Bicyclic alfa-iminophosphonates as highly affinity imidazoline I2 receptor ligands for Alzheimer’s Disease

: 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 synthes...

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Authors: Abás, Sònia, Rodríguez Arévalo, Sergio, Bagán, Andrea, Griñán-Ferré, Christian, Vasilopoulou, Foteini, Brocos Mosquera, Iria, Muguruza, Carolina, Pérez, Belén, Molins, Elies, 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, García Fuster, M. Julia, Radan, Milica, Djikic, Teodora, Nikolic, Katarina, Pallàs, Mercè, Callado, Luis F., Escolano, Carmen
Format: article
Status:Versión aceptada para publicación
Publication Date:2020
Country:España
Institution:Consejo Superior de Investigaciones Científicas (CSIC)
Repository:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/231285
Online Access:http://hdl.handle.net/10261/231285
Access Level:Open access
Keyword:Alzheimer’s disease
Bicyclic alfa-iminophosphonates
Imidazoline I2 receptors
Imidazoline I2 ligands
Neuroprotection
3D-QSAR
5xFAD
Description
Summary:: 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.

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