
  • Allosteric Regulation / physiology
  • Animals
  • Calcium Signaling / drug effects
  • Calcium Signaling / physiology
  • Dose-Response Relationship, Drug
  • Drug Discovery / methods
  • Drug Discovery / trends*
  • Drug Evaluation, Preclinical / methods
  • Drug Evaluation, Preclinical / trends
  • Excitatory Amino Acid Agonists / pharmacology*
  • Excitatory Amino Acid Antagonists / pharmacology*
  • Female
  • HEK293 Cells
  • Humans
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / physiology
  • Mice
  • Receptor, Metabotropic Glutamate 5 / agonists
  • Receptor, Metabotropic Glutamate 5 / antagonists & inhibitors
  • Receptor, Metabotropic Glutamate 5 / physiology*


  • Excitatory Amino Acid Agonists
  • Excitatory Amino Acid Antagonists
  • GRM5 protein, human
  • Receptor, Metabotropic Glutamate 5