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
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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DOI：
10.1021/jm070532r
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发表时间：
2007-08-23
影响因子：
7.3
通讯作者：
Clausen, Rasmus P.
中科院分区：
文献类型：
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作者：
Jensen, Anders A.;Christesen, Thomas;Clausen, Rasmus P.
四个2-取代的Tet-AMPA类似物[Tet=Tetzolyl，AMPA=2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic ACID]在荧光/钙离子分析中研究了4个2-取代的Tet-AMPA类似物在同聚体AMPA受体GluR1I、GluR2Q(I)、GluR3(I)和GluR4(I)上的功能。而2-ET-Tet-AMPA、2-Pr-Tet-AMPA和2-IPR-Tet-AMPA是非选择性GluR激动剂，2-Bn-Tet-AMPA在GluR4(I)上的效价是GluR1(I)的40倍。对含有2-Bn-Tet-AMPA的GluR4和GluR4的S1-S2结构域的同源模型检验表明，邻位立位区域的四个非保守残基可能是GluR4(I)/GluR1(I)选择性的决定因素。在一项突变研究中，在GluR1(I)中双突变M686V/I687A与D399S或E683A一起增加了该受体上2-Bn-Tet-AMPA的效力和最大反应，其水平与激动剂在GluR4(I)上引起的水平相似。2-Bn-Tet-AMPA的选择性对邻位外残基的依赖性突出了通过设计具有突出(S)-Glu结合口袋的取代基的化合物来开发Glr亚型选择性配体的潜力。
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(i) than at GluR1(i). 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 GluR4(i)/GluR1(i) selectivity. In a mutagenesis study, doubly mutating M686V/I687A in GluR1(i) 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 GluR4(i). 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.