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. The imidazoline I2 receptors (I2-IRs) are altered in the brain of AD patients and I2-IR ligands may have therapeutic potential as neuroprotective agents. Since structural data for I2-IR remains unknown, the discovery of selective I2-IR ligands is likely to provide valuable tools in defining the pharmacological characterization of these receptors. In this scenario, we aim to find molecular entities that modulate I2-IR that have been pointed out as relevant targets in AD.
Our group provided several lines of evidence that demonstrate that the I2-IR’s modulation with original structurally selective ligands, from the families of (2-imidazolin-4-yl)phosphonates [1] and bicyclic alpha-iminophosphonates [2,3,4], improves behavioral and psychological symptoms of dementia, including fear-anxiety, depressive like behavior, and memory decline, and ameliorates AD pathological features in well-established animal models of neurodegeneration and AD [5-8].
In a more conservative fashion, having considered structural patterns of known ligands, we explored modifications on the benzofuranyl-2-imidazole nucleus [9] of compound LSL60101 [10], which was proposed by our group as a disease-modifying treatment in an AD mouse model and compared with the gold-standard anti-AD donepezil [11].
1.- Abás, S.; Erdozain, A. M.; Keller, B.; Rodríguez-Arévalo, S.; Callado, L. F.; García-Sevilla, J.A.; Escolano, C. Neuroprotective effects of a structurally new family of high affinity imidazoline I2 receptors ligands. ACS Chem. Neurosci. 2017, 8, 737–742. Neuroprotective Effects of a Structurally New Family of High Affinity Imidazoline I2 Receptor Ligands – PubMed (nih.gov)
2.- Abás, S.; Rodríguez-Arévalo, S.; Bagán, A.; Griñán-Ferré, C.; Vasilopoulou, F.; Brocos-Mosquera, I.; Muguruza, C.; Pérez, B.; Molins, E.; Luque, F.J.; et al. Bicyclic a-iminophosphonates as High Affinity Imidazoline I2 Receptor Ligands for Alzheimer’s Disease. J. Med. Chem. 2020, 7, 3610–3633. Bicyclic α-Iminophosphonates as High Affinity Imidazoline I2 Receptor Ligands for Alzheimer’s Disease – PubMed (nih.gov)
3. Bagán, A.; Morales-García, J. A.; Griñán-Ferré, C.; Díaz, C.; Pérez del Palacio, J.; Ramos, M. C.; Vicente, F.; Pérez, B.; Brea, J.; Brea, J.; Loza, M. I.; Pallàs, M.; Escolano, C. Insights into the pharmacokinetics and in vitro cell-based studies of the imidazoline I2 receptor ligands B06. Int. J. Mol. Sci. 2022, 23, 5408. https://www.mdpi.com/1422-0067/23/10/5408
4. Bagán, A.; Abás, S.; Palà-Pujades, J.; Irisarri, A.; Griñán-Ferré, C.; Pallàs, M.; Muneta-Arrate, I.; Muguruza, C.; Callado, L. F.; Pérez, B.; Molins, E.; Morales-García, J. A.; Escolano, C. Exploring the reactivity of bicyclic α-iminophosphonates to access new imidazoline I2 receptor ligands. Bioorganic Chemistry, 2024, 142, 106935. https://doi.org/10.1016/j.bioorg.2023.106935
