Functional characterization of Tet-AMPA [tetrazolyl-2-amino-3-(3-hydroxy-5-methyl- 4-isoxazolyl)propionic acid] analogues at ionotropic glutamate receptors GluR1-GluR4. The molecular basis for the functional selectivity profile of 2-Bn-Tet-AMPA

J Med Chem. 2007 Aug 23;50(17):4177-85. doi: 10.1021/jm070532r. Epub 2007 Aug 2.


Four 2-substituted Tet-AMPA [Tet = tetrazolyl, AMPA = 2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid] analogues were characterized functionally at the homomeric AMPA receptors GluR1i, GluR2Qi, GluR3i, and GluR4i in a Fluo-4/Ca2+ assay. Whereas 2-Et-Tet-AMPA, 2-Pr-Tet-AMPA, and 2-iPr-Tet-AMPA were nonselective GluR agonists, 2-Bn-Tet-AMPA exhibited a 40-fold higher potency at GluR4i than at GluR1i. Examination of homology models of the S1-S2 domains of GluR1 and GluR4 containing 2-Bn-Tet-AMPA suggested four nonconserved residues in a region adjacent to the orthosteric site as possible determinants of the GluR4i/GluR1i selectivity. In a mutagenesis study, doubly mutating M686V/I687A in GluR1i in combination with either D399S or E683A increased both the potency and the maximal response of 2-Bn-Tet-AMPA at this receptor to levels similar to those elicited by the agonist at GluR4i. The dependence of the novel selectivity profile of 2-Bn-Tet-AMPA upon residues located outside of the orthosteric site underlines the potential for developing GluR subtype selective ligands by designing compounds with substituents that protrude beyond the (S)-Glu binding pocket.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aniline Compounds
  • Animals
  • Binding Sites
  • Cell Line
  • Female
  • Fluorescent Dyes
  • Humans
  • In Vitro Techniques
  • Isoxazoles / chemistry*
  • Isoxazoles / pharmacology
  • Models, Molecular
  • Mutation
  • Oocytes / drug effects
  • Oocytes / physiology
  • Patch-Clamp Techniques
  • Propionates / chemistry*
  • Propionates / pharmacology
  • Rats
  • Receptors, AMPA / agonists*
  • Receptors, AMPA / genetics
  • Receptors, AMPA / physiology
  • Sequence Homology, Amino Acid
  • Stereoisomerism
  • Structure-Activity Relationship
  • Tetrazoles / chemistry*
  • Tetrazoles / pharmacology
  • Thermodynamics
  • Xanthenes
  • Xenopus
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / analogs & derivatives*
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / chemistry
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / pharmacology


  • 2-amino-3-(3-hydroxy-5-(2-benzyl-2H-5-tetrazolyl)-4-isoxazolyl)propionic acid
  • Aniline Compounds
  • Fluo 4
  • Fluorescent Dyes
  • Isoxazoles
  • Propionates
  • Receptors, AMPA
  • Tetrazoles
  • Xanthenes
  • glutamate receptor ionotropic, AMPA 3
  • glutamate receptor ionotropic, AMPA 4
  • alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
  • glutamate receptor ionotropic, AMPA 2
  • glutamate receptor ionotropic, AMPA 1