TY - JOUR
T1 - Exploring the reactivity of bicyclic α-iminophosphonates to access new imidazoline I2 receptor ligands
AU - Bagán, Andrea
AU - Abás, Sònia
AU - Palà-Pujadas, Judith
AU - Irisarri, Alba
AU - Griñán-Ferré, Christian
AU - Pallàs, Mercè
AU - Muneta-Arrate, Itziar
AU - Muguruza, Carolina
AU - Callado, Luis F.
AU - Pérez, Belén
AU - Molins, Elies
AU - Morales-García, José
AU - Escolano, Carmen
N1 - Funding Information:
This work was supported by Ministerio de Ciencia, Innovación y Universidades, Agencia Estatal de Investigación (Spain, PID2019-107991RB-I00, PID2022-1380790B-I00), Basque Government (IT-1211-19 and 1512-22), Generalitat de Catalunya (GC) (2021 SGR 00357) and PDC2022-133441-I00 (MCIN/AEI/ 10.13039/501100011033 and by the “European Union NextGenerationEU/PRTR) and by UCM-Santander (PR44/21-29931 to J.A.M.-G.). The project leading to these results has received funding from “la Caixa” Foundation (ID 100010434) under agreement CI18-00002. This activity has received funding from the European Institute of Innovation and Technology (EIT). This body of the European Union receives support from the European Union’s Horizon 2020 research and innovation programme.
Publisher Copyright:
© 2023 The Author(s)
PY - 2024/1
Y1 - 2024/1
N2 - Recent studies pointed out the modulation of imidazoline I2 receptors (I2-IR) by selective ligands as a putative strategy to face neurodegenerative diseases. Foregoing the classical 2-imidazoline/imidazole-containing I2-IR ligands, we report a family of bicyclic α-iminophosphonates endowed with high affinity and selectivity upon I2-IR and we advanced a representative compound B06 in preclinical phases. In this paper, we describe the synthetic possibilities of bicyclic α-iminophosphonates by exploring its ambivalent reactivity, leading to unprecedented molecules that showed promising activities as I2-IR ligands in human brain tissues and good BBB permeation capabilities. After in silico ADME prediction studies, we assessed the neuroprotective properties of selected compounds and beneficial effect in an in vitro model of Alzheimeŕs and Parkinson's disease. Along with their neuroprotective effect, compounds showed a potent anti-inflammatory response when evaluated in a neuroinflammation cellular model. Moreover, this is the first time that the neuroprotective effects of imidazoline I2-IR ligands in a transgenic Alzheimer's disease Caenorhabditis elegans strain are investigated. Using a thrashing assay, we found a significant cognition improvement in this in vivo model after treatment with the new bicyclic α-phosphoprolines. Therefore, our results confirmed the need of exploring structurally new I2-IR ligands and their potential for therapeutic strategies in neurodegeneration.
AB - Recent studies pointed out the modulation of imidazoline I2 receptors (I2-IR) by selective ligands as a putative strategy to face neurodegenerative diseases. Foregoing the classical 2-imidazoline/imidazole-containing I2-IR ligands, we report a family of bicyclic α-iminophosphonates endowed with high affinity and selectivity upon I2-IR and we advanced a representative compound B06 in preclinical phases. In this paper, we describe the synthetic possibilities of bicyclic α-iminophosphonates by exploring its ambivalent reactivity, leading to unprecedented molecules that showed promising activities as I2-IR ligands in human brain tissues and good BBB permeation capabilities. After in silico ADME prediction studies, we assessed the neuroprotective properties of selected compounds and beneficial effect in an in vitro model of Alzheimeŕs and Parkinson's disease. Along with their neuroprotective effect, compounds showed a potent anti-inflammatory response when evaluated in a neuroinflammation cellular model. Moreover, this is the first time that the neuroprotective effects of imidazoline I2-IR ligands in a transgenic Alzheimer's disease Caenorhabditis elegans strain are investigated. Using a thrashing assay, we found a significant cognition improvement in this in vivo model after treatment with the new bicyclic α-phosphoprolines. Therefore, our results confirmed the need of exploring structurally new I2-IR ligands and their potential for therapeutic strategies in neurodegeneration.
KW - Imidazoline I2 receptors
KW - Imidazoline I2 receptor ligands
KW - Neuroprotection
KW - Neuroinflammation
KW - Bicyclic α-aminophosphonate
KW - Bicyclic α-phosphoproline
KW - Alzheimer’s disease
KW - Parkinsonism
KW - Caenorhabditis elegans
KW - Imidazoline I2 receptors
KW - Imidazoline I2 receptor ligands
KW - Neuroprotection
KW - Neuroinflammation
KW - Bicyclic α-aminophosphonate
KW - Bicyclic α-phosphoproline
KW - Alzheimer’s disease
KW - Parkinsonism
KW - Caenorhabditis elegans
KW - Imidazoline I2 receptors
KW - Imidazoline I2 receptor ligands
KW - Neuroprotection
KW - Neuroinflammation
KW - Bicyclic α-aminophosphonate
KW - Bicyclic α-phosphoproline
KW - Alzheimer’s disease
KW - Parkinsonism
KW - Caenorhabditis elegans
UR - http://www.scopus.com/inward/record.url?scp=85175176403&partnerID=8YFLogxK
UR - https://www.mendeley.com/catalogue/4ff302a8-7103-39b9-98ed-3b8242e7e011/
UR - https://portalrecerca.uab.cat/en/publications/e1bc9624-8e52-4fe5-9ba2-0fbb348fbd2b
U2 - 10.1016/j.bioorg.2023.106935
DO - 10.1016/j.bioorg.2023.106935
M3 - Article
AN - SCOPUS:85175176403
SN - 0045-2068
VL - 142
JO - Bioorganic Chemistry
JF - Bioorganic Chemistry
M1 - 106935
ER -