Sigma-2 Receptor Ligands: Neurobiological Effects

Guo, Lin; Zhen, Xuechu

doi:10.2174/0929867322666150114163607

Cited by 64 publications

(70 citation statements)

References 71 publications

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“…11,12 σ 2R/TMEM97 has long been associated with cancer, 13,14 and it is increasingly being implicated in cellular processes relevant to a variety of CNS disorders, 10,15 including Alzheimer's disease (AD), 8,16–18 schizophrenia, 10 anxiety, pain, 19 and Niemann-Pick disease. 12 …”

Section: Introductionmentioning

confidence: 99%

High-Content Microfluidic Screening Platform Used To Identify σ2R/Tmem97 Binding Ligands that Reduce Age-Dependent Neurodegeneration in C. elegans SC_APP Model

Mondal

Hegarty

Sahn

et al. 2018

ACS Chem. Neurosci.

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The nematode Caenorhabditis elegans, with tractable genetics and a well-defined nervous system, provides a unique whole-animal model system to identify novel drug targets and therapies for neurodegenerative diseases. Large-scale drug or target screens in models that recapitulate the subtle age- and cell-specific aspects of neurodegenerative diseases are limited by a technological requirement for high-throughput analysis of neuronal morphology. Recently, we developed a single-copy model of amyloid precursor protein (SC_APP) induced neurodegeneration that exhibits progressive degeneration of select cholinergic neurons. Our previous work with this model suggests that small molecule ligands of the sigma 2 receptor (σ2R), which was recently cloned and identified as transmembrane protein 97 (TMEM97), are neuroprotective. To determine structure–activity relationships for unexplored chemical space in our σ2R/Tmem97 ligand collection, we developed an in vivo high-content screening (HCS) assay to identify potential drug leads. The HCS assay uses our recently developed large-scale microfluidic immobilization chip and automated imaging platform. We discovered norbenzomorphans that reduced neurodegeneration in our C. elegans model, including two compounds that demonstrated significant neuroprotective activity at multiple doses. These findings provide further evidence that σ2R/Tmem97-binding norbenzomorphans may represent a new drug class for treating neurodegenerative diseases.

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Section: Introductionmentioning

confidence: 99%

High-Content Microfluidic Screening Platform Used To Identify σ2R/Tmem97 Binding Ligands that Reduce Age-Dependent Neurodegeneration in C. elegans SC_APP Model

Mondal

Hegarty

Sahn

et al. 2018

ACS Chem. Neurosci.

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“…223 Much less was known about its role in the CNS, but it has since been increasingly implicated in cellular processes relative to CNS disorders. 224 …”

Section: Mimics Of Natural Productsmentioning

confidence: 99%

Natural Products and Their Mimics as Targets of Opportunity for Discovery

Martin

2017

J. Org. Chem.

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Diverse structural types of natural products and their mimics have served as targets of opportunity in our laboratory to inspire the discovery and development of new methods and strategies to assemble polyfunctional and polycyclic molecular architectures. Furthermore, our efforts toward identifying novel compounds having useful biological properties led to the creation of new targets, many of which posed synthetic challenges that required the invention of new methodology. In this Perspective, selected examples of how we have exploited a diverse range of natural products and their mimics to create, explore, and solve a variety of problems in chemistry and biology will be discussed. The journey was not without its twists and turns, but the unexpected often led to new revelations and insights. Indeed, in our recent excursion into applications of synthetic organic chemistry to neuroscience, avoiding the more-traveled paths was richly rewarding.

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“…The σ 2 receptor has not yet been cloned or crystallized and the knowledge about this receptor has mostly been generated through in vitro receptor radioligand binding studies [7, 8]. As reported the σ 2 receptor has a MW between 18 and 21 kDa [9, 10].…”

Section: Introductionmentioning

confidence: 99%

S2RSLDB: a comprehensive manually curated, internet-accessible database of the sigma-2 receptor selective ligands

et al. 2017

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Background Sigma (σ) receptors are accepted as a particular receptor class consisting of two subtypes: sigma-1 (σ1) and sigma-2 (σ2). The two receptor subtypes have specific drug actions, pharmacological profiles and molecular characteristics. The σ2 receptor is overexpressed in several tumor cell lines, and its ligands are currently under investigation for their role in tumor diagnosis and treatment. The σ2 receptor structure has not been disclosed, and researchers rely on σ2 receptor radioligand binding assay to understand the receptor’s pharmacological behavior and design new lead compounds.Description Here we present the sigma-2 Receptor Selective Ligands Database (S2RSLDB) a manually curated database of the σ2 receptor selective ligands containing more than 650 compounds. The database is built with chemical structure information, radioligand binding affinity data, computed physicochemical properties, and experimental radioligand binding procedures. The S2RSLDB is freely available online without account login and having a powerful search engine the user may build complex queries, sort tabulated results, generate color coded 2D and 3D graphs and download the data for additional screening.ConclusionThe collection here reported is extremely useful for the development of new ligands endowed of σ2 receptor affinity, selectivity, and appropriate physicochemical properties. The database will be updated yearly and in the near future, an online submission form will be available to help with keeping the database widely spread in the research community and continually updated. The database is available at http://www.researchdsf.unict.it/S2RSLDB.Graphical abstract

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Sigma-2 Receptor Ligands: Neurobiological Effects

Cited by 64 publications

References 71 publications

High-Content Microfluidic Screening Platform Used To Identify σ2R/Tmem97 Binding Ligands that Reduce Age-Dependent Neurodegeneration in C. elegans SC_APP Model

High-Content Microfluidic Screening Platform Used To Identify σ2R/Tmem97 Binding Ligands that Reduce Age-Dependent Neurodegeneration in C. elegans SC_APP Model

Natural Products and Their Mimics as Targets of Opportunity for Discovery

S2RSLDB: a comprehensive manually curated, internet-accessible database of the sigma-2 receptor selective ligands

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