Preclinical Evaluation of an Imidazole-Linked Heterocycle for Alzheimer’s Disease
dc.contributor.author | Bagán, Andrea | |
dc.contributor.author | Rodriguez-Arévalo, Sergio | |
dc.contributor.author | Taboada-Jara, Teresa | |
dc.contributor.author | Griñán-Ferré, Christian | |
dc.contributor.author | Pallàs, Mercè | |
dc.contributor.author | Brocos Mosquera, Iria | |
dc.contributor.author | Callado Hernando, Luis Felipe | |
dc.contributor.author | Morales-García, José A. | |
dc.contributor.author | Pérez, Belén | |
dc.contributor.author | Diaz, Caridad | |
dc.contributor.author | Fernández-Godino, Rosario | |
dc.contributor.author | Genilloud, Olga | |
dc.contributor.author | Beljkas, Milan | |
dc.contributor.author | Oljacic, Slavica | |
dc.contributor.author | Nikolic, Katarina | |
dc.contributor.author | Escolano, Carmen | |
dc.date.accessioned | 2023-11-22T18:57:09Z | |
dc.date.available | 2023-11-22T18:57:09Z | |
dc.date.issued | 2023-09-25 | |
dc.identifier.citation | Pharmaceutics 15(10) : (2023) // Article ID 2381 | es_ES |
dc.identifier.issn | 1999-4923 | |
dc.identifier.uri | http://hdl.handle.net/10810/63121 | |
dc.description.abstract | Humanity is facing a vast prevalence of neurodegenerative diseases, with Alzheimer’s disease (AD) being the most dominant, 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. 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. We report the synthesis, the affinity in human I2-IRs, the brain penetration capabilities, the in silico ADMET studies, and the three-dimensional quantitative structure-activity relationship (3D-QSAR) studies of this new bunch of I2-IR ligands. Selected compounds showed neuroprotective properties and beneficial effects in an in vitro model of Parkinson’s disease, rescued the human dopaminergic cell line SH-SY5Y from death after treatment with 6-hydroxydopamine, 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. | es_ES |
dc.description.sponsorship | This work was supported by the Ministerio de Ciencia, Innovación y Universidades, Agencia Estatal de Investigación (Spain, PID2019-107991RB-I00, PID2022-139180OB-I00, PID2022-138079OB-I00)), Basque Government (IT-1211-19 and 1512-22), Generalitat de Catalunya (GC) (2021 SGR 00357) and PDC2022-133441-I00 (MCIN/AEI/ 10.13039/501100011033, and by the European Union NextGenerationEU/PRTR) and UCM-Santander (PR44/21-29931 to J.A.M.-G.). MB, SO and KN acknowledge Ministry of Science, Technological Development and Innovation, Republic of Serbia through Grant Agreement with University of Belgrade—Faculty of Pharmacy No: 451-03-47/ 2023-01/200161 for funding. | es_ES |
dc.language.iso | eng | es_ES |
dc.publisher | MDPI | es_ES |
dc.rights | info:eu-repo/semantics/openAccess | es_ES |
dc.rights.uri | http://creativecommons.org/licenses/by/4.0/ | |
dc.subject | imidazoline I2 receptor ligand | es_ES |
dc.subject | Alzheimer’s disease | es_ES |
dc.subject | imidazoline-linked heterocycle | es_ES |
dc.subject | 2-(benzo[b]thiophen-2-yl)-1H-imidazole | es_ES |
dc.subject | 5XFAD | es_ES |
dc.subject | 3D-QSAR | es_ES |
dc.subject | neuroprotection | es_ES |
dc.title | Preclinical Evaluation of an Imidazole-Linked Heterocycle for Alzheimer’s Disease | es_ES |
dc.type | info:eu-repo/semantics/article | es_ES |
dc.date.updated | 2023-10-27T12:54:23Z | |
dc.rights.holder | © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). | es_ES |
dc.relation.publisherversion | https://www.mdpi.com/1999-4923/15/10/2381 | es_ES |
dc.identifier.doi | 10.3390/pharmaceutics15102381 | |
dc.departamentoes | Farmacología | |
dc.departamentoeu | Farmakologia |
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Except where otherwise noted, this item's license is described as © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).