Electronic Resource
Preclinical Evaluation of an Imidazole-Linked Heterocycle for Alzheimer’s Disease
| العنوان: | Preclinical Evaluation of an Imidazole-Linked Heterocycle for Alzheimer’s Disease |
|---|---|
| المؤلفون: | Farmacología, Farmakologia, Bagán, Andrea, Rodriguez-Arévalo, Sergio, Taboada-Jara, Teresa, Griñán-Ferré, Christian, Pallàs, Mercè, Brocos Mosquera, Iria, Callado Hernando, Luis Felipe, Morales-García, José A., Pérez, Belén, Diaz, Caridad, Fernández-Godino, Rosario, Genilloud, Olga, Beljkas, Milan, Oljacic, Slavica, Nikolic, Katarina, Escolano, Carmen |
| بيانات النشر: | MDPI 2023-09-25 |
| نوع الوثيقة: | Electronic Resource |
| مستخلص: | 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. |
| مصطلحات الفهرس: | imidazoline I2 receptor ligand, Alzheimer’s disease, imidazoline-linked heterocycle, 2-(benzo[b]thiophen-2-yl)-1H-imidazole, 5XFAD, 3D-QSAR, neuroprotection, info:eu-repo/semantics/article |
| URL: | 1999-4923 |
| الاتاحة: | Open access content. Open access content |
| ملاحظة: | 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. English |
| Other Numbers: | ESUPV oai:addi.ehu.eus:10810/63121 1418067351 |
| المصدر المساهم: | REPOSITORIO DE LA UNIVERSIDAD DEL PAIS From OAIster®, provided by the OCLC Cooperative. |
| رقم الانضمام: | edsoai.on1418067351 |
| قاعدة البيانات: | OAIster |
| الوصف غير متاح. |