Bicyclic alfa-iminophosphonates as high affinity imidazoline I2 receptor ligands for Alzheimer's disease
Imidazoline I2 receptors (I2-IR), widely distributed in the CNS and altered in patients that suffered from neurodegenerative disorders, are orphan from the structural point of view and new I2-IR ligands are urgently required for improving their pharmacological characterization. We report the synthes...
| Autores: | , , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Tipo de recurso: | artículo |
| Estado: | Versión aceptada para publicación |
| Fecha de publicación: | 2020 |
| País: | España |
| Institución: | Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
| Repositorio: | Recercat. Dipósit de la Recerca de Catalunya |
| OAI Identifier: | oai:recercat.cat:2445/172618 |
| Acceso en línea: | https://hdl.handle.net/2445/172618 |
| Access Level: | acceso abierto |
| Palabra clave: | Malaltia d'Alzheimer Malalties neurodegeneratives Envelliment Alzheimer's disease Neurodegenerative Diseases Aging |
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Bicyclic alfa-iminophosphonates as high affinity imidazoline I2 receptor ligands for Alzheimer's diseaseAbás Prades, SòniaRodríguez-Arévalo, SergioBagan Polonio, AndreaGriñán Ferré, ChristianVasilopoulou, FoteiniBrocos-Mosquera, IriaMuguruza, CarolinaPérez, BelénMolins i Grau, EliesLuque Garriga, F. XavierPérez Lozano, PilarJonghe, Steven deDaelemans, DirkNaesens, LieveBrea, JoséLoza, María IsabelHernández-Hernández, ElenaGarcía-Sevilla, Jesús A.García-Fuster, M. JuliaRadan, MilicaDjikic, TeodoraNikolic, KatarinaPallàs i Llibería, Mercè, 1964-Callado, Luis F.Escolano Mirón, CarmenMalaltia d'AlzheimerMalalties neurodegenerativesEnvellimentAlzheimer's diseaseNeurodegenerative DiseasesAgingImidazoline I2 receptors (I2-IR), widely distributed in the CNS and altered in patients that suffered from neurodegenerative disorders, are orphan from the structural point of view and new I2-IR ligands are urgently required for improving their pharmacological characterization. We report the synthesis and 3D-QSAR studies of a new family of bicyclic α-iminophosphonates endowed with relevant affinities for human brain I2-IR. Acute treatment in mice with a selected compound significantly decreased the FADD protein in the hippocampus, a key marker in neuroprotective actions. Additionally, in vivo studies in the familial Alzheimer's disease 5xFAD murine model revealed beneficial effects in behavior and cognition. These results are supported by changes in molecular pathways related to cognitive decline and Alzheimer's disease. Therefore bicyclic α-iminophosphonates are tools that may open new therapeutic avenues for I2-IR, particularly for unmet neurodegenerative conditions.American Chemical Society2020202120202020info:eu-repo/semantics/articleinfo:eu-repo/semantics/acceptedVersion24 p.application/pdfhttps://hdl.handle.net/2445/172618Articles publicats en revistes (Farmacologia, Toxicologia i Química Terapèutica)reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésVersió postprint del document publicat a: https://doi.org/10.1021/acs.jmedchem.9b02080Journal of Medicinal Chemistry, 2020, vol. 63, p. 3610-3633https://doi.org/10.1021/acs.jmedchem.9b02080info:eu-repo/grantAgreement/EC/H2020/747487(c) American Chemical Society , 2020info:eu-repo/semantics/openAccessoai:recercat.cat:2445/1726182026-05-29T05:05:01Z |
| dc.title.none.fl_str_mv |
Bicyclic alfa-iminophosphonates as high affinity imidazoline I2 receptor ligands for Alzheimer's disease |
| title |
Bicyclic alfa-iminophosphonates as high affinity imidazoline I2 receptor ligands for Alzheimer's disease |
| spellingShingle |
Bicyclic alfa-iminophosphonates as high affinity imidazoline I2 receptor ligands for Alzheimer's disease Abás Prades, Sònia Malaltia d'Alzheimer Malalties neurodegeneratives Envelliment Alzheimer's disease Neurodegenerative Diseases Aging |
| title_short |
Bicyclic alfa-iminophosphonates as high affinity imidazoline I2 receptor ligands for Alzheimer's disease |
| title_full |
Bicyclic alfa-iminophosphonates as high affinity imidazoline I2 receptor ligands for Alzheimer's disease |
| title_fullStr |
Bicyclic alfa-iminophosphonates as high affinity imidazoline I2 receptor ligands for Alzheimer's disease |
| title_full_unstemmed |
Bicyclic alfa-iminophosphonates as high affinity imidazoline I2 receptor ligands for Alzheimer's disease |
| title_sort |
Bicyclic alfa-iminophosphonates as high affinity imidazoline I2 receptor ligands for Alzheimer's disease |
| dc.creator.none.fl_str_mv |
