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Modulateurs du transport vésiculaire du glutamate : développement d'outils pharmacologiques et de diagnostic pour la maladie d'Alzheimer Preview this item
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Modulateurs du transport vésiculaire du glutamate : développement d'outils pharmacologiques et de diagnostic pour la maladie d'Alzheimer

Author: Franck-Cyril Favre-BesseFrancine AcherNicolas PietrancostaBruno GasnierMartine DemeunynckAll authors
Publisher: 2012.
Dissertation: Thèse de doctorat : Chimie : Paris 5 : 2012.
Edition/Format:   Computer file : Document : Thesis/dissertation : French
Summary:
Les transporteurs vésiculaires du glutamate (VGLUTs) sont impliqués dans la recapture du glutamate du cytosol vers les vésicules présynaptiques. Depuis leurs caractérisations récentes en 2000, leurs implications dans plusieurs maladies neurodégénératives ont été démontrées. Ils jouent ainsi un rôle primordial dans la transmission nerveuse glutamatergique. Deux colorants naturels, le Rose Bengale et le
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Details

Genre/Form: Thèses et écrits académiques
Material Type: Document, Thesis/dissertation, Internet resource
Document Type: Internet Resource, Computer File
All Authors / Contributors: Franck-Cyril Favre-Besse; Francine Acher; Nicolas Pietrancosta; Bruno Gasnier; Martine Demeunynck; Jean Dessolin; Marie-Noëlle Rager; Université Paris Descartes (1970-2019).; École doctorale Médicament, toxicologie, chimie, environnement (2010-2013 / Paris).
OCLC Number: 867005798
Notes: Titre provenant de l'écran-titre.
Description: 1 online resource
Responsibility: Franck-Cyril Favre-Besse ; sous la direction de Francine Acher et de Nicolas Pietrancosta.

Abstract:

Les transporteurs vésiculaires du glutamate (VGLUTs) sont impliqués dans la recapture du glutamate du cytosol vers les vésicules présynaptiques. Depuis leurs caractérisations récentes en 2000, leurs implications dans plusieurs maladies neurodégénératives ont été démontrées. Ils jouent ainsi un rôle primordial dans la transmission nerveuse glutamatergique. Deux colorants naturels, le Rose Bengale et le Bleu Trypan, restent les meilleurs inhibiteurs connus à ce jour, avec respectivement des CI50 de 25 et 50 nM. Dans un premier temps, nous avons conçu et optimisé une série d'analogues basée sur le synthon Rose Bengale (inhibiteur non-compétitif). Ce travail a notamment permis de mettre en évidence l'effet des formes tautomères (quinone et lactone) sur l'inhibition des VGLUTs. Ainsi la forme quinonique, présente à pH physiologique, a été confirmée comme étant la seule capable de bloquer la recapture du glutamate. Dans un second temps, nous nous sommes intéressés à la famille du Bleu Trypan (inhibiteur compétitif) et nous avons déterminé la structure minimale active avec l'objectif de rendre ces molécules plus « drug-like ». En effet, l'intérêt de ce projet est de développer de petites structures aisément radiomarquables pour une utilisation dans un contexte physio-pathologique.

Vesicular glutamate transporters (VGLUTs) are involved in the recapture and storage of glutamate from cytol to secretory synaptic vesicules. Since their recent characterization in 2000, their implication in several neurodegenerative disorders have been demonstrated. They play a crucial role in glutamatergic neurotransmission. Natural dyes, such as Rose Bengal and Tryptan Blue are the best known inhibitors with IC50 values of 25 and 50 nM, respectively. Firstly, we designed and optimized a series of analogues based on the synthon Rose Bengal (non-competitive inhibitor). This work has especially enabled to highlight the effect of tautomeric forms (quinone and lactone) on the inhibition of VGLUTs. Thus, the quinone form, present at physiological pH, was confirmed as the only able to block the reuptake of glutamate. Secondly, we have been interested in the family of Trypan Blue (competitive inhibitor) and we determined the minimal active structure in order to render these molecules more "drug-like". Indeed, the interest of this project is to develop small structures easily radiomarquable to use in a physiopathological context.

