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...

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Authors: 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
Format: Article
Status:Accepted version
Publication date:2020
Country:España
Institution:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repository:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/172618
Online Access:https://hdl.handle.net/2445/172618
Access Level:Open access
Keyword:Malaltia d'Alzheimer
Malalties neurodegeneratives
Envelliment
Alzheimer's disease
Neurodegenerative Diseases
Aging
Summary: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.

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