Abás Prades, Sònia Rodríguez-Arévalo, Sergio Bagan Polonio, Andrea Griñán Ferré, Christian Vasilopoulou, Foteini Brocos-Mosquera, Iria Muguruza, Carolina Pérez, Belén Molins i Grau, Elies Luque Garriga, F. Xavier Pérez Lozano, Pilar Jonghe, Steven de Daelemans, Dirk Naesens, Lieve Brea, José Loza, María Isabel Hernández-Hernández, Elena García-Sevilla, Jesús A. García-Fuster, M. Julia Radan, Milica Djikic, Teodora Nikolic, Katarina Pallàs i Llibería, Mercè, 1964- Callado, Luis F. Escolano Mirón, Carmen |
| author |
Abás Prades, Sònia |
| author_facet |
Abás Prades, Sònia Rodríguez-Arévalo, Sergio Bagan Polonio, Andrea Griñán Ferré, Christian Vasilopoulou, Foteini Brocos-Mosquera, Iria Muguruza, Carolina Pérez, Belén Molins i Grau, Elies Luque Garriga, F. Xavier Pérez Lozano, Pilar Jonghe, Steven de Daelemans, Dirk Naesens, Lieve Brea, José Loza, María Isabel Hernández-Hernández, Elena García-Sevilla, Jesús A. García-Fuster, M. Julia Radan, Milica Djikic, Teodora Nikolic, Katarina Pallàs i Llibería, Mercè, 1964- Callado, Luis F. Escolano Mirón, Carmen |
| author_role |
author |
| author2 |
Rodríguez-Arévalo, Sergio Bagan Polonio, Andrea Griñán Ferré, Christian Vasilopoulou, Foteini Brocos-Mosquera, Iria Muguruza, Carolina Pérez, Belén Molins i Grau, Elies Luque Garriga, F. Xavier Pérez Lozano, Pilar Jonghe, Steven de Daelemans, Dirk Naesens, Lieve Brea, José Loza, María Isabel Hernández-Hernández, Elena García-Sevilla, Jesús A. García-Fuster, M. Julia Radan, Milica Djikic, Teodora Nikolic, Katarina Pallàs i Llibería, Mercè, 1964- Callado, Luis F. Escolano Mirón, Carmen |
| author2_role |
author author author author author author author author author author author author author author author author author author author author author author author author |
| dc.subject.none.fl_str_mv |
Malaltia d'Alzheimer Malalties neurodegeneratives Envelliment Alzheimer's disease Neurodegenerative Diseases Aging |
| topic |
Malaltia d'Alzheimer Malalties neurodegeneratives Envelliment Alzheimer's disease Neurodegenerative Diseases Aging |
| description |
Imidazoline I2 receptors (I2-IR), widely distributed in the CNS and altered in patients that suffered from neurodegenerative disorders, are orphan from the structural point of view and new I2-IR ligands are urgently required for improving their pharmacological characterization. We report the synthesis and 3D-QSAR studies of a new family of bicyclic α-iminophosphonates endowed with relevant affinities for human brain I2-IR. Acute treatment in mice with a selected compound significantly decreased the FADD protein in the hippocampus, a key marker in neuroprotective actions. Additionally, in vivo studies in the familial Alzheimer's disease 5xFAD murine model revealed beneficial effects in behavior and cognition. These results are supported by changes in molecular pathways related to cognitive decline and Alzheimer's disease. Therefore bicyclic α-iminophosphonates are tools that may open new therapeutic avenues for I2-IR, particularly for unmet neurodegenerative conditions. |
| publishDate |
2020 |
| dc.date.none.fl_str_mv |
2020 2020 2020 2021 |
| dc.type.none.fl_str_mv |
info:eu-repo/semantics/article info:eu-repo/semantics/acceptedVersion |
| format |
article |
| status_str |
acceptedVersion |
| dc.identifier.none.fl_str_mv |
https://hdl.handle.net/2445/172618 |
| url |
https://hdl.handle.net/2445/172618 |
| dc.language.none.fl_str_mv |
Inglés |
| language_invalid_str_mv |
Inglés |
| dc.relation.none.fl_str_mv |
Versió postprint del document publicat a: https://doi.org/10.1021/acs.jmedchem.9b02080 Journal of Medicinal Chemistry, 2020, vol. 63, p. 3610-3633 https://doi.org/10.1021/acs.jmedchem.9b02080 info:eu-repo/grantAgreement/EC/H2020/747487 |
| dc.rights.none.fl_str_mv |
(c) American Chemical Society , 2020 info:eu-repo/semantics/openAccess |
| rights_invalid_str_mv |
(c) American Chemical Society , 2020 |
| eu_rights_str_mv |
openAccess |
| dc.format.none.fl_str_mv |
24 p. application/pdf |
| dc.publisher.none.fl_str_mv |
American Chemical Society |
| publisher.none.fl_str_mv |
American Chemical Society |
| dc.source.none.fl_str_mv |
Articles publicats en revistes (Farmacologia, Toxicologia i Química Terapèutica) reponame:Recercat. Dipósit de la Recerca de Catalunya instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
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Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya) |
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Recercat. Dipósit de la Recerca de Catalunya |
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Recercat. Dipósit de la Recerca de Catalunya |
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|
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1869416109741965312 |
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15.81155 |