A Diversity Oriented Synthesis Approach to New 2,3-trans-Substituted l-Proline Analogs as Potential Ligands for the Ionotropic Glutamate Receptors.,ACS Chemical Neuroscience

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A Diversity Oriented Synthesis Approach to New 2,3-trans-Substituted l-Proline Analogs as Potential Ligands for the Ionotropic Glutamate Receptors.
ACS Chemical Neuroscience ( IF 4.1 ) Pub Date : 2020-02-18 , DOI: 10.1021/acschemneuro.0c00005
Silke Kayser ₁ , Piero Temperini ₁ , Christian B M Poulie ₁ , Markus Staudt ₁ , Birgitte Nielsen ₁ , Darryl S Pickering ₁ , Lennart Bunch ₁

Affiliation

Discovery of chemical tools for the ionotropic glutamate receptors continues to be a challenging task. Herein we report a diversity-oriented approach to new 2,3-trans-l-proline analogs whereby we study how the spatial orientation of the distal carboxylate group influences the binding affinity and receptor class and subtype selectivity. In total, 10 new analogs were synthesized and 14 stereoisomers characterized in binding assays at native rat ionotropic glutamate receptors, and at cloned human homomeric kainic acid (KA) receptor subtypes GluK1-3. The study identified isoxazole analogs 3d,e, which displayed selectivity in binding at native N-methyl-d-aspartate (NMDA) receptors over native α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and KA receptors, in the high nanomolar to low micromolar range. Furthermore, analogs 3i-A/B showed a preference in binding affinity for GluK3 over GluK1,2. Finally, analog 3j displayed high nanomolar affinity for native NMDA receptors as well as for homomeric GluK3 receptors.

中文翻译：

面向新的2,3-trans取代的l-脯氨酸类似物作为离子型谷氨酸受体的潜在配体的面向多样性的合成方法。

寻找离子型谷氨酸受体的化学工具仍然是一项艰巨的任务。本文中，我们报告了一种针对新的2，3-反式-1-脯氨酸类似物的多样性导向方法，从而研究了远端羧酸酯基团的空间取向如何影响结合亲和力，受体类别和亚型选择性。总共合成了10种新的类似物和14种立体异构体，其特征是在天然大鼠离子型谷氨酸受体和克隆的人类同型海藻酸（KA）受体亚型GluK1-3的结合试验中表征。该研究确定了异恶唑类似物3d，e，其对天然N-甲基-d-天冬氨酸（NMDA）受体的结合选择性优于天然α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）和KA受体，范围从高纳摩尔到低微摩尔。此外，类似物3i-A / B显示出对GluK3的结合亲和力优于GluK1,2。最后，类似物3j对天然NMDA受体以及同型GluK3受体表现出高纳摩尔亲和力。

更新日期：2020-02-19

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