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 Fun

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• 作者：Anders A. Jensen ; Thomas Christesen ; Ulrik B//pubs.acs.org/images/gifchars/oslash.gif" border="0">lcho ; Jeremy R. Greenwood ; Giovanna Postorino ; Stine B. Vogensen ; Tommy N. Johansen ; J
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：August 23, 2007
• 年：2007
• 卷：50
• 期：17
• 页码：4177 - 4185
• 全文大小：533K
• 年卷期：v.50,no.17(August 23, 2007)
• ISSN：1520-4804

文摘

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 GluR1_i,GluR2Q_i, GluR3_i, and GluR4_i 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 GluR4_ithan at GluR1_i. Examination of homology models of the S1-S2 domains of GluR1 and GluR4 containing2-Bn-Tet-AMPA suggested four nonconserved residues in a region adjacent to the orthosteric site as possibledeterminants of the GluR4_i/GluR1_i selectivity. In a mutagenesis study, doubly mutating M686V/I687A inGluR1_i in combination with either D399S or E683A increased both the potency and the maximal responseof 2-Bn-Tet-AMPA at this receptor to levels similar to those elicited by the agonist at GluR4_i. The dependenceof the novel selectivity profile of 2-Bn-Tet-AMPA upon residues located outside of the orthosteric siteunderlines the potential for developing GluR subtype selective ligands by designing compounds withsubstituents that protrude beyond the (S)-Glu binding pocket.