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

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

doi:10.1021/jm070532r

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

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

14 Citations (Scopus)

Abstract

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.

Original language	English
Journal	Journal of Medicinal Chemistry
Volume	50
Issue number	17
Pages (from-to)	4177-4185
Number of pages	9
ISSN	0022-2623
DOIs	https://doi.org/10.1021/jm070532r
Publication status	Published - 2007

Keywords

Aniline Compounds
Animals
Binding Sites
Cell Line
Female
Fluorescent Dyes
Humans
Isoxazoles
Models, Molecular
Mutation
Oocytes
Patch-Clamp Techniques
Propionic Acids
Rats
Receptors, AMPA
Sequence Homology, Amino Acid
Stereoisomerism
Structure-Activity Relationship
Tetrazoles
Thermodynamics
Xanthenes
Xenopus
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid

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Jensen, A. A., Christesen, T., Bølcho, U., Greenwood, J. R., Postorino, G., Vogensen, S. B., Johansen, T. N., Egebjerg, J., Bräuner-Osborne, H., & Clausen, R. P. (2007). 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. Journal of Medicinal Chemistry, 50(17), 4177-4185. https://doi.org/10.1021/jm070532r

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 et al.

In: Journal of Medicinal Chemistry, Vol. 50, No. 17, 2007, p. 4177-4185.

Research output: Contribution to journal › Journal article › Research › peer-review

Jensen, AA, Christesen, T, Bølcho, U, Greenwood, JR, Postorino, G, Vogensen, SB, Johansen, TN, Egebjerg, J, Bräuner-Osborne, H & Clausen, RP 2007, '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', Journal of Medicinal Chemistry, vol. 50, no. 17, pp. 4177-4185. https://doi.org/10.1021/jm070532r

Jensen AA, Christesen T, Bølcho U, Greenwood JR, Postorino G, Vogensen SB et al. 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. Journal of Medicinal Chemistry. 2007;50(17):4177-4185. doi: 10.1021/jm070532r

Jensen, Anders A. ; Christesen, Thomas ; Bølcho, Ulrik et al. / 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. In: Journal of Medicinal Chemistry. 2007 ; Vol. 50, No. 17. pp. 4177-4185.

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abstract = "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.",

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AU - Jensen, Anders A.

AU - Christesen, Thomas

AU - Bølcho, Ulrik

AU - Greenwood, Jeremy R

AU - Postorino, Giovanna

AU - Vogensen, Stine B

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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.

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KW - Thermodynamics

KW - Xanthenes

KW - Xenopus

KW - alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid

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