A critical pocket close to the glutamate binding site of mGlu receptors opens new possibilities for agonist design

Neuropharmacology. 2011 Jan;60(1):102-7. doi: 10.1016/j.neuropharm.2010.07.002. Epub 2010 Jul 16.


A recent publication from Ogawa et al. suggested a possible allosteric chloride binding site in the extracellular domain of metabotropic glutamate receptors (mGluRs) by comparison with a similar site found in atrial natriuretic peptide receptor. We simultaneously reported about (S)-PCEP an agonist of subtype 4 mGluR that would bind to a similar pocket, adjacent to the glutamate binding site. Here we disclose LSP1-2093, a new derivative of (S)-PCEP that holds a nitrophenyl substituent. Docking experiments predict that the nitro group binds to the receptor at the putative chloride ion site. It is thus possible to take advantage of this putative chloride binding site to develop new types of mGluR agonists. This pocket is present in the structural family of Leucine Isoleucine Valine Binding Protein that includes class C GPCRs, suggesting that extended agonists may be identified at receptors bearing such a structural domain.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation
  • Allosteric Site / physiology*
  • Drug Design
  • Glutamic Acid / metabolism*
  • HEK293 Cells
  • Humans
  • Models, Molecular
  • Protein Conformation
  • Receptors, Metabotropic Glutamate / agonists*
  • Receptors, Metabotropic Glutamate / metabolism*
  • Structure-Activity Relationship


  • Receptors, Metabotropic Glutamate
  • Glutamic Acid