RT Journal Article
T1 Exploring the reactivity of bicyclic α-iminophosphonates to access new imidazoline I2 receptor ligands
A1 Bagán, Andrea
A1 Abás, Sònia
A1 Palà-Pujadas, Judith
A1 Irisarri, Alba
A1 Griñán-Ferré, Christian
A1 Pallàs, Mercè
A1 Muneta-Arrate, Itziar
A1 Muguruza, Carolina
A1 Callado, Luis F.
A1 Pérez, Belén
A1 Molins, Elies
A1 Escolano, Carmen
A1 Morales García, José Ángel
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.
SN 0045-2068
YR 2024
FD 2024-01-25
LK https://hdl.handle.net/20.500.14352/97397
UL https://hdl.handle.net/20.500.14352/97397
LA eng
NO Bagán, Andrea, Sònia Abás, Judith Palà-Pujadas, Alba Irisarri, Christian Griñán-Ferré, Mercè Pallàs, Itziar Muneta-Arrate, et al. 2024. "Exploring the Reactivity of Bicyclic Α-Iminophosphonates to Access New Imidazoline I2 Receptor Ligands." Bioorganic Chemistry 142: 106935. doi:10.1016/j.bioorg.2023.106935.
DS Docta Complutense
RD 20 abr 2025