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

descriptionPublicationkeyboard_double_arrow_right Article 09 Mar 2020 Spain, Belgium, Serbia English Publisher:American Chemical Society (ACS)Journal:Journal of Medicinal Chemistry, volume 63, pages 3,610-3,633 (issn: 0022-2623, eissn: 1520-4804,

Copyright policy )Funded by:MESTD | Synthesis, Quantitative S..., EC | Schizo-EPICOG

Authors: Abas, Sonia; Rodriguez-Arevalo, Sergio; Bagan, Andrea; Grinan-Ferre, Christian; Vasilopoulou, Foteini; Brocos-Mosquera, Iria; Muguruza, Carolina; +18 Authors

doi: 10.1021/acs.jmedchem.9b02080

pmid: 32150414

handle: 10261/231285 , 2445/172618

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

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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.

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Spain, Belgium, Serbia

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Keywords

Aging, Bicyclic alfa-iminophosphonates, Quantitative Structure-Activity Relationship, Chemistry, Medicinal, BRAIN-INJURY, Ligands, 0305 Organic Chemistry, Hippocampus, Madin Darby Canine Kidney Cells, Mice, Chlorocebus aethiops, Pharmacology & Pharmacy, Nootropic Agents, Cycloaddition Reaction, Molecular Structure, Malalties neurodegeneratives, Imidazoles, Neurodegenerative Diseases, Alzheimer's disease, 5xFAD, Neuroprotection, ISCHEMIA, Imidazoline I2 ligands, Female, 1115 Pharmacology and Pharmaceutical Sciences, 3405 Organic chemistry, Life Sciences & Biomedicine, Alzheimer’s disease, PROTEINS, Medicinal & Biomolecular Chemistry, MODELS, 3214 Pharmacology and pharmaceutical sciences, Organophosphonates, 610, SELECTIVE LIGAND, RAT-BRAIN, Dogs, Envelliment, Alzheimer Disease, DRUGS, Animals, Humans, Vero Cells, 3404 Medicinal and biomolecular chemistry, 3D-QSAR, Science & Technology, IDAZOXAN BINDING-SITES, 0304 Medicinal and Biomolecular Chemistry, ALPHA(2)-ADRENOCEPTOR SUBTYPES, Imidazoline I2 receptors, Malaltia d'Alzheimer, DENSITY, Hela Cells, Imidazoline Receptors, HeLa Cells

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