Preclinical Evaluation of an Imidazole-Linked Heterocycle for Alzheimer's Disease
Bagán, Andrea (Universitat de Barcelona)
Rodriguez-Arévalo, Sergio (Universitat de Barcelona)
Taboada-Jara, Teresa (Universitat de Barcelona)
Griñán-Ferré, Christian (Universitat de Barcelona)
Pallàs, Mercè (Universitat de Barcelona)
Brocos Mosquera, Iria (Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM, Madrid)
Callado, Luis F. (Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM, Madrid)
Morales-García, José A. (Universidad Complutense de Madrid)
Pérez, Belén (Universitat Autònoma de Barcelona. Departament de Farmacologia, de Terapèutica i de Toxicologia)
Diaz, Caridad (Fundación MEDINA Centro de Excelencia en Investigación de Medicamentos Innovadores en Andalucía)
Fernández-Godino, Rosario (Fundación MEDINA Centro de Excelencia en Investigación de Medicamentos Innovadores en Andalucía)
Genilloud, Olga (Fundación MEDINA Centro de Excelencia en Investigación de Medicamentos Innovadores en Andalucía)
Beljkas, Milan (University of Belgrade, Serbia)
Oljacic, Slavica (University of Belgrade, Serbia)
Nikolic, Katarina (University of Belgrade, Serbia)
Escolano, Carmen (Universitat de Barcelona)

Fecha:	2023
Descripción:	26 pàg.
Resumen:	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.
Ayudas:	Agencia Estatal de Investigación PID2019-107991RB-I00 Agencia Estatal de Investigación PID2022-139180OB-I00 Agencia Estatal de Investigación PID2022- 138079OB-I00 Agencia Estatal de Investigación PDC2022-133441-I00
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Materia:	Imidazoline I2 receptor ligand ; Alzheimer's disease ; Imidazoline-linked heterocycle ; 2-(benzo[b]thiophen-2-yl)-1H-imidazole ; 5XFAD ; 3D-QSAR ; Neuroprotection
Publicado en:	Pharmaceutics, Vol. 15 Núm. 10 (2023) , p. 2381, ISSN 1999-4923

DOI: 10.3390/pharmaceutics15102381
PMID: 37896141

26 p, 4.4 MB

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