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Since their recent characterization in 2000, their implication in several neurodegenerative disorders have been demonstrated. They play a crucial role in glutamatergic neurotransmission. Natural dyes, such as Rose Bengal and Tryptan Blue are the best known inhibitors with IC50 values of 25 and 50 nM, respectively. Firstly, we designed and optimized a series of analogues based on the synthon Rose Bengal (non-competitive inhibitor). This work has especially enabled to highlight the effect of tautomeric forms (quinone and lactone) on the inhibition of VGLUTs. Thus, the quinone form, present at physiological pH, was confirmed as the only able to block the reuptake of glutamate. Secondly, we have been interested in the family of Trypan Blue (competitive inhibitor) and we determined the minimal active structure in order to render these molecules more \"drug-like\". 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Ce travail a notamment permis de mettre en \u00E9vidence l\'effet des formes tautom\u00E8res (quinone et lactone) sur l\'inhibition des VGLUTs. Ainsi la forme quinonique, pr\u00E9sente \u00E0 pH physiologique, a \u00E9t\u00E9 confirm\u00E9e comme \u00E9tant la seule capable de bloquer la recapture du glutamate. Dans un second temps, nous nous sommes int\u00E9ress\u00E9s \u00E0 la famille du Bleu Trypan (inhibiteur comp\u00E9titif) et nous avons d\u00E9termin\u00E9 la structure minimale active avec l\'objectif de rendre ces mol\u00E9cules plus \u00AB drug-like \u00BB. En effet, l\'int\u00E9r\u00EAt de ce projet est de d\u00E9velopper de petites structures ais\u00E9ment radiomarquables pour une utilisation dans un contexte physio-pathologique.<\/span>\"@fr<\/a> ;\u00A0\u00A0\u00A0\nschema:exampleOfWork<\/a> <http:\/\/worldcat.org\/entity\/work\/id\/1748207302<\/a>> ;\u00A0\u00A0\u00A0\nschema:genre<\/a> \"Th\u00E8ses et \u00E9crits acad\u00E9miques<\/span>\"@fr<\/a> ;\u00A0\u00A0\u00A0\nschema:inLanguage<\/a> \"fr<\/span>\" ;\u00A0\u00A0\u00A0\nschema:name<\/a> \"Modulateurs du transport v\u00E9siculaire du glutamate : d\u00E9veloppement d\'outils pharmacologiques et de diagnostic pour la maladie d\'Alzheimer<\/span>\"@fr<\/a> ;\u00A0\u00A0\u00A0\nschema:productID<\/a> \"867005798<\/span>\" ;\u00A0\u00A0\u00A0\nschema:url<\/a> <http:\/\/www.theses.fr\/2012PA05P639\/abes<\/a>> ;\u00A0\u00A0\u00A0\nschema:url<\/a> <http:\/\/www.theses.fr\/2012PA05P639\/document<\/a>> ;\u00A0\u00A0\u00A0\nschema:url<\/a> <http:\/\/app.parisdescartes.fr\/gedfs\/these\/2013\/2\/18165448\/vd_favre-besse_franck-cyril.pdf<\/a>> ;\u00A0\u00A0\u00A0\nschema:url<\/a> <https:\/\/tel.archives-ouvertes.fr\/tel-00923157<\/a>> ;\u00A0\u00A0\u00A0\nwdrs:describedby<\/a> <http:\/\/www.worldcat.org\/title\/-\/oclc\/867005798<\/a>> ;\u00A0\u00A0\u00A0\u00A0.\n\n\n<\/div>\n\n

