Tuning melatonin receptor subtype selectivity in oxadiazolone-based analogues: Discovery of QR2 ligands and NRF2 activators with neurogenic properties
Author
Herrera-Arozamena, Clara; Estrada-Valencia, Martín; Pérez, Concepción; Lagartera, Laura; Morales-García, José A.; Pérez-Castillo, Ana; Franco-Gonzalez, Juan Felipe; Michalska, Patrycja; Duarte, Pablo; León, Rafael; López, Manuela G.; Mills, Alberto; Gago, Federico; García-Yagüe, Ángel Juan; Fernández-Ginés, Raquel; Cuadrado Pastor, Antonio
Entity
UAM. Departamento de Bioquímica; Instituto de Investigaciones Biomédicas "Alberto Sols" (IIBM); Instituto Teófilo Hernando de I+D del Medicamento (ITH)Publisher
Elsevier Masson SASDate
2020-01-25Citation
10.1016/j.ejmech.2020.112090
European Journal of Medicinal Chemistry 190 (2020): 112090
ISSN
0223-5234 (print); 1768-3254 (online)DOI
10.1016/j.ejmech.2020.112090Funded by
The authors gratefully acknowledge the following financial supports: Spanish Ministry of Science, Innovation and Universities; Spanish Research Agency; and European Regional Development Funds (grants RTI2018-093955-B-C21 and SAF2015-64948-C2-1-R to M.I.R.-F.; RTI2018-095793-B-I00 to M.G.L., SAF2015-64629-C2- 2-R to F.G.), General Council for Research and Innovation of the Community of Madrid and European Structural Funds (grant B2017/BMD-3827 e NRF24ADCM), Health Institute Carlos III (Miguel Servet II ProgramCP16/00014 and grant PI17/01700 to R.L.). CH-A and P.M. thank their PhD fellowships from Spanish Ministry of Education (MEC, PhD grant FPU16/01704 and mobility grant FPUEST17/00233 to CH-A and FPU13/03737 to P.M.).Project
Gobierno de España. RTI2018-095793-B-I00; Comunidad de Madrid. B2017/BMD-3827/NRF24AD; Gobierno de España. PI17/01700Editor's Version
https://doi.org/10.1016/j.ejmech.2020.112090Subjects
Indole 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); MedicinaRights
© 2020 The AuthorsAbstract
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
Files in this item
Google Scholar:Herrera-Arozamena, Clara
-
Estrada-Valencia, Martín
-
Pérez, Concepción
-
Lagartera, Laura
-
Morales-García, José A.
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Pérez-Castillo, Ana
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Franco-Gonzalez, Juan Felipe
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Michalska, Patrycja
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Duarte, Pablo
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León, Rafael
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López, Manuela G.
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Mills, Alberto
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Gago, Federico
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García-Yagüe, Ángel Juan
-
Fernández-Ginés, Raquel
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Cuadrado Pastor, Antonio
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Rodríguez-Franco, María Isabel
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