Benzofuranyl-2-imidazoles as imidazoline I-2 receptor ligands for Alzheimer's disease

Recent 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...

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Detalles Bibliográficos
Autores: Rodriguez-Arevalo, Sergio, Bagan, Andrea, Grinan-Ferre, Christian, Vasilopoulou, Foteini, Pallas, Merce, Brocos-Mosquera, Iria, Callado, Luis F, Isabel Loza, M, Martinez, Anton L, Brea, Jose, Perez, Belen, Molins, Elies, de Jonghe, Steven, Daelemans, Dirk, Radan, Milica, Djikic, Teodora, Nikolic, Katarina, Hernández-Hernández, Elena, García-Fuster, M Julia, Garcia-Sevilla, Jesus A, Escolano, Carmen
Tipo de recurso: artículo
Fecha de publicación:2021
País:España
Institución:Instituto de Salud Carlos III (ISCIII)
Repositorio:Repisalud
Idioma:inglés
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/23190
Acceso en línea:https://hdl.handle.net/20.500.12105/23190
Access Level:acceso abierto
Palabra clave:Imidazoline I-2 receptors
Imidazoline I-2 receptor ligands
Neuroprotection
5xFAD
Benzofuranyl-2-imidazoles
Oxidative stress
Animales
Línea Celular Tumoral
Imidazoles
Ligandos
Apoptosis
Relación Estructura-Actividad
Masculino
Receptores de Imidazolina
Benzofuranos
Relación Dosis-Respuesta a Droga
Humanos
Enfermedad de Alzheimer
Estrés Oxidativo
Ratones
Estructura Molecular
Oxidative Stress
Alzheimer Disease
Dose-Response Relationship, Drug
Molecular Structure
Benzofurans
Humans
Cell Line, Tumor
Ligands
Male
Structure-Activity Relationship
Animals
Imidazoline Receptors
Mice
Descripción
Sumario:Recent 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.

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