Carmen Escolanoa, Carla Barbaracia, Andrea Bagána, Christian Griñán-Ferréb,c, Mercè Pallàsb, José Ángel Morales-Garcíad, José Breae, Mabel Lozae, Caridad Diazf, Rosario Fernández-Godinof, Olga Genilloudf
a Laboratory of Medicinal Chemistry (Associated Unit to CSIC), Department of Pharmacology, Toxicology and Medicinal Chemistry, Faculty of Pharmacy and Food Sciences, and Institute of Biomedicine (IBUB), University of Barcelona, Av. Joan XXIII, 27-31, E-08028, Barcelona, Spain; firstname.lastname@example.org
b Pharmacology Section, Toxicology and Medicinal Chemistry, Faculty of Pharmacy and Food Sciences, and Institut de Neurociències, University of Barcelona, Av. Joan XXIII, 27-31. E-08028, Barcelona, Spain.
c Department of Pharmacology, University of the Basque Country, UPV/EHU, Biocruces Bizkaia Health Research Institute and Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), 48940 Leioa, Bizkaia, Spain.
d Department of Cell Biology, School of Medicine, Complutense University (UCM), 28040 Madrid, Spain
e Drug Screening Platform/ Biofarma Research Group, CIMUS Research Center, University of Santiago de Compostela (USC), Santiago de Compostela 15782, Spain.
f Fundación MEDINA Centro de Excelencia en Investigación de Medicamentos Innovadores en Andalucía, Avda. del Conocimiento 34, 18016 Armilla, Spain
Alzheimer’s disease (AD) is the most dominant neurodegenerative diseases, without efficacious drugs, and with only a few therapeutic targets identified. In this scenario, we aim to find molecular entities that modulate imidazoline I2 receptors (I2-IRs) that have been pointed out as relevant targets in AD.1,2 In this work, we explored structural modifications of well-established I2-IR ligands, giving access to derivatives with an imidazole-linked heterocycle as a common key feature that showed good brain permeation and affinity/selectivity upon I2-IR. It permitted the proposal of a pharmacophore after 3D-QSAR, and the theoretical ADME and physicochemical parameters were calculated to rule out warnings to continue with the medicinal chemistry program. Selected compounds showed neuroprotective properties and beneficial effects in an in vitro model of Parkinson’s disease and showed crucial anti-inflammatory effects in a cellular model of neuroinflammation. After a preliminary pharmacokinetic study, we explored the action of our representative 2-(benzo[b]thiophen-2-yl)-1H-imidazole LSL33 in a mouse model of AD (5xFAD). Oral administration of LSL33 at 2 mg/Kg for 4 weeks ameliorated 5XFAD cognitive impairment and synaptic plasticity, as well as reduced neuroinflammation markers. In summary, this new I2-IR ligand that promoted beneficial effects in a well-established AD mouse model should be considered a promising therapeutic strategy for neurodegeneration.
 F. Vasilopolou, S. Rodríguez-Arévalo, A. Bagán, C. Escolano, C. Griñán-Ferré, M. Pallàs, , Br. J. Pharmacol. (2021) 1-17.
 S. Rodriguez-Arévalo, A. Bagán, C. Griñán-Ferré, F. Vasilopoulou, M. Pallàs, I. Brocos-Mosquera, L. F. Callado, M. I. Loza, A. L. Martínez, J. Brea, B. Pérez, E. Molins, S. De Jonghe, D. Daelemans, M. Radan, T. Dijikic, K. Nikolic, E. Hernández-Hernández, M. J. García-Fuster, J. A. García-Sevilla, C. Escolano, Eur. J. Med. Chem. 222 (2021) 113540.
 Bagán, A.; Rodriguez-Arévalo, S.; Taboada-Jara, T.; Griñán-Ferré, C.; Pallàs, M.; Brocos-Mosquera, I.; Callado, L.F.; Morales-García, J.A.; Pérez, B.; Diaz, C.; et al. Pharmaceutics 15 (2023) 2381.