We have synthesized a novel small molecule based on the pyrrolidinone–containing core structure of clausenamide, which is a candidate anti–dementia drug. The synthetic route yielded multi–gram quantities of an isomeric racemate mixture in a short number of steps. When tested in hippocampal slices from young adult rats the compound enhanced AMPA receptor–mediated signalling at mossy fibre synapses, and potentiated inward currents evoked by local application of l–glutamate onto CA3 pyramidal neurons. It facilitated the induction of mossy fibre LTP, but the magnitude of potentiation was smaller than that observed in untreated slices. The racemic mixture was separated and it was shown that only the (−) enantiomer was active. Toxicity analysis indicated that cell lines tolerated the compound at concentrations well above those enhancing synaptic transmission. Our results unveil a small molecule whose physiological signature resembles that of a potent nootropic drug.

我们基于含吡咯烷酮的黄嘌呤酰胺核心结构合成了一种新型小分子，这是一种抗痴呆候选药物。合成路线可在很短的步骤中产生数克量的异构体外消旋混合物。当在成年幼鼠的海马切片中进行测试时，该化合物增强了苔藓纤维突触处的AMPA受体介导的信号传导，并增强了局部应用l引起的内向电流-谷氨酸到CA3锥体神经元上。它促进了长满苔藓的纤维LTP的诱导，但增强作用的幅度小于未处理切片中观察到的增强作用。分离了外消旋混合物，表明仅（-）对映异构体是活性的。毒性分析表明，细胞系以远高于增强突触传递的浓度耐受该化合物。我们的研究结果揭示了一种小分子，其生理特征类似于有效的促智药物。