The Glutamate Receptor GluR5 Agonist (S)-2-Amino-3-(3-hydroxy-7,8-dihydro-6H-cyclohepta[d]isoxazol-4-yl)propionic Acid and the 8-Methyl Analogue: Synthesis, Molecular Pharmacology, and Biostructural Characterization
The Glutamate Receptor GluR5 Agonist (S)-2-Amino-3-(3-hydroxy-7,8-dihydro-6H-cyclohepta[d]isoxazol-4-yl)propionic Acid and the 8-Methyl Analogue: Synthesis, Molecular Pharmacology, and Biostructural Characterization
复制标题
DOI：
10.1021/jm900565c
复制
发表时间：
2009-08-13
影响因子：
7.3
通讯作者：
Kastrup, Jette S.
中科院分区：
文献类型：
--
作者：
Clausen, Rasmus P.;Naur, Peter;Kastrup, Jette S.
报道了一种高效选择性谷氨酸GluR 5激动剂的设计、合成和药理学特性。（S）-2-氨基-3-（（RS）-3-羟基-8-甲基-7，8-二氢-6H-环庚并[d]异恶唑-4-基）丙酸（5）是（S）-2-氨基-3-（3-羟基-7，8-二氢-6H-环庚并[d]异恶唑-4-基）丙酸（（S）-4-AHCP，4）的8-甲基类似物。与4相比，化合物5显示出改善的选择性曲线。一个通用的立体选择性的合成路线，这类化合物的沿着与离子型谷氨酸受体（iGluRs）的结合亲和力的表征。使用钙成像测定和电压钳记录对5 at克隆的iGluR进行功能表征，显示GluR 5与（S）谷氨酸（Glu）、红藻氨酸（KA，1）和（S）-2-氨基-3-（3-羟基-5-叔丁基-4-异恶唑基）丙酸（（S）-ATPA，3）相比的不同活化，如先前对4所证明的。的X-射线晶体学分析4和计算分析4和5绑定的GluR 5激动剂结合域（ABD），包括一个watermap分析，这表明，在激动剂结合位点的水分子是重要的选择性决定因素。
The design, Synthesis, and pharmacological characterization of a highly potent and selective glutamate GluR5 agonist is reported. (S)-2-Amino-3-((RS)-3-hydroxy-8-methyl-7,8-dihydro-6H-cyclohepta-[d]i soxazol-4-yl)propionic acid (5) is the 8-methyl analogue of (S)-2-amino-3-(3-hydroxy-7,8-dihydro-6H-cyclohepta[d]isoxazol-4-yl)propionic acid ((S)-4-AHCP, 4). Compound 5 displays an improved selectivity profile compared to 4. A versatile stereoselective synthetic route for this class of compounds is presented along with the characterization of the binding affinity of 5 to ionotropic glutamate receptors (iGluRs). Functional characterization of 5 at cloned iGluRs using a calcium imaging assay and voltage-clamp recordings show a different activation of GluR5 compared to (S)glutamic acid (Glu), kainic acid (KA, 1), and (S)-2-amino-3-(3-hydroxy-5-tert-butyl-4-isoxazolyl)propionic acid ((S)-ATPA, 3) as previously demonstrated for 4. An X-ray crystallographic analysis of 4 and computational analyses of 4 and 5 bound to the GluR5 agonist binding domain (ABD) are presented, including a watermap analysis, which suggests that water molecules in the agonist binding site are important selectivity determinants.