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Bicyclic α-Iminophosphonates as High Affinity Imidazoline I 2 Receptor Ligands for Alzheimer's Disease.
- Source :
-
Journal of medicinal chemistry [J Med Chem] 2020 Apr 09; Vol. 63 (7), pp. 3610-3633. Date of Electronic Publication: 2020 Mar 19. - Publication Year :
- 2020
-
Abstract
- Imidazoline I <subscript>2</subscript> receptors (I <subscript>2</subscript> -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 I <subscript>2</subscript> -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 I <subscript>2</subscript> -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 I <subscript>2</subscript> -IR, particularly for unmet neurodegenerative conditions.
- Subjects :
- Animals
Chlorocebus aethiops
Cycloaddition Reaction
Dogs
Female
HeLa Cells
Hippocampus drug effects
Humans
Imidazoles chemical synthesis
Imidazoles metabolism
Imidazoles pharmacokinetics
Ligands
Madin Darby Canine Kidney Cells
Mice
Molecular Structure
Nootropic Agents chemical synthesis
Nootropic Agents metabolism
Nootropic Agents pharmacokinetics
Organophosphonates chemical synthesis
Organophosphonates metabolism
Organophosphonates pharmacokinetics
Quantitative Structure-Activity Relationship
Vero Cells
Alzheimer Disease drug therapy
Imidazoles therapeutic use
Imidazoline Receptors metabolism
Nootropic Agents therapeutic use
Organophosphonates therapeutic use
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4804
- Volume :
- 63
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Journal of medicinal chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 32150414
- Full Text :
- https://doi.org/10.1021/acs.jmedchem.9b02080