Studies on an (S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptor antagonist IKM-159: asymmetric synthesis, neuroactivity, and structural characterization.
Studies on an (S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptor antagonist IKM-159: asymmetric synthesis, neuroactivity, and structural characterization.
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DOI：
10.1021/jm301590z
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发表时间：
2013-03-28
影响因子：
7.3
通讯作者：
Oikawa, Masato
中科院分区：
文献类型：
--
作者：
Juknaite, Lina;Sugamata, Yutaro;Tokiwa, Kazuya;Ishikawa, Yuichi;Takamizawa, Satoshi;Eng, Andrew;Sakai, Ryuichi;Pickering, Darryl S.;Frydenvang, Karla;Swanson, Geoffrey T.;Kastrup, Jette S.;Oikawa, Masato
IKM-159被开发并鉴定为一类新的杂三环谷氨酸类似物的成员，其作为AMPA受体选择性拮抗剂。然而，尚不清楚IKM-159的哪种对映异构体负责其药理活性。在这里，我们报告在体内和体外的神经元活性的两个对映体的IKM-159制备的对映体的不对称合成。通过使用（R）-2-氨基-2-（4-甲氧基苯基）乙醇作为手性辅助剂，在总共18个步骤中成功地合成了（2 R）-IKM-159和（2S）-对应物，产率分别为0.70%和1.5%。行为和电生理学测定均表明，外消旋混合物观察到的生物活性仅用（2 R）-IKM-159再现，而（2S）-对应物在两种测定中均无活性。外消旋IKM-159与GluA 2的配体结合结构域一起结晶，结构显示在谷氨酸结合位点含有（2 R）-IKM-159的复合物。（2 R）-IKM-159以开放形式锁定GluA 2，与作为AMPA受体的竞争性拮抗剂的药理学作用一致。
IKM-159 was developed and identified as a member of a new class of heterotricyclic glutamate analogues that act as AMPA receptor-selective antagonists. However, it was not known which enantiomer of IKM-159 was responsible for its pharmacological activities. Here, we report in vivo and in vitro neuronal activities of both enantiomers of IKM-159 prepared by enantioselective asymmetric synthesis. By employment of (R)-2-amino-2-(4-methoxyphenyl)ethanol as a chiral auxiliary, (2R)-IKM-159 and the (2S)-counterpart were successfully synthesized in 0.70% and 1.5% yields, respectively, over a total of 18 steps. Both behavioral and electrophysiological assays showed that the biological activity observed for the racemic mixture was reproduced only with (2R)-IKM-159, whereas the (2S)-counterpart was inactive in both assays. Racemic IKM-159 was crystallized with the ligand-binding domain of GluA2, and the structure revealed a complex containing (2R)-IKM-159 at the glutamate binding site. (2R)-IKM-159 locks the GluA2 in an open form, consistent with a pharmacological action as competitive antagonist of AMPA receptors.
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DOI：
10.1107/s0907444909029436
发表时间：
2009-10-01
影响因子：
2.2
作者：
Moriarty, Nigel W.;Grosse-Kunstleve, Ralf W.;Adams, Paul D.
通讯作者：
Adams, Paul D.
影响因子：
7.3
作者：
More, JCA;Troop, HM;Jane, DE
通讯作者：
Jane, DE
影响因子：
4.9
作者：
Kan, T;Fukuyama, T
通讯作者：
Fukuyama, T
影响因子：
7.3
作者：
Gill, M. B.;Frausto, S.;Swanson, G. T.
通讯作者：
Swanson, G. T.
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH