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 op...en new therapeutic avenues for I2-IR, particularly for unmet neurodegenerative conditions.
Source:
Journal of Medicinal Chemistry, 2020, 63, 7, 3610-3633
TY - JOUR
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 - Đikić, Teodora
AU - Nikolić, Katarina
AU - Pallàs, Mercè
AU - Callado, Luis F.
AU - Escolano, Carmen
PY - 2020
UR - https://farfar.pharmacy.bg.ac.rs/handle/123456789/3576
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.
PB - American Chemical Society
T2 - Journal of Medicinal Chemistry
T1 - Bicyclic α-Iminophosphonates as High Affinity Imidazoline I2 Receptor Ligands for Alzheimer's Disease
VL - 63
IS - 7
SP - 3610
EP - 3633
DO - 10.1021/acs.jmedchem.9b02080
ER -
@article{
author = "Abás, Sònia and Rodríguez-Arévalo, Sergio and Bagán, Andrea and Griñán-Ferré, Christian and Vasilopoulou, Foteini and Brocos-Mosquera, Iria and Muguruza, Carolina and Pérez, Belén and Molins, Elies and Luque, F. Javier and Pérez-Lozano, Pilar and De Jonghe, Steven and Daelemans, Dirk and Naesens, Lieve and Brea, José and Loza, M. Isabel and Hernández-Hernández, Elena and García-Sevilla, Jesús A. and García-Fuster, M. Julia and Radan, Milica and Đikić, Teodora and Nikolić, Katarina and Pallàs, Mercè and Callado, Luis F. and Escolano, Carmen",
year = "2020",
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.",
publisher = "American Chemical Society",
journal = "Journal of Medicinal Chemistry",
title = "Bicyclic α-Iminophosphonates as High Affinity Imidazoline I2 Receptor Ligands for Alzheimer's Disease",
volume = "63",
number = "7",
pages = "3610-3633",
doi = "10.1021/acs.jmedchem.9b02080"
}
Abás, S., Rodríguez-Arévalo, S., Bagán, A., Griñán-Ferré, C., Vasilopoulou, F., Brocos-Mosquera, I., Muguruza, C., Pérez, B., Molins, E., Luque, F. J., Pérez-Lozano, P., De Jonghe, S., Daelemans, D., Naesens, L., Brea, J., Loza, M. I., Hernández-Hernández, E., García-Sevilla, J. A., García-Fuster, M. J., Radan, M., Đikić, T., Nikolić, K., Pallàs, M., Callado, L. F.,& Escolano, C.. (2020). Bicyclic α-Iminophosphonates as High Affinity Imidazoline I2 Receptor Ligands for Alzheimer's Disease. in Journal of Medicinal Chemistry
American Chemical Society., 63(7), 3610-3633.
https://doi.org/10.1021/acs.jmedchem.9b02080
Abás S, Rodríguez-Arévalo S, Bagán A, Griñán-Ferré C, Vasilopoulou F, Brocos-Mosquera I, Muguruza C, Pérez B, Molins E, Luque FJ, Pérez-Lozano P, De Jonghe S, Daelemans D, Naesens L, Brea J, Loza MI, Hernández-Hernández E, García-Sevilla JA, García-Fuster MJ, Radan M, Đikić T, Nikolić K, Pallàs M, Callado LF, Escolano C. Bicyclic α-Iminophosphonates as High Affinity Imidazoline I2 Receptor Ligands for Alzheimer's Disease. in Journal of Medicinal Chemistry. 2020;63(7):3610-3633.
doi:10.1021/acs.jmedchem.9b02080 .
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, De Jonghe, Steven, Daelemans, Dirk, Naesens, Lieve, Brea, José, Loza, M. Isabel, Hernández-Hernández, Elena, García-Sevilla, Jesús A., García-Fuster, M. Julia, Radan, Milica, Đikić, Teodora, Nikolić, Katarina, Pallàs, Mercè, Callado, Luis F., Escolano, Carmen, "Bicyclic α-Iminophosphonates as High Affinity Imidazoline I2 Receptor Ligands for Alzheimer's Disease" in Journal of Medicinal Chemistry, 63, no. 7 (2020):3610-3633,
https://doi.org/10.1021/acs.jmedchem.9b02080 . .
