自闭症谱系障碍 (ASD) 是一种复杂的神经发育障碍，其特征是社交沟通和互动不足以及行为受限和刻板。目前批准的治疗方法缓解的是合并症，而不是核心症状。由于自闭症谱系障碍中兴奋/抑制平衡和突触可塑性被破坏，因此针对兴奋性突触传递的分子似乎是治疗这种病理学的极有希望的候选者。在谷氨酸能受体中，NMDA 受体在过去十年中受到特别关注，以开发新型变构调节剂。在这里，我们证明了 zelquistinel（一种螺环 β-内酰胺平台化学物质）对 NMDA 受体的正向调节可缓解两种遗传性自闭症谱系障碍（ASD）小鼠模型和一种环境性自闭症谱系障碍（ASD）小鼠模型的核心症状。单次口服剂量的泽奎司汀以剂量反应的方式挽救了小鼠的社交缺陷和刻板行为，而长期腹膜内给药则促进了这些小鼠的此类自闭症样特征的长期缓解。亚慢性口服中剂量泽奎斯汀治疗在 、 和丙戊酸暴露小鼠中显示出持久效果。残留效应在无效小鼠模型中得到了最好的维持，社交参数在治疗停止后两周仍完全恢复。在最近开发的 NMDA 受体亚基调节剂中，泽奎斯汀在缓解 ASD 患者的核心症状方面显示出有希望的治疗潜力，其口服生物利用度和持久效果预示着临床应用的良好前景。具有不同病因的三种小鼠模型的功效支持高转化价值。 此外，该化合物代表了一种创新的药理学工具，可用于研究 ASD 动物模型行为缺陷的可塑性机制。
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The NMDA receptor modulator zelquistinel durably relieves behavioral deficits in three mouse models of autism spectrum disorder
Autism spectrum disorders (ASD) are complex neurodevelopmental disorders characterized by deficient social communication and interaction together with restricted, stereotyped behaviors. Currently approved treatments relieve comorbidities rather than core symptoms. Since excitation/inhibition balance and synaptic plasticity are disrupted in ASD, molecules targeting excitatory synaptic transmission appear as highly promising candidates to treat this pathology. Among glutamatergic receptors, the NMDA receptor has received particular attention through the last decade to develop novel allosteric modulators. Here, we show that positive NMDA receptor modulation by zelquistinel, a spirocyclic β-lactam platform chemical, relieves core symptoms in two genetic and one environmental mouse models of ASD. A single oral dose of zelquistinel rescued, in a dose-response manner, social deficits and stereotypic behavior in mice while chronic intraperitoneal administration promoted a long-lasting relief of such autistic-like features in these mice. Subchronic oral mid-dose zelquistinel treatment demonstrated durable effects in , and valproate-exposed mice. Carry-over effects were best maintained in the null mouse model, with social parameters being still fully recovered two weeks after treatment withdrawal. Among recently developed NMDA receptor subunit modulators, zelquistinel displays a promising therapeutic potential to relieve core symptoms in ASD patients, with oral bioavailability and long-lasting effects boding well for clinical applications. Efficacy in three mouse models with different etiologies supports high translational value. Further, this compound represents an innovative pharmacological tool to investigate plasticity mechanisms underlying behavioral deficits in animal models of ASD.
