Academic Journal
Preclinical Evaluation of an Imidazole-Linked Heterocycle for Alzheimer’s Disease
| العنوان: | Preclinical Evaluation of an Imidazole-Linked Heterocycle for Alzheimer’s Disease |
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| المؤلفون: | Bagán, Andrea, Morales García, José Ángel, Escolano, Carmen |
| بيانات النشر: | MDPI |
| سنة النشر: | 2023 |
| المجموعة: | Universidad Complutense de Madrid (UCM): E-Prints Complutense |
| مصطلحات موضوعية: | 616.894-053.9, Imidazoline I2 receptor ligand, Alzheimer’s disease, Imidazoline-linked heterocycle, 2-(benzo[b]thiophen-2-yl)-1H-imidazole, 5XFAD, 3D-QSAR, Neuroprotection, Medicina, Biología celular (Biología), 32 Ciencias Médicas, 2407 Biología Celular |
| الوصف: | 2023 Descuento MDPI ; 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. ; Ministerio de Ciencia, Innovación y Universidades (España) ; European Commission ; Gobierno Vasco ; Generalitat de Catalunya ; Universidad Complutense de Madrid ; Banco Santander ; Depto. de Biología Celular ; Fac. de Medicina ; TRUE ; pub |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | application/pdf |
| اللغة: | English |
| Relation: | info:eu-repo/grantAgreement/AEI/Plan Estatal de Investigación Científica y Técnica y de Innovación 2017-2020/PID2019-107991RB-I00/ES/REACCIONES MULTICOMPONENTE: DESCUBRIMIENTO, DEASARROLLO Y APLICACIONES EN BIOMEDICINA/; info:eu-repo/grantAgreement/AEI/PPlan Estatal de Investigación Científica, Técnica y de Innovación 2021-2023/PID2022-139180OB-I00; info:eu-repo/grantAgreement/AEI/PPlan Estatal de Investigación Científica, Técnica y de Innovación 2021-2023/PID2022-138079OB-I00; info:eu-repo/grantAgreement/AEI/PPlan Estatal de Investigación Científica, Técnica y de Innovación 2021-2023/PDC2022-133441-I00; Bagán, A.; RodriguezArévalo, 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. Preclinical Evaluation of an Imidazole-Linked Heterocycle for Alzheimer’s Disease. Pharmaceutics 2023, 15, 2381. https://doi.org/10.3390/pharmaceutics15102381; https://hdl.handle.net/20.500.14352/110680 |
| DOI: | 10.3390/pharmaceutics15102381 |
| الاتاحة: | https://hdl.handle.net/20.500.14352/110680 https://doi.org/10.3390/pharmaceutics15102381 |
| Rights: | Attribution 4.0 International ; http://creativecommons.org/licenses/by/4.0/ ; open access |
| رقم الانضمام: | edsbas.81EFD75C |
| قاعدة البيانات: | BASE |
| DOI: | 10.3390/pharmaceutics15102381 |
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