RT Journal Article
T1 Discovery of (3-Phenylcarbamoyl-3,4-dihydro-2H-pyrrol-2-yl)phosphonates as Imidazoline I2 Receptor Ligands with Anti-Alzheimer and Analgesic Properties
A1 Bagám, Andrea
A1 Morales García, José Ángel
A1 Escolano, Carmen
AB Imidazoline I2 receptors (I2-IRs) are altered in Alzheimer’s disease (AD) patients and are associated with analgesia. I2-IRs are not structurally described, and their pharmacological characterization relies on their modulation by highly affine ligands. Herein, we describe the synthesis of (3-phenylcarbamoyl-3,4-dihydro-2H-pyrrol-2-yl)phosphonates endowed with relevant affinities for I2-IRs in human brain tissues. The optimal ADME and pharmacokinetic profile of a selected compound, 12d, secured its in vivo exploration in a senescence accelerated prone 8 mice revealing improvement in the cognitive impairment and unveiling the mechanism of action by analyzing specific AD biomarkers. The treatment of a capsaicin-induced mechanical hypersensitivity murine model with 12d revealed analgesic properties devoid of motor coordination issues. The target engagement of 12d was demonstrated by suppression of the analgesic effect by pretreatment with idazoxan. Overall, 12d is a putative candidate for advancing preclinical phases and supports the modulation of I2-IRs as an innovative approach for therapeutics.
PB American Chemical Society
SN 0022-2623
YR 2025
FD 2025-01-17
LK https://hdl.handle.net/20.500.14352/118846
UL https://hdl.handle.net/20.500.14352/118846
LA eng
NO Bagán, A., López-Ruiz, A., Abás, S., Ruiz-Cantero, M. C., Vasilopoulou, F., Taboada-Jara, T., Griñán-Ferré, C., Pallàs, M., Muguruza, C., Diez-Alarcia, R., Callado, L. F., Entrena, J. M., Cobos, E. J., Pérez, B., Morales-García, J. A., Molins, E., De Jonghe, S., Daelemans, D., Brea, J., Val, C., … Escolano, C. (2025). Discovery of (3-Phenylcarbamoyl-3,4-dihydro-2H-pyrrol-2-yl)phosphonates as Imidazoline I2 Receptor Ligands with Anti-Alzheimer and Analgesic Properties. Journal of medicinal chemistry, 68(3), 2551–2573. https://doi.org/10.1021/acs.jmedchem.4c01644
NO Ministerio de Ciencia, Innovación y Universidades (España)
NO Unión Europea
NO Gobierno del País Vasco
NO Generalitat de Catalunya
DS Docta Complutense
RD 28 dic 2025