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Preclinical Evaluation of an Imidazole-Linked Heterocycle for Alzheimer’s Disease
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 I(2) receptors (I(2)...
Autores principales: | , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10610545/ https://www.ncbi.nlm.nih.gov/pubmed/37896141 http://dx.doi.org/10.3390/pharmaceutics15102381 |
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author | Bagán, Andrea Rodriguez-Arévalo, Sergio Taboada-Jara, Teresa Griñán-Ferré, Christian Pallàs, Mercè Brocos-Mosquera, Iria Callado, Luis F. Morales-García, José A. Pérez, Belén Diaz, Caridad Fernández-Godino, Rosario Genilloud, Olga Beljkas, Milan Oljacic, Slavica Nikolic, Katarina Escolano, Carmen |
author_facet | Bagán, Andrea Rodriguez-Arévalo, Sergio Taboada-Jara, Teresa Griñán-Ferré, Christian Pallàs, Mercè Brocos-Mosquera, Iria Callado, Luis F. Morales-García, José A. Pérez, Belén Diaz, Caridad Fernández-Godino, Rosario Genilloud, Olga Beljkas, Milan Oljacic, Slavica Nikolic, Katarina Escolano, Carmen |
author_sort | Bagán, Andrea |
collection | PubMed |
description | 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 I(2) receptors (I(2)-IRs) that have been pointed out as relevant targets in AD. In this work, we explored structural modifications of well-established I(2)-IR ligands, giving access to derivatives with an imidazole-linked heterocycle as a common key feature. We report the synthesis, the affinity in human I(2)-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 I(2)-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 I(2)-IR ligand that promoted beneficial effects in a well-established AD mouse model should be considered a promising therapeutic strategy for neurodegeneration. |
format | Online Article Text |
id | pubmed-10610545 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-106105452023-10-28 Preclinical Evaluation of an Imidazole-Linked Heterocycle for Alzheimer’s Disease Bagán, Andrea Rodriguez-Arévalo, Sergio Taboada-Jara, Teresa Griñán-Ferré, Christian Pallàs, Mercè Brocos-Mosquera, Iria Callado, Luis F. Morales-García, José A. Pérez, Belén Diaz, Caridad Fernández-Godino, Rosario Genilloud, Olga Beljkas, Milan Oljacic, Slavica Nikolic, Katarina Escolano, Carmen Pharmaceutics Article 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 I(2) receptors (I(2)-IRs) that have been pointed out as relevant targets in AD. In this work, we explored structural modifications of well-established I(2)-IR ligands, giving access to derivatives with an imidazole-linked heterocycle as a common key feature. We report the synthesis, the affinity in human I(2)-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 I(2)-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 I(2)-IR ligand that promoted beneficial effects in a well-established AD mouse model should be considered a promising therapeutic strategy for neurodegeneration. MDPI 2023-09-25 /pmc/articles/PMC10610545/ /pubmed/37896141 http://dx.doi.org/10.3390/pharmaceutics15102381 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/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/). |
spellingShingle | Article Bagán, Andrea Rodriguez-Arévalo, Sergio Taboada-Jara, Teresa Griñán-Ferré, Christian Pallàs, Mercè Brocos-Mosquera, Iria Callado, Luis F. Morales-García, José A. Pérez, Belén Diaz, Caridad Fernández-Godino, Rosario Genilloud, Olga Beljkas, Milan Oljacic, Slavica Nikolic, Katarina Escolano, Carmen Preclinical Evaluation of an Imidazole-Linked Heterocycle for Alzheimer’s Disease |
title | Preclinical Evaluation of an Imidazole-Linked Heterocycle for Alzheimer’s Disease |
title_full | Preclinical Evaluation of an Imidazole-Linked Heterocycle for Alzheimer’s Disease |
title_fullStr | Preclinical Evaluation of an Imidazole-Linked Heterocycle for Alzheimer’s Disease |
title_full_unstemmed | Preclinical Evaluation of an Imidazole-Linked Heterocycle for Alzheimer’s Disease |
title_short | Preclinical Evaluation of an Imidazole-Linked Heterocycle for Alzheimer’s Disease |
title_sort | preclinical evaluation of an imidazole-linked heterocycle for alzheimer’s disease |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10610545/ https://www.ncbi.nlm.nih.gov/pubmed/37896141 http://dx.doi.org/10.3390/pharmaceutics15102381 |
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