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Title: Bicyclic alfa-iminophosphonates as high affinity imidazoline I2 receptor ligands for Alzheimer's disease
Author: 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
Keywords: Malaltia d'Alzheimer
Malalties neurodegeneratives
Alzheimer's disease
Neurodegenerative Diseases
Issue Date: 19-Mar-2020
Publisher: American Chemical Society
Abstract: 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.
Note: Versió postprint del document publicat a:
It is part of: Journal of Medicinal Chemistry, 2020, vol. 63, p. 3610-3633
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ISSN: 0022-2623
Appears in Collections:Articles publicats en revistes (Nutrició, Ciències de l'Alimentació i Gastronomia)
Articles publicats en revistes (Farmacologia, Toxicologia i Química Terapèutica)
Articles publicats en revistes (Farmàcia, Tecnologia Farmacèutica i Fisicoquímica)

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