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<http:\/\/experiment.worldcat.org\/entity\/work\/data\/1748207302#Organization\/universite_paris_descartes_1970_2019<\/a>> # Universit\u00E9 Paris Descartes (1970-2019).<\/span>\n\u00A0\u00A0\u00A0\u00A0a \nschema:Organization<\/a> ;\u00A0\u00A0\u00A0\nschema:name<\/a> \"Universit\u00E9 Paris Descartes (1970-2019).<\/span>\" ;\u00A0\u00A0\u00A0\u00A0.\n\n\n<\/div>\n
<http:\/\/experiment.worldcat.org\/entity\/work\/data\/1748207302#Person\/acher_francine<\/a>> # Francine Acher<\/span>\n\u00A0\u00A0\u00A0\u00A0a \nschema:Person<\/a> ;\u00A0\u00A0\u00A0\nschema:familyName<\/a> \"Acher<\/span>\" ;\u00A0\u00A0\u00A0\nschema:givenName<\/a> \"Francine<\/span>\" ;\u00A0\u00A0\u00A0\nschema:name<\/a> \"Francine Acher<\/span>\" ;\u00A0\u00A0\u00A0\u00A0.\n\n\n<\/div>\n
<http:\/\/experiment.worldcat.org\/entity\/work\/data\/1748207302#Person\/demeunynck_martine<\/a>> # Martine Demeunynck<\/span>\n\u00A0\u00A0\u00A0\u00A0a \nschema:Person<\/a> ;\u00A0\u00A0\u00A0\nschema:familyName<\/a> \"Demeunynck<\/span>\" ;\u00A0\u00A0\u00A0\nschema:givenName<\/a> \"Martine<\/span>\" ;\u00A0\u00A0\u00A0\nschema:name<\/a> \"Martine Demeunynck<\/span>\" ;\u00A0\u00A0\u00A0\u00A0.\n\n\n<\/div>\n
<http:\/\/experiment.worldcat.org\/entity\/work\/data\/1748207302#Person\/dessolin_jean<\/a>> # Jean Dessolin<\/span>\n\u00A0\u00A0\u00A0\u00A0a \nschema:Person<\/a> ;\u00A0\u00A0\u00A0\nschema:familyName<\/a> \"Dessolin<\/span>\" ;\u00A0\u00A0\u00A0\nschema:givenName<\/a> \"Jean<\/span>\" ;\u00A0\u00A0\u00A0\nschema:name<\/a> \"Jean Dessolin<\/span>\" ;\u00A0\u00A0\u00A0\u00A0.\n\n\n<\/div>\n
<http:\/\/experiment.worldcat.org\/entity\/work\/data\/1748207302#Person\/favre_besse_franck_cyril_1983<\/a>> # Franck-Cyril Favre-Besse<\/span>\n\u00A0\u00A0\u00A0\u00A0a \nschema:Person<\/a> ;\u00A0\u00A0\u00A0\nschema:birthDate<\/a> \"1983<\/span>\" ;\u00A0\u00A0\u00A0\nschema:deathDate<\/a> \"\" ;\u00A0\u00A0\u00A0\nschema:familyName<\/a> \"Favre-Besse<\/span>\" ;\u00A0\u00A0\u00A0\nschema:givenName<\/a> \"Franck-Cyril<\/span>\" ;\u00A0\u00A0\u00A0\nschema:name<\/a> \"Franck-Cyril Favre-Besse<\/span>\" ;\u00A0\u00A0\u00A0\u00A0.\n\n\n<\/div>\n
<http:\/\/experiment.worldcat.org\/entity\/work\/data\/1748207302#Person\/gasnier_bruno<\/a>> # Bruno Gasnier<\/span>\n\u00A0\u00A0\u00A0\u00A0a \nschema:Person<\/a> ;\u00A0\u00A0\u00A0\nschema:familyName<\/a> \"Gasnier<\/span>\" ;\u00A0\u00A0\u00A0\nschema:givenName<\/a> \"Bruno<\/span>\" ;\u00A0\u00A0\u00A0\nschema:name<\/a> \"Bruno Gasnier<\/span>\" ;\u00A0\u00A0\u00A0\u00A0.\n\n\n<\/div>\n
