Novel S1R agonists counteracting NMDA excitotoxicity and oxidative stress: A step forward in the discovery of neuroprotective agents

Linciano, Pasquale; Sorbi, Claudia; Rossino, Giacomo; Rossi, Daniela; Marsala, Andrea; Denora, Nunzio; Bedeschi, Martina; Marino, Noemi; Miserocchi, Giacomo; Dondio, Giulio; Peviani, Marco; Tesei, Anna; Collina, Simona; Franchini, Silvia

doi:10.1016/j.ejmech.2023.115163

Cited by 10 publications

(6 citation statements)

References 68 publications

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“…S1R is known to be activated, i.e., to initiate the separation of S1R and BiP, by cellular stress such as ER calcium depletion [ 2 ] and oxidative stress [ 23 , 45 ]. From a molecular point of view, the way that these phenoma impact S1R and its structure is not known.…”

Section: Resultsmentioning

confidence: 99%

Benzomorphan and non-benzomorphan agonists differentially alter sigma-1 receptor quaternary structure, as does types of cellular stress

Couly,

Yasui,

Foncham

et al. 2024

Cell. Mol. Life Sci.

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Sigma-1 receptor (S1R) is a calcium-sensitive, ligand-operated receptor chaperone present on the endoplasmic reticulum (ER) membrane. S1R plays an important role in ER-mitochondrial inter-organelle calcium signaling and cell survival. S1R and its agonists confer resilience against various neurodegenerative diseases; however, the molecular mechanism of S1R is not yet fully understood. At resting state, S1R is either in a monomeric or oligomeric state but the ratio of these concentrations seems to change upon activation of S1R. S1R is activated by either cellular stress, such as ER-calcium depletion, or ligands. While the effect of ligands on S1R quaternary structure remains unclear, the effect of cellular stress has not been studied. In this study we utilize cellular and an in-vivo model to study changes in quaternary structure of S1R upon activation. We incubated cells with cellular stressors (H2O2 and thapsigargin) or exogenous ligands, then quantified monomeric and oligomeric forms. We observed that benzomorphan-based S1R agonists induce monomerization of S1R and decrease oligomerization, which was confirmed in the liver tissue of mice injected with (+)-Pentazocine. Antagonists block this effect but do not induce any changes when used alone. Oxidative stress (H2O2) increases the monomeric/oligomeric S1R ratio whereas ER calcium depletion (thapsigargin) has no effect. We also analyzed the oligomerization ability of various truncated S1R fragments and identified the fragments favorizing oligomerization. In this publication we demonstrate that quaternary structural changes differ according to the mechanism of S1R activation. Therefore, we offer a novel perspective on S1R activation as a nuanced phenomenon dependent on the type of stimulus.

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Section: Resultsmentioning

confidence: 99%

Benzomorphan and non-benzomorphan agonists differentially alter sigma-1 receptor quaternary structure, as does types of cellular stress

Couly,

Yasui,

Foncham

et al. 2024

Cell. Mol. Life Sci.

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“…DE to give 0.008 g (0.011 mmol, 63% yield) of an iridescent orange solid. HRMS-ESI: m/z Binding affinity at human S2R was performed with Eurofins using a radioligand displacement assay in the presence of [ 3 H]-ditolylguanidine (at 25 nM) as nonselective S2R radioligand plus (+)pentazocine (at 1 µM) as selective S1R radioligand, as previously reported [64,65].…”

Section: Synthesis Of Bs148-fluomentioning

confidence: 99%

BS148 Reduces the Aggressiveness of Metastatic Melanoma via Sigma-2 Receptor Targeting

Sorbi

Belluti

Atene

et al. 2023

IJMS

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The management of advanced-stage melanoma is clinically challenging, mainly because of its resistance to the currently available therapies. Therefore, it is important to develop alternative therapeutic strategies. The sigma-2 receptor (S2R) is overexpressed in proliferating tumor cells and represents a promising vulnerability to target. Indeed, we have recently identified a potent S2R modulator (BS148) that is effective in melanoma. To elucidate its mechanism of action, we designed and synthesized a BS148 fluorescent probe that enters SK-MEL-2 melanoma cells as assessed using confocal microscopy analysis. We show that S2R knockdown significantly reduces the anti-proliferative effect induced by BS148 administration, indicating the engagement of S2R in BS148-mediated cytotoxicity. Interestingly, BS148 treatment showed similar molecular effects to S2R RNA interference-mediated knockdown. We demonstrate that BS148 administration activates the endoplasmic reticulum stress response through the upregulation of protein kinase R-like ER kinase (PERK), activating transcription factor 4 (ATF4) genes, and C/EBP homologous protein (CHOP). Furthermore, we show that BS148 treatment downregulates genes related to the cholesterol pathway and activates the MAPK signaling pathway. Finally, we translate our results into patient-derived xenograft (PDX) cells, proving that BS148 treatment reduces melanoma cell viability and migration. These results demonstrate that BS148 is able to inhibit metastatic melanoma cell proliferation and migration through its interaction with the S2R and confirm its role as a promising target to treat cancer.

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“…The latter was shown to participate in chlorination as well as chloroformylation reactions [16]. Compounds containing a 2-chloroethoxy chain are of particular interest, as they can be readily modified through a nucleophilic substitution reaction with various amines to furnish aminoalkoxy-functionalized potential anti-cancer, neuroprotective, or biological imaging agents [17][18][19]. 2-Amino-6-(2-chloroethoxy)benzothiazole was used in the preparation of cationic azo dyes [20], while 2-chloroethoxyacetaldehyde has been revealed to participate in an organocatalytic asymmetric direct cross-aldol reaction with aromatic aldehydes to yield chiral dioxanes and morpholines, which often possess various biological activities [21].…”

Section: Introductionmentioning

confidence: 99%

3-(2-Chloroethoxy)-1-(4-methoxyphenyl)-1H-pyrazole-4-carbaldehyde

Varvuolytė,

Bieliauskas,

Kleizienė

et al. 2024

Molbank

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Novel S1R agonists counteracting NMDA excitotoxicity and oxidative stress: A step forward in the discovery of neuroprotective agents

Cited by 10 publications

References 68 publications

Benzomorphan and non-benzomorphan agonists differentially alter sigma-1 receptor quaternary structure, as does types of cellular stress

Benzomorphan and non-benzomorphan agonists differentially alter sigma-1 receptor quaternary structure, as does types of cellular stress

BS148 Reduces the Aggressiveness of Metastatic Melanoma via Sigma-2 Receptor Targeting

3-(2-Chloroethoxy)-1-(4-methoxyphenyl)-1H-pyrazole-4-carbaldehyde

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