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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >Tuning melatonin receptor subtype selectivity in oxadiazolone-based analogues: Discovery of QR2 ligands and NRF2 activators with neurogenic properties
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Tuning melatonin receptor subtype selectivity in oxadiazolone-based analogues: Discovery of QR2 ligands and NRF2 activators with neurogenic properties

机译：在基于恶日唑酮的类似物中调整褪黑激素受体亚型选择性：发现QR2配体和NRF2激活剂的神经源性特性

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摘要

New multi-target indole and naphthalene derivatives containing the oxadiazolone scaffold as a bioisostere of the melatonin acetamido group have been developed. The novel compounds were characterized at melatonin receptors MT1R and MT2R, quinone reductase 2 (QR2), lipoxygenase-5 (LOX-5), and monoamine oxidases (MAO-A and MAO-B), and also as radical scavengers. We found that selectivity within the oxadiazolone series can be modulated by modifying the side chain functionality and coplanarity with the indole or naphthalene ring. In phenotypic assays, several oxadiazolone-based derivatives induced signalling mediated by the transcription factor NRF2 and promoted the maturation of neural stem-cells into a neuronal phenotype. Activation of NRF2 could be due to the binding of indole derivatives to KEAP1, as deduced from surface plasmon resonance (SPR) experiments. Molecular modelling studies using the crystal structures of QR2 and the KEAP1 Kelch-domain, as well as the recently described X-ray free-electron laser (XFEL) structures of chimeric MT1R and MT2R, provided a rationale for the experimental data and afforded valuable insights for future drug design endeavours. (C) 2020 The Authors. Published by Elsevier Masson SAS.
机译：已经开发出含有恶酰丙酮支架作为褪黑激素乙酰氨基甲酰乙酰氨基基团的生物异型吲哚和萘甲烯衍生物的新型多目标吲哚和萘衍生物。在褪黑激素受体MT1R和MT2R，醌还原酶2（QR2），脂氧合酶-5（LOX-5）和单胺氧化酶（MAO-A和MAO-B）中，以及作为自由基清除剂的新化合物。我们发现，通过用吲哚或萘环改变侧链官能度和共面，可以调节恶二唑酮系列中的选择性。在表型测定中，几种基于恶氮沸醇的衍生物诱导由转录因子NRF2介导的信号传导，并将神经干细胞的成熟促进到神经元表型中。 NRF2的活化可能是由于吲哚衍生物与Keap1的结合，从表面等离子体共振（SPR）实验中推断出。使用QR2的晶体结构和KEAP1 KELCH域，以及最近描述的X射线自由电子激光（XFEL）嵌合MT1R和MT2R的结构，分子建模研究的实验数据提供的理由，并得到有价值的见解对于未来的药物设计努力。 （c）2020作者。由Elsevier Masson SA出版。

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