AimsWe aimed to evaluate the potential of a novel selective α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole‐propionic acid receptor (AMPAR) potentiator, LT‐102, in treating cognitive impairments associated with schizophrenia (CIAS) and elucidating its mechanism of action.MethodsThe activity of LT‐102 was examined by Ca2+ influx assays and patch‐clamp in rat primary hippocampal neurons. The structure of the complex was determined by X‐ray crystallography. The selectivity of LT‐102 was evaluated by hERG tail current recording and kinase‐inhibition assays. The electrophysiological characterization of LT‐102 was characterized by patch‐clamp recording in mouse hippocampal slices. The expression and phosphorylation levels of proteins were examined by Western blotting. Cognitive function was assessed using the Morris water maze and novel object recognition tests.ResultsLT‐102 is a novel and selective AMPAR potentiator with little agonistic effect, which binds to the allosteric site formed by the intradimer interface of AMPAR's GluA2 subunit. Treatment with LT‐102 facilitated long‐term potentiation in mouse hippocampal slices and reversed cognitive deficits in a phencyclidine‐induced mouse model. Additionally, LT‐102 treatment increased the protein level of brain‐derived neurotrophic factor and the phosphorylation of GluA1 in primary neurons and hippocampal tissues.ConclusionWe conclude that LT‐102 ameliorates cognitive impairments in a phencyclidine‐induced model of schizophrenia by enhancing synaptic function, which could make it a potential therapeutic candidate for CIAS.

中文翻译：

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新型α-氨基-3-羟基-5-甲基-4-异恶唑-丙酸受体（AMPAR）增强剂LT-102：一种有前途的治疗精神分裂症相关认知障碍的治疗剂

目的我们旨在评估新型选择性 α-氨基-3-羟基-5-甲基-4-异恶唑-丙酸受体 (AMPAR) 增强剂 LT-102 在治疗与精神分裂症 (CIAS) 相关的认知障碍 (CIAS) 方面的潜力，并阐明方法Ca2+检测LT-102的活性2+大鼠原代海马神经元的流入测定和膜片钳。通过X射线晶体学确定了配合物的结构。通过 hERG 尾电流记录和激酶抑制测定评估 LT-102 的选择性。 LT-102 的电生理学特征通过小鼠海马切片的膜片钳记录来表征。通过Western blotting检测蛋白质的表达和磷酸化水平。使用Morris水迷宫和新物体识别测试评估认知功能。结果LT-102是一种新型选择性AMPAR增效剂，几乎没有激动作用，它与AMPAR GluA2亚基内二聚体界面形成的变构位点结合。 LT-102 治疗促进了小鼠海马切片的长期增强，并逆转了苯环己哌啶诱导的小鼠模型中的认知缺陷。此外，LT-102 治疗增加了脑源性神经营养因子的蛋白质水平以及原代神经元和海马组织中 GluA1 的磷酸化。结论我们得出结论，LT-102 通过增强突触功能来改善苯环己哌啶诱导的精神分裂症模型中的认知障碍，这可能使其成为 CIAS 的潜在治疗候选者。