Allosteric Modulators of Sigma-1 Receptor: A Review

Vāvers, Edijs; Zvejniece, Liga; Maurice, Tangui; Dambrova, Maija

doi:10.3389/fphar.2019.00223

Cited by 45 publications

(50 citation statements)

References 110 publications

(150 reference statements)

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“…For example, SKF-83959 shows promise in the 6-OHDA-induced rat model of Parkinson’s disease (Zhang et al, 2005, 2007; Guo et al, 2013). Also, OZP002 attenuated learning deficits from scopolamine, ICV injection of amyloid Aβ 25 – 35 , or the APP Swe transgene and protected against neurotoxicity associated with ICV injection of amyloid Aβ 25 – 35 (Vavers et al, 2019). Several selective allosteric modulators for S1R have been discovered (methylphenylpiracetam and SOMCL-668) (see Vavers et al, 2019 for a review) and it will be interesting to see whether they are efficacious in models of neurodegenerative diseases.…”

Section: Role Of S1r In Alzheimer’s Disease (Ad)mentioning

confidence: 99%

“…Also, OZP002 attenuated learning deficits from scopolamine, ICV injection of amyloid Aβ 25 – 35 , or the APP Swe transgene and protected against neurotoxicity associated with ICV injection of amyloid Aβ 25 – 35 (Vavers et al, 2019). Several selective allosteric modulators for S1R have been discovered (methylphenylpiracetam and SOMCL-668) (see Vavers et al, 2019 for a review) and it will be interesting to see whether they are efficacious in models of neurodegenerative diseases. Hinting at potential utility, SOMCL-668 enhanced (+)-SKF-10047-stimulated neurite growth and BDNF production in an S1R-dependent manner (Wang et al, 2016).…”

Section: Role Of S1r In Alzheimer’s Disease (Ad)mentioning

confidence: 99%

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Neuronal Sigma-1 Receptors: Signaling Functions and Protective Roles in Neurodegenerative Diseases

et al. 2019

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Sigma-1 receptor (S1R) is a multi-functional, ligand-operated protein situated in endoplasmic reticulum (ER) membranes and changes in its function and/or expression have been associated with various neurological disorders including amyotrophic lateral sclerosis/frontotemporal dementia, Alzheimer’s (AD) and Huntington’s diseases (HD). S1R agonists are broadly neuroprotective and this is achieved through a diversity of S1R-mediated signaling functions that are generally pro-survival and anti-apoptotic; yet, relatively little is known regarding the exact mechanisms of receptor functioning at the molecular level. This review summarizes therapeutically relevant mechanisms by which S1R modulates neurophysiology and implements neuroprotective functions in neurodegenerative diseases. These mechanisms are diverse due to the fact that S1R can bind to and modulate a large range of client proteins, including many ion channels in both ER and plasma membranes. We summarize the effect of S1R on its interaction partners and consider some of the cell type- and disease-specific aspects of these actions. Besides direct protein interactions in the endoplasmic reticulum, S1R is likely to function at the cellular/interorganellar level by altering the activity of several plasmalemmal ion channels through control of trafficking, which may help to reduce excitotoxicity. Moreover, S1R is situated in lipid rafts where it binds cholesterol and regulates lipid and protein trafficking and calcium flux at the mitochondrial-associated membrane (MAM) domain. This may have important implications for MAM stability and function in neurodegenerative diseases as well as cellular bioenergetics. We also summarize the structural and biochemical features of S1R proposed to underlie its activity. In conclusion, S1R is incredibly versatile in its ability to foster neuronal homeostasis in the context of several neurodegenerative disorders.

