Synthesis and mode of action of photoswitchable ligands for neuromodulation

Tesi realitzada a l'Institut de Química Avançada de Catalunya (IQAC-CSIC), en cotutel·la amb la Université de Montpellier (França)

Detalles Bibliográficos
Autor: Dumaze, Anaëlle
Tipo de recurso: tesis doctoral
Estado:Versión publicada
Fecha de publicación:2023
País:España
Institución:CBUC, CESCA
Repositorio:TDR. Tesis Doctorales en Red
OAI Identifier:oai:www.tdx.cat:10803/690684
Acceso en línea:http://hdl.handle.net/10803/690684
Access Level:acceso embargado
Palabra clave:Fotofarmacologia
Fotofarmacología
Photopharmacology
Química clínica
Clinical chemistry
Fotoquímica
Photochemistry
Neurotransmissors
Neurotransmisores
Neurotransmitters
Ciències de la Salut
577
id ES_7c5bbf12de675e098b0dfd2ed96195fe
oai_identifier_str oai:www.tdx.cat:10803/690684
network_acronym_str ES
network_name_str España
repository_id_str
dc.title.none.fl_str_mv Synthesis and mode of action of photoswitchable ligands for neuromodulation
title Synthesis and mode of action of photoswitchable ligands for neuromodulation
spellingShingle Synthesis and mode of action of photoswitchable ligands for neuromodulation
Dumaze, Anaëlle
Fotofarmacologia
Fotofarmacología
Photopharmacology
Química clínica
Clinical chemistry
Fotoquímica
Photochemistry
Neurotransmissors
Neurotransmisores
Neurotransmitters
Ciències de la Salut
577
title_short Synthesis and mode of action of photoswitchable ligands for neuromodulation
title_full Synthesis and mode of action of photoswitchable ligands for neuromodulation
title_fullStr Synthesis and mode of action of photoswitchable ligands for neuromodulation
title_full_unstemmed Synthesis and mode of action of photoswitchable ligands for neuromodulation
title_sort Synthesis and mode of action of photoswitchable ligands for neuromodulation
dc.creator.none.fl_str_mv Dumaze, Anaëlle
author Dumaze, Anaëlle
author_facet Dumaze, Anaëlle
author_role author
dc.contributor.none.fl_str_mv Goudet, Cyril
Llebaria Soldevila, Amadeu
Baldomà Llavinés, Laura
Universitat de Barcelona. Facultat de Farmàcia i Ciències de l'Alimentació
dc.subject.none.fl_str_mv Fotofarmacologia
Fotofarmacología
Photopharmacology
Química clínica
Clinical chemistry
Fotoquímica
Photochemistry
Neurotransmissors
Neurotransmisores
Neurotransmitters
Ciències de la Salut
577
topic Fotofarmacologia
Fotofarmacología
Photopharmacology
Química clínica
Clinical chemistry
Fotoquímica
Photochemistry
Neurotransmissors
Neurotransmisores
Neurotransmitters
Ciències de la Salut
577
description Tesi realitzada a l'Institut de Química Avançada de Catalunya (IQAC-CSIC), en cotutel·la amb la Université de Montpellier (França)
publishDate 2023
dc.date.none.fl_str_mv 2023
2024
2026
dc.type.none.fl_str_mv info:eu-repo/semantics/doctoralThesis
info:eu-repo/semantics/publishedVersion
format doctoralThesis
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10803/690684
url http://hdl.handle.net/10803/690684
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/embargoedAccess
eu_rights_str_mv embargoedAccess
dc.format.none.fl_str_mv 201 p.
application/pdf
dc.publisher.none.fl_str_mv Universitat de Barcelona
publisher.none.fl_str_mv Universitat de Barcelona
dc.source.none.fl_str_mv TDX (Tesis Doctorals en Xarxa)
reponame:TDR. Tesis Doctorales en Red
instname:CBUC, CESCA
instname_str CBUC, CESCA
reponame_str TDR. Tesis Doctorales en Red
collection TDR. Tesis Doctorales en Red
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869411584147718144
spelling Synthesis and mode of action of photoswitchable ligands for neuromodulationDumaze, AnaëlleFotofarmacologiaFotofarmacologíaPhotopharmacologyQuímica clínicaClinical chemistryFotoquímicaPhotochemistryNeurotransmissorsNeurotransmisoresNeurotransmittersCiències de la Salut577Tesi realitzada a l'Institut de Química Avançada de Catalunya (IQAC-CSIC), en cotutel·la amb la Université de Montpellier (França)[eng] My thesis was part of a collaborative project at the interface of neuropharmacology and medicinal chemistry that aimed to better understand the neuromodulation mechanisms associated with Alzheimer’s Disease (AD). In this context, my role was to develop