Rodriguez-Arevalo, SergioBagan, AndreaGrinan-Ferre, ChristianVasilopoulou, FoteiniPallas, MerceBrocos-Mosquera, IriaCallado, Luis FIsabel Loza, MMartinez, Anton LBrea, JosePerez, BelenMolins, Eliesde Jonghe, StevenDaelemans, DirkRadan, MilicaDjikic, TeodoraNikolic, KatarinaHernández-Hernández, ElenaGarcía-Fuster, M JuliaGarcia-Sevilla, Jesus AEscolano, Carmen2024-09-182024-09-182021-10-15Rodriguez-Arevalo S, Bagan A, Grinan-Ferre C, Vasilopoulou F, Pallas M, Brocos-Mosquera I, et al. Benzofuranyl-2-imidazoles as imidazoline I-2 receptor ligands for Alzheimer's disease. Eur J Med Chem. 2021 Oct 15;222:113540.0223-5234https://hdl.handle.net/20.500.13003/19466https://hdl.handle.net/20.500.12105/23190Recent findings unveil the pharmacological modulation of imidazoline I-2 receptors (I-2-IR) as a novel strategy to face unmet medical neurodegenerative diseases. In this work, we report the chemical characterization, three-dimensional quantitative structure-activity relationship (3D-QSAR) and ADMET in silico of a family of benzofuranyl-2-imidazoles that exhibit affinity against human brain I-2-IR and most of them have been predicted to be brain permeable. Acute treatment in mice with 2-(2-benzofuranyl)-2imidazole, known as LSL60101 (garsevil), showed non-warning properties in the ADMET studies and an optimal pharmacokinetic profile. Moreover, LSL60101 induced hypothermia in mice while decreased pro-apoptotic FADD protein in the hippocampus. In vivo studies in the familial Alzheimer's disease 5xFAD murine model with the representative compound, revealed significant decreases in the protein expression levels of antioxidant enzymes superoxide dismutase and glutathione peroxidase in hippocampus. Overall, LSL60101 plays a neuroprotective role by reducing apoptosis and modulating oxidative stress. (C) 2021 Elsevier Masson SAS. All rights reserved.enghttp://creativecommons.org/licenses/by/4.0/Imidazoline I-2 receptorsImidazoline I-2 receptor ligandsNeuroprotection5xFADBenzofuranyl-2-imidazolesOxidative stressOxidative StressAlzheimer DiseaseDose-Response Relationship, DrugMolecular StructureBenzofuransHumansCell Line, TumorLigandsMaleApoptosisStructure-Activity RelationshipAnimalsImidazolesImidazoline ReceptorsMiceresearch articleAttribution 4.0 International3411872022211354010.1016/j.ejmech.2021.1135401768-3254European Journal of Medicinal Chemistryopen accessAnimalesLínea Celular TumoralImidazolesLigandosApoptosisRelación Estructura-ActividadMasculinoReceptores de ImidazolinaBenzofuranosRelación Dosis-Respuesta a DrogaHumanosEnfermedad de AlzheimerEstrés OxidativoRatonesEstructura Molecular2-s2.0-85111006876685593800001L2012927091