Common and selective molecular determinants involved in metabotopic glutamate receptor agonist activity

J Med Chem. 2002 Jul 18;45(15):3171-83. doi: 10.1021/jm010323l.


Several potent and group selective agonists of metabotropic glutamate receptors (mGluRs) have been docked at mGlu1,2,4R binding sites in the closed conformation of the bilobate extracellular domain. Quisqualic acid and (S)-3,5-dihydroxyphenylglycine (3,5-DHPG) were selected for mGlu1R, dicarboxycyclopropylglycine (DCG-IV), LY354740, (S)-4-carboxyphenylglycine (4CPG) for mGlu2R, and (S)-2-amino-4-phosphonobutyric acid (AP4), 1-aminocyclopentane-1,3,4-tricarboxylic acid (ACPT-I), (S)-4-phosphonophenylglycine (PPG) for mGlu4R. The models show a conserved binding pattern for the glycine moiety (alpha-amino and alpha-acidic functions) and group specific bindings for the distal acidic function. The best agonists allow optimized interaction with both lobes of the binding domain. Interlobe connections around the ligand are also described and participate in stabilizing the closed form of the amino-terminal domain. Altogether, the docking models support the proposal that the stabilization of a closed state represents a key step in agonist activation of mGluRs.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Crystallography, X-Ray
  • Excitatory Amino Acid Agonists / chemistry*
  • Glutamic Acid / chemistry
  • Ligands
  • Models, Molecular
  • Receptors, Metabotropic Glutamate / chemistry*
  • Sequence Homology, Amino Acid
  • Structure-Activity Relationship


  • Excitatory Amino Acid Agonists
  • Ligands
  • Receptors, Metabotropic Glutamate
  • metabotropic glutamate receptor 2
  • metabotropic glutamate receptor type 1
  • Glutamic Acid
  • metabotropic glutamate receptor 4