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
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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. / 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.
I: Journal of Medicinal Chemistry, Bind 50, Nr. 17, 2007, s. 4177-4185.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - 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
AU - Jensen, Anders A.
AU - Christesen, Thomas
AU - Bølcho, Ulrik
AU - Greenwood, Jeremy R
AU - Postorino, Giovanna
AU - Vogensen, Stine B
AU - Johansen, Tommy N
AU - Egebjerg, Jan
AU - Bräuner-Osborne, Hans
AU - Clausen, Rasmus P
PY - 2007
Y1 - 2007
N2 - 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.
AB - 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.
KW - Aniline Compounds
KW - Animals
KW - Binding Sites
KW - Cell Line
KW - Female
KW - Fluorescent Dyes
KW - Humans
KW - Isoxazoles
KW - Models, Molecular
KW - Mutation
KW - Oocytes
KW - Patch-Clamp Techniques
KW - Propionic Acids
KW - Rats
KW - Receptors, AMPA
KW - Sequence Homology, Amino Acid
KW - Stereoisomerism
KW - Structure-Activity Relationship
KW - Tetrazoles
KW - Thermodynamics
KW - Xanthenes
KW - Xenopus
KW - alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
U2 - 10.1021/jm070532r
DO - 10.1021/jm070532r
M3 - Journal article
C2 - 17672447
VL - 50
SP - 4177
EP - 4185
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 17
ER -
ID: 2507560