photo- controllable ligands targeting two GPCRs known to be involved in this disease: the main target of the project was mGlu5 and A2AR was a subsidiary target. In addition to their involvement in AD and others neurodegenerative diseases, mGlu5 and A2A receptors are also drug targets of interest in a wider range of therapeutic areas, from pain to cancer. Photoswitchable ligands provide a high degree of spatiotemporal control of the ligand activity by using light as an external stimulus that could greatly facilitate the unraveling of the downstream mechanisms that lead to the pathology. Furthermore, in addition to their use in fundamental research, they may also offer unique advantages for clinical research in the future. Along this thesis, the following specific objectives were pursued: I. To explore the light sensitivity of clinical drug istradefylline (106) and its potential applicability in photopharmacology as a photoinactivatable A2AR antagonist. A full characterization of the molecular mechanisms underlying istradefylline photosensitivity and its use in pilot dynamic photopharmacological experiments in cellulo and in vivo are presented in chapter 1. II. To develop the first selective A2AR photoswitchable antagonist using istradefylline and related molecules as scaffold for the azologization process. The molecular design and the photochemical and photopharmacological characterization of three series of compounds are described in chapter 2. Additionally, an in vivo proof of concept of the use of one of these ligands in the context of chronic pain is reported. III. To obtain the first mGlu5 positive allosteric modulators (PAM) derived from the scaffolds of the two potent mGlu5 PAM VU0424465 (118) and VU0403602 (119) by an azologization process. The molecular design and the photochemical and photopharmacological characterization of these two photoswitchable compounds are described in chapter 3. IV. To develop a new generation of photoswitchable mGlu5 negative allosteric modulators (NAM) with light-on properties (i.e. inactive ligands in the dark that are switched-on at a specific wavelenght) using the recent strategy of ‘sign inversion’. The general design along with the photochemical and photopharmacological properties of a first series of ligands are presented in chapter 4. In addition, a comparison of the photopharmacological properties of our new ligands and the previously developed light-off mGlu5 NAM alloswitch-1 (69) in cells and in zebrafish are shown. Finally, the first results obtained by our collaborators using these new light-on ligands in a mouse model of Alzheimer's disease will be presented.Universitat de BarcelonaGoudet, CyrilLlebaria Soldevila, AmadeuBaldomà Llavinés, LauraUniversitat de Barcelona. Facultat de Farmàcia i Ciències de l'Alimentació202420232026info:eu-repo/semantics/doctoralThesisinfo:eu-repo/semantics/publishedVersion201 p.application/pdfhttp://hdl.handle.net/10803/690684TDX (Tesis Doctorals en Xarxa)reponame:TDR. Tesis Doctorales en Redinstname:CBUC, CESCAInglésADVERTIMENT. Tots els drets reservats. L'accés als continguts d'aquesta tesi doctoral i la seva utilització ha de respectar els drets de la persona autora. Pot ser utilitzada per a consulta o estudi personal, així com en activitats o materials d'investigació i docència en els termes establerts a l'art. 32 del Text Refós de la Llei de Propietat Intel·lectual (RDL 1/1996). Per altres utilitzacions es requereix l'autorització prèvia i expressa de la persona autora. En qualsevol cas, en la utilització dels seus continguts caldrà indicar de forma clara el nom i cognoms de la persona autora i el títol de la tesi doctoral. No s'autoritza la seva reproducció o altres formes d'explotació efectuades amb finalitats de lucre ni la seva comunicació pública des d'un lloc aliè al servei TDX. Tampoc s'autoritza la presentació del seu contingut en una finestra o marc aliè a TDX (framing). Aquesta reserva de drets afecta tant als continguts de la tesi com als seus resums i índexs.info:eu-repo/semantics/embargoedAccessoai:www.tdx.cat:10803/6906842026-06-14T12:46:07Z
score 15,300719

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