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SIR-BUCHE-AD
Novel sigma-1 pharmacological agents for photopharmacology and neuroprotection
FunderFrench National Research Agency (ANR)
Funder Contribution €230,230.00
DurationFrom 01 Jan 2023
Project codeANR-22-CE92-0080
Identifiers
Description
Neurodegenerative diseases, and particularly Alzheimer's disease, amyotrophic lateral sclerosis and Huntington's disease, constitute a major issue for human health. Among the most promising therapeutic tracks, several academic teams and pharma companies are exploring drugs targeting an intracellular chaperone, the sigma-1 receptor (S1R). However, even if some drug candidates (blarcamesine, pridopidine) may soon and hopefully be the first-in-class S1R drugs approved, with successful results in phase II clinical trials for Alzheimer's disease and Huntington's disease, best-in-class compounds and innovative strategies are still to be found to better implement effective S1R-based therapies. Moreover, innovative pharmacological tools are crucially needed to better understand the S1R mechanism of action. This is the positioning of the present project, which will take benefit from ongoing collaborations between medicinal chemists (Pr M. Decker's lab in Würzburg), neuropharmacologists (Dr T. Maurice's team in Montpellier), and cellular biologists (Dr T.P. Su's lab in Baltimore). The project combines innovative chemistry and pharmacological studies and aims to develop innovative photopharmacological tools (molecular probes) to enable addressing open questions regarding the neuroprotective effects of S1R in neurodegenerative diseases and explore a novel hypothesis to achieve efficient neuroprotection based on concomitant S1R activation and butyrylcholinesterase (BChE) inhibition, with BChE being a novel target in neuroprotection that our labs are currently exploring. We will design and validate novel photopharmacological probes, based on S1R agonists and antagonists, to control with high spatio-temporal control S1R activity and further investigate acute and chronic effects of S1R inhibition or activation. The compounds will be characterized pharmacologyically and their potentialities explored in vivo in a zebrafish model and in vitro on axonal transport and cell pruning using microfluidics, as examples of potential impacts of S1R on brain pathophysiology. We will examine the potential of drug combination between a S1R agonist and a BChE inhibitor and develop novel hybrid S1R-BChE compounds with over-additive neuroprotective properties, based on thorough structure-activity relationships, determination of biological activities in a non-transgenic and a transgenic mouse model of Alzheimer's disease, and examination of the molecular mechanism of action of synergic activities of these hybrid molecules.
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Neurodegenerative diseases, and particularly Alzheimer's disease, amyotrophic lateral sclerosis and Huntington's disease, constitute a major issue for human health. Among the most promising therapeutic tracks, several academic teams and pharma companies are exploring drugs targeting an intracellular chaperone, the sigma-1 receptor (S1R). However, even if some drug candidates (blarcamesine, pridopidine) may soon and hopefully be the first-in-class S1R drugs approved, with successful results in phase II clinical trials for Alzheimer's disease and Huntington's disease, best-in-class compounds and innovative strategies are still to be found to better implement effective S1R-based therapies. Moreover, innovative pharmacological tools are crucially needed to better understand the S1R mechanism of action. This is the positioning of the present project, which will take benefit from ongoing collaborations between medicinal chemists (Pr M. Decker's lab in Würzburg), neuropharmacologists (Dr T. Maurice's team in Montpellier), and cellular biologists (Dr T.P. Su's lab in Baltimore). The project combines innovative chemistry and pharmacological studies and aims to develop innovative photopharmacological tools (molecular probes) to enable addressing open questions regarding the neuroprotective effects of S1R in neurodegenerative diseases and explore a novel hypothesis to achieve efficient neuroprotection based on concomitant S1R activation and butyrylcholinesterase (BChE) inhibition, with BChE being a novel target in neuroprotection that our labs are currently exploring. We will design and validate novel photopharmacological probes, based on S1R agonists and antagonists, to control with high spatio-temporal control S1R activity and further investigate acute and chronic effects of S1R inhibition or activation. The compounds will be characterized pharmacologyically and their potentialities explored in vivo in a zebrafish model and in vitro on axonal transport and cell pruning using microfluidics, as examples of potential impacts of S1R on brain pathophysiology. We will examine the potential of drug combination between a S1R agonist and a BChE inhibitor and develop novel hybrid S1R-BChE compounds with over-additive neuroprotective properties, based on thorough structure-activity relationships, determination of biological activities in a non-transgenic and a transgenic mouse model of Alzheimer's disease, and examination of the molecular mechanism of action of synergic activities of these hybrid molecules.
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Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name greekSession Description Stores the user session ID for Academic Bibliometrics & Assessment Computational Utility Service. Provider Academic Bibliometrics & Assessment Computational Utility Service Expiration Session Name openAIRESession Description Stores the user session ID for OpenAIRE Services. 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