TY - JOUR
T1 - Bicyclic α-Iminophosphonates as High Affinity Imidazoline I2 Receptor Ligands for Alzheimer's Disease
AU - Abás, Sònia
AU - Rodríguez-Arévalo, Sergio
AU - Bagán, Andrea
AU - Griñán-Ferré, Christian
AU - Vasilopoulou, Foteini
AU - Brocos-Mosquera, Iria
AU - Muguruza, Carolina
AU - Pérez, Belén
AU - Molins, Elies
AU - Luque, F. Javier
AU - Pérez-Lozano, Pilar
AU - De Jonghe, Steven
AU - Daelemans, Dirk
AU - Naesens, Lieve
AU - Brea, José
AU - Loza, M. Isabel
AU - Hernández-Hernández, Elena
AU - García-Sevilla, Jesús A.
AU - García-Fuster, M. Julia
AU - Radan, Milica
AU - Djikic, Teodora
AU - Nikolic, Katarina
AU - Pallàs, Mercè
AU - Callado, Luis F.
AU - Escolano, Carmen
N1 - Publisher Copyright:
© 2020 American Chemical Society.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/4/9
Y1 - 2020/4/9
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85083077827&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.9b02080
DO - 10.1021/acs.jmedchem.9b02080
M3 - Article
C2 - 32150414
AN - SCOPUS:85083077827
SN - 0022-2623
VL - 63
SP - 3610
EP - 3633
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 7
ER -