(R)-7 [(R)-AS-1] showed broad-spectrum antiseizure activity across in vivo mouse seizure models: maximal electroshock (MES), 6 Hz (32/44 mA), acute pentylenetetrazol (PTZ), and PTZ-kindling. A remarkable separation between antiseizure activity and CNS-related adverse effects was also observed. In vitro studies with primary glia cultures and COS-7 cells expressing the glutamate transporter EAAT2 showed enhancement of glutamate uptake, revealing a stereoselective positive allosteric modulator (PAM) effect, further supported by molecular docking simulations. (R)-7 [(R)-AS-1] was not active in EAAT1 and EAAT3 assays and did not show significant off-target activity, including interactions with targets reported for marketed antiseizure drugs, indicative of a novel and unprecedented mechanism of action. Both in vivo pharmacokinetic and in vitro absorption, distribution, metabolism, excretion, toxicity (ADME-Tox) profiles confirmed the favorable drug-like potential of the compound. Thus, (R)-7 [(R)-AS-1] may be considered as the first-in-class small-molecule PAM of EAAT2 with potential for further preclinical and clinical development in epilepsy and possibly other CNS disorders.

中文翻译：

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发现 (R)-N-Benzyl-2-(2,5-dioxopyrrolidin-1-yl)propanamide [(R)-AS-1]，一种新型口服生物可利用的 EAAT2 调节剂，具有药物样特性和强大的抗癫痫活性活体

( R )-7 [ ( R )-AS-1 ] 在体内小鼠癫痫发作模型中表现出广谱抗癫痫活性：最大电击 (MES)、6 Hz (32/44 mA)、急性戊四氮 (PTZ) 和 PTZ -点燃。还观察到抗癫痫活性和 CNS 相关不良反应之间的显着分离。对原代神经胶质细胞培养物和表达谷氨酸转运蛋白 EAAT2 的 COS-7 细胞进行的体外研究表明，谷氨酸摄取增强，揭示了立体选择性正变构调节剂 (PAM) 效应，并得到分子对接模拟的进一步支持。( R )-7 [ ( R )-AS-1] 在 EAAT1 和 EAAT3 检测中没有活性，也没有显示出显着的脱靶活性，包括与已上市抗癫痫药物报告的靶标相互作用，表明存在一种前所未有的新型作用机制。体内药代动力学和体外吸收、分布、代谢、排泄、毒性 (ADME-Tox) 曲线均证实了该化合物具有良好的类药潜力。因此，( R )-7 [ ( R )-AS-1 ] 可被视为 EAAT2 的一流小分子 PAM，具有在癫痫和可能的其他中枢神经系统疾病中进一步临床前和临床开发的潜力。