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

Herrera-Arozamena, Clara; Estrada-Valencia, Martín; Pérez, Concepción; Lagartera, Laura; Morales-García, José A.; Pérez-Castillo, Ana; Franco-González, Juan Felipe; Michalska, Patrycja; Duarte, Pablo Daniel Palacios; León, Rafael; López, Manuela G.; Mills, Alberto; Gago, Federico; García-Yagüe, Ángel Juan; Fernández-Ginés, Raquel; Cuadrado, Antonio; Rodríguez‐Franco, María Isabel

doi:10.1016/j.ejmech.2020.112090

Cited by 18 publications

(21 citation statements)

References 96 publications

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“…Many anti-inflammatory mediators have been demonstrated to enhance HO-1 expression, which subsequently inhibits inflammation (Lee and Chau, 2002;Lee et al, 2003). Recently it has been demonstrated that melatonin acts through the Nrf2 pathway and prevents the decline of antioxidant enzyme activities during brain pathological conditions (Moezi et al, 2011;Mendez-David et al, 2015;Herrera-Arozamena et al, 2020;Zhi W. et al, 2020), supporting our results that endogenous melatonin counterbalances the oxidative stress by boosting the body antioxidants system via its receptors. Our results are also in agreement with growing evidence that melatonin enhances HO-1 expression via NF-κB, p38 MAPK, and Nrf2 cascade signaling mechanism (Santofimia-Castaño et al, 2015;Yu et al, 2017;Shah et al, 2017;Ma et al, 2018;Zhao et al, 2018;Rehman et al, 2019;Xi et al, 2019;García et al, 2020;Hein et al, 2020;Zhou et al, 2020;Zhi W. et al, 2020).…”

Section: Discussionsupporting

confidence: 89%

Melatonin Act as an Antidepressant via Attenuation of Neuroinflammation by Targeting Sirt1/Nrf2/HO-1 Signaling

Ali

Hao

Ullah

et al. 2020

Front. Mol. Neurosci.

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Physical or psychological stress can cause an immunologic imbalance that disturbs the central nervous system followed by neuroinflammation. The association between inflammation and depression has been widely studied in recent years, though the molecular mechanism is still largely unknown. Thus, targeting the signaling pathways that link stress to neuroinflammation might be a useful strategy against depression. The current study investigated the protective effect of melatonin against lipopolysaccharide (LPS)-induced neuroinflammation and depression. Our results showed that LPS treatment significantly induced depressive-like behavior in mice. Moreover, LPStreatment enhanced oxidative stress, pro-inflammatory cytokines including TNFα, IL-6, and IL-1β, NF-κB phosphorylation, and glial cell activation markers including GFAP and Iba-1 in the brain of mice. Melatonin treatment significantly abolished the effect of LPS, as indicated by improved depressive-like behaviors, reduced cytokines level, reduced oxidative stress, and normalized LPS-altered Sirt1, Nrf2, and HO-1 expression. However, the melatonin protective effects were reduced after luzindole administration. Collectively, it is concluded that melatonin receptor-dependently protects against LPSinduced depressive-like behaviors via counteracting LPS-induced neuroinflammation.

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Section: Discussionsupporting

confidence: 89%

Melatonin Act as an Antidepressant via Attenuation of Neuroinflammation by Targeting Sirt1/Nrf2/HO-1 Signaling

Ali

Hao

Ullah

et al. 2020

Front. Mol. Neurosci.

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“…The MD simulations of the membrane-embedded glycosylated gp120:gp41 trimer and the complex of the external region with 33 ( AL-518 ) were run for 400 ns essentially as described before for other membrane receptors , and EV71 VP1, respectively.…”

Section: Methodsmentioning

confidence: 99%

Double Arylation of the Indole Side Chain of Tri- and Tetrapodal Tryptophan Derivatives Renders Highly Potent HIV-1 and EV-A71 Entry Inhibitors

et al. 2021

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We have recently described a new generation of potent human immunodeficiency virus (HIV) and EV-A71 entry inhibitors. The prototypes contain three or four tryptophan (Trp) residues bearing an isophthalic acid moiety at the C2 position of each side-chain indole ring. This work is now extended by both shifting the position of the isophthalic acid to C7 and synthesizing doubly arylated C2/C7 derivatives. The most potent derivative (50% effective concentration (EC 50 ) HIV-1, 6 nM; EC 50 EV-A71, 40 nM), 33 ( AL-518 ), is a C2/C7 doubly arylated tetrapodal compound. Its superior anti-HIV potency with respect to the previous C2-arylated prototype is in consonance with its higher affinity for the viral gp120. 33 ( AL-518 ) showed comparable antiviral activities against X4 and R5 HIV-1 strains and seems to interact with the tip and base of the gp120 V3 loop. Taken together, these findings support the interest in 33 ( AL-518 ) as a useful new prototype for anti-HIV/EV71 drug development.

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“…A FluoStar Optima plate reader (BMG LABTECH, GmbH, Offenburg, Germany) with 485 nm excitation and 520 nm emission filters [ 32 , 33 ] was used for this assay. 2,2′-Azobis-(amidinopropane) dihydrochloride (AAPH), trolox and fluorescein (FL) were purchased from Sigma-Aldrich and 75 mM phosphate buffer (pH 7.4) was used as the reaction medium.…”

Section: Methodsmentioning

confidence: 99%

Curcumin-Piperlongumine Hybrids with a Multitarget Profile Elicit Neuroprotection in In Vitro Models of Oxidative Stress and Hyperphosphorylation

et al. 2021

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Curcumin shows a broad spectrum of activities of relevance in the treatment of Alzheimer’s disease (AD); however, it is poorly absorbed and is also chemically and metabolically unstable, leading to a very low oral bioavailability. A small library of hybrid compounds designed as curcumin analogues and incorporating the key structural fragment of piperlongumine, a natural neuroinflammation inhibitor, were synthesized by a two-step route that combines a three-component reaction between primary amines, β-ketoesters and α-haloesters and a base-promoted acylation with cinnamoyl chlorides. These compounds were predicted to have good oral absorption and CNS permeation, had good scavenging properties in the in vitro DPPH experiment and in a cellular assay based on the oxidation of dichlorofluorescin to a fluorescent species. The compounds showed low toxicity in two cellular models, were potent inductors of the Nrf2-ARE phase II antioxidant response, inhibited PHF6 peptide aggregation, closely related to Tau protein aggregation and were active against the LPS-induced inflammatory response. They also afforded neuroprotection against an oxidative insult induced by inhibition of the mitochondrial respiratory chain with the rotenone-oligomycin A combination and against Tau hyperphosphorylation induced by the phosphatase inhibitor okadaic acid. This multitarget pharmacological profile is highly promising in the development of treatments for AD and provides a good hit structure for future optimization efforts.

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

Cited by 18 publications

References 96 publications

Melatonin Act as an Antidepressant via Attenuation of Neuroinflammation by Targeting Sirt1/Nrf2/HO-1 Signaling

Melatonin Act as an Antidepressant via Attenuation of Neuroinflammation by Targeting Sirt1/Nrf2/HO-1 Signaling

Double Arylation of the Indole Side Chain of Tri- and Tetrapodal Tryptophan Derivatives Renders Highly Potent HIV-1 and EV-A71 Entry Inhibitors

Curcumin-Piperlongumine Hybrids with a Multitarget Profile Elicit Neuroprotection in In Vitro Models of Oxidative Stress and Hyperphosphorylation

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