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857584.pdf (4.38 MB)

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2023-10-01

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cc-by (c) Bagan Andrea et al., 2023
Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/219228

Preclinical Evaluation of an Imidazole-Linked Heterocycle for Alzheimer's Disease

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Recurs relacionat

https://doi.org/10.3390/pharmaceutics15102381

Resum

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. Keywords: 2-(benzo[b]thiophen-2-yl)-1H-imidazole; 3D-QSAR; 5XFAD; Alzheimer’s disease; imidazoline I2 receptor ligand; imidazoline-linked heterocycle; neuroprotection.

Matèries

Malalties neurodegeneratives, Malaltia d'Alzheimer, Envelliment

Matèries (anglès)

Neurodegenerative Diseases, Alzheimer's disease, Aging

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Col·leccions

Articles publicats en revistes (Farmacologia, Toxicologia i Química Terapèutica)

Citació

BAGAN POLONIO, Andrea, et al. Preclinical Evaluation of an Imidazole-Linked Heterocycle for Alzheimer's Disease. Pharmaceutics. 2023. Vol. 15, num. 10. ISSN 1999-4923. [consulted: 9 of August of 2026]. Available at: https://hdl.handle.net/2445/219228

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