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Título: | Bicyclic alfa-iminophosphonates as highly affinity imidazoline I2 receptor ligands for Alzheimer’s Disease |
Autor: | Abás, Sònia; Rodríguez Arévalo, Sergio; Bagán, Andrea; Griñán-Ferré, Christian; Vasilopoulou, Foteini; Brocos Mosquera, Iria; Muguruza, Carolina; Pérez, Belén CSIC ORCID; Molins, Elies CSIC ORCID ; Luque, F. Javier; Pérez Lozano, Pilar; Jonghe, Steven de; Daelemans, Dirk; Naesens, Lieve; Brea, José Manuel; Loza, María Isabel; Hernández Hernández, Elena; García-Sevilla, Jesús Andrés CSIC; García Fuster, M. Julia; Radan, Milica; Djikic, Teodora; Nikolic, Katarina; Pallàs, Mercè; Callado, Luis F.; Escolano, Carmen | Palabras clave: | Alzheimer’s disease Bicyclic alfa-iminophosphonates Imidazoline I2 receptors Imidazoline I2 ligands Neuroprotection 3D-QSAR 5xFAD |
Fecha de publicación: | 9-abr-2020 | Editor: | American Chemical Society | Citación: | Journal of Medicinal Chemistry 63(7): 3610-3633 (2020) | Resumen: | : Imidazoline I2 receptors (I2-IR), widely distributed in the CNS and altered in patients that suffer from neurodegenerative disorders, are orphans from a structural point of view, and new I2-IR ligands are urgently required for improving their pharmacological characterization. We report the synthesis and three-dimensional quantitative structure−activity relationship (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 Fas-associated protein with death domain (FADD) in the hippocampus, a key signaling mediator of 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. | Versión del editor: | http://dx.doi.org/10.1021/acs.jmedchem.9b02080 | URI: | http://hdl.handle.net/10261/231285 | ISSN: | 0022-2623 |
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