Bicyclic α-Iminophosphonates as High Affinity Imidazoline I2 Receptor Ligands for Alzheimer's Disease
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Luque, F. Javier
De Jonghe, Steven
Loza, M. Isabel
García-Sevilla, Jesús A.
García-Fuster, M. Julia
Callado, Luis F.
Article (Published version)
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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
- American Chemical Society
- Synthesis, Quantitative Structure and Activity Relationship, Physico-Chemical Characterisation and Analysis of Pharmacologically Active Substances (RS-172033)
- Ministerio de Economı́a y Competitividad of Spain(SAF2016-77703) and the Basque Government (IT1211-19)
- Spanish Ministerio de Economı́a, Industria yCompetitividad (grant MDM-2017-0767; AEI/FEDER UE),and Generalitat de Catalunya (grant 2017SGR1746)