<http:\/\/experiment.worldcat.org\/entity\/work\/data\/1748207302#Person\/pietrancosta_nicolas_1978<\/a>> # Nicolas Pietrancosta<\/span>\n\u00A0\u00A0\u00A0\u00A0a \nschema:Person<\/a> ;\u00A0\u00A0\u00A0\nschema:birthDate<\/a> \"1978<\/span>\" ;\u00A0\u00A0\u00A0\nschema:deathDate<\/a> \"\" ;\u00A0\u00A0\u00A0\nschema:familyName<\/a> \"Pietrancosta<\/span>\" ;\u00A0\u00A0\u00A0\nschema:givenName<\/a> \"Nicolas<\/span>\" ;\u00A0\u00A0\u00A0\nschema:name<\/a> \"Nicolas Pietrancosta<\/span>\" ;\u00A0\u00A0\u00A0\u00A0.\n\n\n<\/div>\n
<http:\/\/experiment.worldcat.org\/entity\/work\/data\/1748207302#Person\/rager_marie_noelle_1967<\/a>> # Marie-No\u00EBlle Rager<\/span>\n\u00A0\u00A0\u00A0\u00A0a \nschema:Person<\/a> ;\u00A0\u00A0\u00A0\nschema:birthDate<\/a> \"1967<\/span>\" ;\u00A0\u00A0\u00A0\nschema:deathDate<\/a> \"\" ;\u00A0\u00A0\u00A0\nschema:familyName<\/a> \"Rager<\/span>\" ;\u00A0\u00A0\u00A0\nschema:givenName<\/a> \"Marie-No\u00EBlle<\/span>\" ;\u00A0\u00A0\u00A0\nschema:name<\/a> \"Marie-No\u00EBlle Rager<\/span>\" ;\u00A0\u00A0\u00A0\u00A0.\n\n\n<\/div>\n
<http:\/\/experiment.worldcat.org\/entity\/work\/data\/1748207302#Thing\/bleu_trypan<\/a>> # Bleu Trypan<\/span>\n\u00A0\u00A0\u00A0\u00A0a \nschema:Thing<\/a> ;\u00A0\u00A0\u00A0\nschema:name<\/a> \"Bleu Trypan<\/span>\" ;\u00A0\u00A0\u00A0\u00A0.\n\n\n<\/div>\n
<http:\/\/experiment.worldcat.org\/entity\/work\/data\/1748207302#Thing\/glutamate<\/a>> # Glutamate<\/span>\n\u00A0\u00A0\u00A0\u00A0a \nschema:Thing<\/a> ;\u00A0\u00A0\u00A0\nschema:name<\/a> \"Glutamate<\/span>\" ;\u00A0\u00A0\u00A0\u00A0.\n\n\n<\/div>\n
<http:\/\/experiment.worldcat.org\/entity\/work\/data\/1748207302#Thing\/neurotransmission<\/a>> # Neurotransmission<\/span>\n\u00A0\u00A0\u00A0\u00A0a \nschema:Thing<\/a> ;\u00A0\u00A0\u00A0\nschema:name<\/a> \"Neurotransmission<\/span>\" ;\u00A0\u00A0\u00A0\u00A0.\n\n\n<\/div>\n
<http:\/\/experiment.worldcat.org\/entity\/work\/data\/1748207302#Thing\/rose_bengale<\/a>> # Rose Bengale<\/span>\n\u00A0\u00A0\u00A0\u00A0a \nschema:Thing<\/a> ;\u00A0\u00A0\u00A0\nschema:name<\/a> \"Rose Bengale<\/span>\" ;\u00A0\u00A0\u00A0\u00A0.\n\n\n<\/div>\n
<http:\/\/experiment.worldcat.org\/entity\/work\/data\/1748207302#Thing\/structure_activite<\/a>> # Structure-activit\u00E9<\/span>\n\u00A0\u00A0\u00A0\u00A0a \nschema:Thing<\/a> ;\u00A0\u00A0\u00A0\nschema:name<\/a> \"Structure-activit\u00E9<\/span>\" ;\u00A0\u00A0\u00A0\u00A0.\n\n\n<\/div>\n
<http:\/\/experiment.worldcat.org\/entity\/work\/data\/1748207302#Thing\/vglut<\/a>> # VGLUT<\/span>\n\u00A0\u00A0\u00A0\u00A0a \nschema:Thing<\/a> ;\u00A0\u00A0\u00A0\nschema:name<\/a> \"VGLUT<\/span>\" ;\u00A0\u00A0\u00A0\u00A0.\n\n\n<\/div>\n
<http:\/\/experiment.worldcat.org\/entity\/work\/data\/1748207302#Topic\/alzheimer_maladie_d<\/a>> # Alzheimer, Maladie d\'<\/span>\n\u00A0\u00A0\u00A0\u00A0a \nschema:Intangible<\/a> ;\u00A0\u00A0\u00A0\nschema:name<\/a> \"Alzheimer, Maladie d\'<\/span>\"@fr<\/a> ;\u00A0\u00A0\u00A0\u00A0.\n\n\n<\/div>\n
