Department of Chemical and Pharmaceutical Sciences, University of Trieste, Via Giorgieri 1, 34127 Trieste, Italy.
Department of Life Sciences, University of Trieste, Via Valerio 28, 34127 Trieste, Italy.
Molecules. 2023 Apr 13;28(8):3431. doi: 10.3390/molecules28083431.
Neurodegeneration is a slow and progressive loss of neuronal cells or their function in specific regions of the brain or in the peripheral system. Among several causes responsible for the most common neurodegenerative diseases (NDDs), cholinergic/dopaminergic pathways, but also some endogenous receptors, are often involved. In this context, sigma 1 receptor (S1R) modulators can be used as neuroprotective and antiamnesic agents. Herein, we describe the identification of novel S1R ligands endowed with antioxidant properties, potentially useful as neuroprotective agents. We also computationally assessed how the most promising compounds might interact with the S1R protein's binding sites. The in silico predicted ADME properties suggested that they could be able to cross the brain-blood-barrier (BBB), and to reach the targets. Finally, the observation that at least two novel ifenprodil analogues ( and ) induce an increase of the mRNA levels of the antioxidant NRF2 and SOD1 genes in SH-SY5Y cells suggests that they might be effective agents for protecting neurons against oxidative damage.
神经退行性变是大脑特定区域或外周系统中神经元细胞或其功能的缓慢进行性丧失。在导致最常见神经退行性疾病（NDDs）的几个原因中，胆碱能/多巴胺能途径，以及一些内源性受体，通常涉及其中。在这种情况下，sigma 1 受体（S1R）调节剂可用作神经保护和抗健忘药物。本文描述了鉴定具有抗氧化特性的新型 S1R 配体的方法，这些配体可能可用作神经保护剂。我们还通过计算评估了最有前途的化合物可能与 S1R 蛋白的结合位点相互作用的方式。计算机预测的 ADME 特性表明，它们可能能够穿过血脑屏障（BBB）并到达靶点。最后，观察到至少两种新型ifenprodil 类似物（和）可诱导 SH-SY5Y 细胞中抗氧化 NRF2 和 SOD1 基因的 mRNA 水平增加，这表明它们可能是保护神经元免受氧化损伤的有效药物。
