Abstract
Recent findings unveil the pharmacological modulation of imidazoline I2 receptors (I2-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 I2-IR and most of them have been predicted to be brain permeable. Acute treatment in mice with 2-(2-benzofuranyl)-2-imidazole, 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. Invivo 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.
Highlights
Imidazoline I2 receptors (I2-IR) are heterogeneous entities, often described as nonadrenergic binding sites for imidazolines [1], thatBoth authors contribute to this work.bind with high affinity to [3H]idazoxan and with lower affinity to [3H]p-aminoclonidine and [3H]clonidine [2,3]
The literature is non-uniform in the I2-IR affinity values across species, given the radioligand considered as a reference and the tissues used for analysis
The remarkable affinity of LSL60101 for I2-IR and the excellent selectivity ratio I2/a2-adrenergic receptor (a2-AR) (3090) could guarantee, from the kinetic profile observed in plasma, that the concentrations reached at the site of action are enough to demonstrate the efficacy of this drug
Summary
Benzofuranyl-2-imidazoles as imidazoline I2 receptor ligands for Alzheimer's disease pp. 1e17. Benzofuranyl-2-imidazoles as imidazoline I2 receptor ligands for Alzheimer's disease pp. García-Sevilla, Milica Radan, Teodora Djikic, Katarina Nikolic, Elena Herna. Benzofuranyl-2-imidazoles show affinity/selectivity for imidazoline I2 receptors. Modulation of imidazoline I2 receptors by LSL60101 for AD therapeutics. ~ an-Ferre et al, Benzofuranyl-2-imidazoles as imidazoline I2 receptor ligands for Please cite this article as: S. Benzofuranyl-2-imidazoles as imidazoline I2 receptor ligands for Alzheimer's disease valo a, 1, Andrea Baga n a, Christian Grin b, 1,. Steven De Jonghe , Dirk Daelemans , Milica Radan , Teodora Djikic i, Katarina Nikolic i, ndez j, M. Pharmacology Section, Toxicology and Medicinal Chemistry, Faculty of Pharmacy and Food Sciences, Institut de Neuroci encies, University of Barcelona, Av. Centro de Investigacio edica en Red de Salud Mental, CIBERSAM, Spain e n en Medicina Molecular y Enfermedades Cro nica (CIMUS), Universidad. LSL60101 plays a neuroprotective role by reducing apoptosis and modulating oxidative stress
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