<http:\/\/experiment.worldcat.org\/entity\/work\/data\/1748207302#Topic\/bleu_de_trypan_dissertation_universitaire<\/a>> # Bleu de trypan--Dissertation universitaire<\/span>\n\u00A0\u00A0\u00A0\u00A0a \nschema:Intangible<\/a> ;\u00A0\u00A0\u00A0\nschema:name<\/a> \"Bleu de trypan--Dissertation universitaire<\/span>\"@fr<\/a> ;\u00A0\u00A0\u00A0\u00A0.\n\n\n<\/div>\n
<http:\/\/experiment.worldcat.org\/entity\/work\/data\/1748207302#Topic\/colorants<\/a>> # Colorants<\/span>\n\u00A0\u00A0\u00A0\u00A0a \nschema:Intangible<\/a> ;\u00A0\u00A0\u00A0\nschema:name<\/a> \"Colorants<\/span>\"@fr<\/a> ;\u00A0\u00A0\u00A0\u00A0.\n\n\n<\/div>\n
<http:\/\/experiment.worldcat.org\/entity\/work\/data\/1748207302#Topic\/glutamate_ion<\/a>> # Glutamate (ion)<\/span>\n\u00A0\u00A0\u00A0\u00A0a \nschema:Intangible<\/a> ;\u00A0\u00A0\u00A0\nschema:name<\/a> \"Glutamate (ion)<\/span>\"@fr<\/a> ;\u00A0\u00A0\u00A0\u00A0.\n\n\n<\/div>\n
<http:\/\/experiment.worldcat.org\/entity\/work\/data\/1748207302#Topic\/rose_de_bengale_dissertation_universitaire<\/a>> # Rose de Bengale--Dissertation universitaire<\/span>\n\u00A0\u00A0\u00A0\u00A0a \nschema:Intangible<\/a> ;\u00A0\u00A0\u00A0\nschema:name<\/a> \"Rose de Bengale--Dissertation universitaire<\/span>\"@fr<\/a> ;\u00A0\u00A0\u00A0\u00A0.\n\n\n<\/div>\n
<http:\/\/experiment.worldcat.org\/entity\/work\/data\/1748207302#Topic\/transporteurs_vesiculaires_du_glutamate_dissertation_universitaire<\/a>> # Transporteurs v\u00E9siculaires du glutamate--Dissertation universitaire<\/span>\n\u00A0\u00A0\u00A0\u00A0a \nschema:Intangible<\/a> ;\u00A0\u00A0\u00A0\nschema:name<\/a> \"Transporteurs v\u00E9siculaires du glutamate--Dissertation universitaire<\/span>\"@fr<\/a> ;\u00A0\u00A0\u00A0\u00A0.\n\n\n<\/div>\n
<http:\/\/id.loc.gov\/vocabulary\/countries\/fr<\/a>>\u00A0\u00A0\u00A0\u00A0a \nschema:Place<\/a> ;\u00A0\u00A0\u00A0\ndcterms:identifier<\/a> \"fr<\/span>\" ;\u00A0\u00A0\u00A0\u00A0.\n\n\n<\/div>\n
<http:\/\/www.theses.fr\/2012PA05P639\/document<\/a>>\u00A0\u00A0\u00A0\nrdfs:comment<\/a> \"Acc\u00E8s au texte int\u00E9gral de la version partielle<\/span>\" ;\u00A0\u00A0\u00A0\u00A0.\n\n\n<\/div>\n
<http:\/\/www.worldcat.org\/title\/-\/oclc\/867005798<\/a>>\u00A0\u00A0\u00A0\u00A0a \ngenont:InformationResource<\/a>, genont:ContentTypeGenericResource<\/a> ;\u00A0\u00A0\u00A0\nschema:about<\/a> <http:\/\/www.worldcat.org\/oclc\/867005798<\/a>> ; # Modulateurs du transport v\u00E9siculaire du glutamate : d\u00E9veloppement d\'outils pharmacologiques et de diagnostic pour la maladie d\'Alzheimer<\/span>\n\u00A0\u00A0\u00A0\nschema:dateModified<\/a> \"2020-05-17<\/span>\" ;\u00A0\u00A0\u00A0\nvoid:inDataset<\/a> <http:\/\/purl.oclc.org\/dataset\/WorldCat<\/a>> ;\u00A0\u00A0\u00A0\u00A0.\n\n\n<\/div>\n\n

Content-negotiable representations<\/p>\n