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Bicyclic α‑Iminophosphonates as High Affinity Imidazoline I2 Receptor Ligands for Alzheimer’s Disease
journal contribution
posted on 2020-03-19, 14:39 authored by Sònia Abás, Sergio Rodríguez-Arévalo, Andrea Bagán, Christian Griñán-Ferré, Foteini Vasilopoulou, Iria Brocos-Mosquera, Carolina Muguruza, Belén Pérez, Elies Molins, F. Javier Luque, Pilar Pérez-Lozano, Steven de Jonghe, Dirk Daelemans, Lieve Naesens, José Brea, M. Isabel Loza, Elena Hernández-Hernández, Jesús A. García-Sevilla, M. Julia García-Fuster, Milica Radan, Teodora Djikic, Katarina Nikolic, Mercè Pallàs, Luis F. Callado, Carmen EscolanoImidazoline
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.