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Title

Tuning melatonin receptor subtype selectivity in oxadiazolone-based analogues: Discovery of QR2 ligands and NRF2 activators with neurogenic properties

AuthorsHerrera-Arozamena, Clara; Estrada-Valencia, M.; Pérez, Concepción; Lagartera, Laura ; Morales-García, José A. ; Perez-Castillo, Ana; Franco-Gonzalez, Juan Felipe ; Michalska, P.; Duarte, P.; León, R.; López, Manuela G.; Mills, Alberto; Gago, Federico ; García-Yagüe, Ángel Juan; Fernández-Ginés, Raquel; Cuadrado, Antonio ; Rodríguez-Franco, María Isabel
KeywordsIndole or naphthalene e oxadiazolones
Melatonin receptors (MT1R and MT2R)
Quinone reductase-2 (QR2)
Nuclear erythroid 2-related factor (NRF2)
Kelch-like ECH associated protein 1 (KEAP1)
Issue Date2020
PublisherElsevier
CitationEuropean Journal of Medicinal Chemistry 190 (2020)
AbstractNew 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 MTR and MTR, 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 co-planarity 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 MTR and MTR, provided a rationale for the experimental data and afforded valuable insights for future drug design endeavours.
Publisher version (URL)http://dx.doi.org/10.1016/j.ejmech.2020.112090
URIhttp://hdl.handle.net/10261/219073
Identifiersdoi: 10.1016/j.ejmech.2020.112090
issn: 1768-3254
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(IQM) Artículos
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