Prostaglandin E2 (PGE₂) via its Gα_s-coupled EP2 receptor protects cerebral cortical neurons from excitotoxic and anoxic injury, though EP2 receptor activation can also cause secondary neurotoxicity in chronic inflammation. We performed a high-throughput screen of a library of 292 000 small molecules and identified several compounds that have a 2-piperidinyl phenyl benzamide or trisubstituted pyrimidine core as positive modulators for human EP2 receptor. The most active compounds increased the potency of PGE₂ on EP2 receptor 4–5-fold at 20 μM without altering efficacy, indicative of an allosteric mechanism. These compounds did not augment the activity of the other Gα_s-coupled PGE₂ receptor subtype EP4 and showed neuroprotection against N-methyl-d-aspartate (NMDA)-induced excitotoxicity. These newly developed compounds represent second-generation allosteric potentiators for EP2 receptor and shed light on a promising neuroprotective strategy. They should prove valuable as molecular tools to achieve a better understanding of the dichotomous action of brain EP2 receptor activation.

中文翻译：

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发现 2-哌啶基苯基苯甲酰胺和三取代嘧啶作为前列腺素受体 EP2 的正变构调节剂

前列腺素 E2 (PGE ₂ ) 通过其 Gα _s偶联 EP2 受体保护大脑皮层神经元免受兴奋性毒性和缺氧损伤，尽管 EP2 受体激活也可能导致慢性炎症中的继发性神经毒性。我们对 292 000 个小分子库进行了高通量筛选，并鉴定了几种具有 2-哌啶基苯基苯甲酰胺或三取代嘧啶核心的化合物作为人 EP2 受体的正调节剂。最活跃的化合物在 20 μM 浓度下可将PGE _{2对 EP2 受体的效力提高 4-5 倍，而不会改变功效，这表明存在变构机制。}这些化合物不会增强其他 Gα _s偶联的 PGE ₂受体亚型 EP4 的活性，并且显示出针对N-甲基-d-天冬氨酸 (NMDA) 诱导的兴奋性毒性的神经保护作用。这些新开发的化合物代表了 EP2 受体的第二代变构增强剂，并揭示了一种有前景的神经保护策略。它们应该被证明是有价值的分子工具，可以更好地理解大脑 EP2 受体激活的二分作用。