Details

Autor(en) / Beteiligte

• Jensen, Anders A
• Christesen, Thomas
• Bølcho, Ulrik
• Greenwood, Jeremy R
• Postorino, Giovanna
• Vogensen, Stine B
• Johansen, Tommy N
• Egebjerg, Jan
• Bräuner-Osborne, Hans
• Clausen, Rasmus P

Titel

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

Ist Teil von

• Journal of medicinal chemistry, 2007-08, Vol.50 (17), p.4177-4185

Ort / Verlag

Washington, DC: American Chemical Society

Erscheinungsjahr

2007

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.