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Section: Role Of S1r In Alzheimer’s Disease (Ad)mentioning

confidence: 99%

Section: Role Of S1r In Alzheimer’s Disease (Ad)mentioning

confidence: 99%

Neuronal Sigma-1 Receptors: Signaling Functions and Protective Roles in Neurodegenerative Diseases

et al. 2019

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“…The sigma-1 and sigma-2 receptors are resident proteins in the endoplasmic reticulum (ER) and have historically been associated with neurological disorders, HIV, and cancer. It is also widely known for its interaction with ion channels on the plasma membrane of cells [ 106 ]. They are found to modulate potassium and ion channels and play dual roles of molecular chaperones and receptors [ 104 , 106 ].…”

Section: Small Molecules For Host Directed Therapy Of Sars-cov-2mentioning

confidence: 99%

The HMOX1 Pathway as a Promising Target for the Treatment and Prevention of SARS-CoV-2 of 2019 (COVID-19)

Batra

Souza

Batra

et al. 2020

IJMS

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The coronavirus disease of 2019 (COVID-19) or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is a global pandemic with increasing incidence and mortality rates. Recent evidence based on the cytokine profiles of severe COVID-19 cases suggests an overstimulation of macrophages and monocytes associated with reduced T-cell abundance (lymphopenia) in patients infected with SARS-CoV-2. The SARS-CoV-2 open reading frame 3 a (ORF3a) protein was found to bind to the human HMOX1 protein at a high confidence through high-throughput screening experiments. The HMOX1 pathway can inhibit platelet aggregation, and can have anti-thrombotic and anti-inflammatory properties, amongst others, all of which are critical medical conditions observed in COVID-19 patients. Here, we review the potential of modulating the HMOX1-ORF3a nexus to regulate the innate immune response for therapeutic benefits in COVID-19 patients. We also review other potential treatment strategies and suggest novel synthetic and natural compounds that may have the potential for future development in clinic.

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“…Moreover, several ligands were recently characterized as positive allosteric modulators of S1R [32]. Among them, 4R,5S-methylphenylpiracetam (E1R; Fig.…”

Section: Preclinical Observationsmentioning

confidence: 99%

Bi-phasic dose response in the preclinical and clinical developments of sigma-1 receptor ligands for the treatment of neurodegenerative disorders

Maurice

2020

Expert Opinion on Drug Discovery

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Introduction: The sigma-1 receptor (S1R) is attracting much attention as a target for diseasemodifying therapies in neurodegenerative diseases. It is a highly conserved protein, present in plasma and endoplasmic reticulum (ER) membranes and enriched in mitochondria-associated ER membranes (MAMs). It modulates ER-mitochondria Ca 2+ transfer and activation of the ER stress pathways. Mitochondrial and MAM dysfunctions contribute to neurodegenerative processes in pathologies such as Alzheimer's disease, Parkinson's disease, Huntington's disease or Amyotrophic Lateral Sclerosis. Interestingly, the S1R can be activated by small druggable molecules and accumulating preclinical data suggest that S1R agonists are effective protectants in these neurodegenerative diseases. Area covered: In this review, we will present the data showing the high therapeutic potential of S1R drugs for the treatment of neurodegenerative diseases, focusing on pridopidine as a potent and selective S1R agonist under clinical development. Of particular interest is the biphasic (bell-shaped) dose-response effect, representing a common feature of all S1R agonists and described in numerous preclinical models in vitro, in vivo and in clinical trials. Expert opinion: S1R agonists modulate essential inter-organelles communication altered in all neurodegenerative diseases and activate numerous intracellular survival pathways. Research in the field will continue growing in the near future. The particular cellular nature of this unique chaperone protein must be better understood to facilitate the developement of promising molecules at the clinical stage.

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Allosteric Modulators of Sigma-1 Receptor: A Review

Cited by 45 publications

References 110 publications

Neuronal Sigma-1 Receptors: Signaling Functions and Protective Roles in Neurodegenerative Diseases

Neuronal Sigma-1 Receptors: Signaling Functions and Protective Roles in Neurodegenerative Diseases

The HMOX1 Pathway as a Promising Target for the Treatment and Prevention of SARS-CoV-2 of 2019 (COVID-19)

Bi-phasic dose response in the preclinical and clinical developments of sigma-1 receptor ligands for the treatment of neurodegenerative disorders

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