5. Griñán-Ferré, C.; Vasilopoulou, F.; Abás, S.; Rodríguez-Arévalo, S.; Bagán, A.; Sureda, F.X.; Pérez, B.; Callado, L.F.; García-Sevilla, J.A.; García-Fuster, M.J.; et al. Behavioral and cognitive improvement induced by novel imidazoline I2 receptor ligands in female SAMP8 mice. Neurotherapeutics 2019, 16, 416–431. Behavioral and Cognitive Improvement Induced by Novel Imidazoline I2 Receptor Ligands in Female SAMP8 Mice – PubMed (nih.gov)
6. Vasilopoulou, F.; Bagán, A.; Rodríguez-Arévalo, S.; Escolano, C.; Griñán-Ferré, C.; Pallàs, M. Amelioration of BPSD-like phenotype and cognitive decline in SAMP8 mice model accompanied by molecular changes after treatment with I1-imidazoline receptor ligand MCR5. Pharmaceutics 2020, 12, 475. Pharmaceutics | Free Full-Text | Amelioration of BPSD-Like Phenotype and Cognitive Decline in SAMP8 Mice Model Accompanied by Molecular Changes after Treatment with I2-Imidazoline Receptor Ligand MCR5 (mdpi.com)
7. Jiménez-Altayó, F.; Cabrera, A.; Bagán, A.; Giménez-Llort, L.; D’Ocon, P.; Pérez, B.; Pallàs, M.; Escolano, C. An imidazoline 2 receptor ligand relaxes mouse aorta via off-target mechanisms resistant to aging. Front. Pharmacol. 2022, 13, 826837. Frontiers | An Imidazoline 2 Receptor Ligand Relaxes Mouse Aorta via Off-Target Mechanisms Resistant to Aging (frontiersin.org)
8. Vasilopoulou, F.; Griñán-Ferré, C.; Rodríguez-Arévalo, S.; Bagán, A.; Abás, S.; Escolano, C.; Pallàs, M. I2 imidazoline receptor modulation protects aged SAMP8 mice against cognitive decline by suppressing the calcineurin pathway. GeroScience 2021, 43, 965–983. I2 imidazoline receptor modulation protects aged SAMP8 mice against cognitive decline by suppressing the calcineurin pathway | GeroScience (springer.com)
9. Bagán, A.; Rodriguez-Arévalo, S.; Taboada-Jara, T.; Griñán-Ferré, C.; Pallàs, M.; Brocos-Mosquera, I.; Callado, L. F.; Morales-García, J. A.; Pérez, B.; Diaz, C.; Fernández-Godino, R.; Genilloud, O.; Beljkas, M.; Oljacic, S.; Nikolic, K.; Escolano, C. Preclinical Evaluation of an Imidazole-Linked Heterocycle for Alzheimer’s Disease, Pharmaceutics 2023, 15, 2381. Pharmaceutics | Free Full-Text | Preclinical Evaluation of an Imidazole-Linked Heterocycle for Alzheimer’s Disease (mdpi.com)
10. Rodriguez-Arévalo, S.; Bagán, A.; Griñán-Ferré, C.; Vasilopoulou, F.; Pallàs, M.; Brocos-Mosquera, I.; Callado, L.F.; Loza, M.I.; Martínez, A.L.; Brea, J.; Pérez, B.; Molins, E. De Jonghe, S.; Daelemans, D.; Radan, M.; Djikic, T.; Nikolic, K.; Hernández-Hernández, E.; García-Fuster, M. J.; García-Sevilla, J. A.; Escolano, C. Benzofuranyl-2-imidazoles as Imidazoline I2 Receptor Ligands for Alzheimer’s Disease. Eur. J. Med. Chem. 2021, 222, 113540. Benzofuranyl-2-imidazoles as imidazoline I2 receptor ligands for Alzheimer’s disease (sciencedirectassets.com)
11. Vasilopolou, F.; Rodríguez-Arévalo, S.; Bagán, A.; Escolano, C.; Griñán-Ferré, C.; Pallàs, M. Disease-modifying treatment with I2 imidazoline receptor ligand LSL60101 in an Alzheimer’s disease mouse model: A comparative study with donepezil. Br. J. Pharmacol. 2021, 178, 3016–3033. Disease‐modifying treatment with I2 imidazoline receptor ligand LSL60101 in an Alzheimer’s disease mouse model: a comparative study with donepezil – Vasilopoulou – 2021 – British Journal of Pharmacology – Wiley Online Library
