Bicyclic α-Iminophosphonates as High Affinity Imidazoline I2 Receptor Ligands for Alzheimer's Disease

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 RadanTeodora Djikic, Katarina Nikolic, Mercè Pallàs, Luis F. Callado, Carmen Escolano*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

9 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)3610-3633
Number of pages24
JournalJournal of Medicinal Chemistry
Volume63
Issue number7
DOIs
Publication statusPublished - 9 Apr 2020

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