Discovery of (3-Phenylcarbamoyl-3,4-dihydro-2H-pyrrol-2-yl)phosphonates as Imidazoline I2 Receptor Ligands with Anti-Alzheimer and Analgesic Properties

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dc.contributor.authorBagán, Andrea
dc.contributor.authorLópez Ruiz, Alba
dc.contributor.authorAbás Prades, Sònia
dc.contributor.authorRuiz Cantero, María del Carmen
dc.contributor.authorVasilopoulou, Foteini
dc.contributor.authorTaboada Jara, Teresa
dc.contributor.authorGriñán Ferré, Christian
dc.contributor.authorPallàs, Mercè
dc.contributor.authorMuguruza, Carolina
dc.contributor.authorDiez Alarcia, Rebeca
dc.contributor.authorCallado Hernando, Luis Felipe
dc.contributor.authorEntrena Fernández, José Manuel
dc.contributor.authorCobos del Moral, Enrique José
dc.contributor.authorPérez, Belén
dc.contributor.authorMorales García, José Ángel
dc.contributor.authorMolins Grau, Elies
dc.contributor.authorDe Jonghe, Steven
dc.contributor.authorDaelemans, Dirk
dc.contributor.authorBrea Floriani, José Manuel
dc.contributor.authorVal, Cristina
dc.contributor.authorLoza García, M. Isabel
dc.contributor.authorHernández Hernández, Elena
dc.contributor.authorGarcía Sevilla, Jesús Andrés
dc.contributor.authorGarcía Fuster, María Julia
dc.contributor.authorDíaz, Caridad
dc.contributor.authorFernández Godino, Rosario
dc.contributor.authorGenilloud Rodríguez, Olga
dc.contributor.authorBeljkaš, Milan
dc.contributor.authorOljačić, Slavika
dc.contributor.authorNikolic, Katarina
dc.contributor.authorEscolano Mirón, Carmen
dc.date.accessioned2025-02-12T10:25:44Z
dc.date.available2025-02-12T10:25:44Z
dc.date.issued2025
dc.date.updated2025-02-12T10:25:44Z
dc.description.abstractImidazoline 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.en
dc.description.sponsorshipThis work was supported by Ministerio de Ciencia, Innovación y Universidades, Agencia Estatal de Investigación (Spain, PID2022-1380790B-I00 to C.E., and PID2021-138079OB-I00 to M.P.; MICIU/AEI/10.13039/501100011033 and FEDER, UE; and PDC2022-133441-I00 to C.E.; MICIU/AEI/10.13039/501100011033 Europea Next GenerationEU/PRTR), Basque Government (IT-1512-22) and Generalitat de Catalunya (2021 SGR 00357). Financial support was provided for A.L.-R. (PRE2022-105091 ministerio de Ciencia e Innovación). E.H.-H. was first funded by the Margarita Salas Program (Ministerio de Universidades; Plan de Recuperación, Transformación y Resilencia; NextGenerationEU) with the participation of the University of the Balearic Islands, and currently holds grant FJC2022-048338-I, funded by MCIN/ AEI/10.13039/501100011033 and by the European Union NextGenerationEU/PRTR. The authors acknowledge grant support from the Ministry of Science and Innovation, Spain, with funds from the European Union NextGenerationEU (PRTRC17.I1) and the Autonomous Community of Galicia within the framework of the 2023 Biotechnology Plan Applied to Health, Xunta de Galicia (ED431C 2022/20) and the European Regional Development Fund (ERDF). This study was partially supported by the Andalusian Regional Government (grant CTS- 109). Authors also thank the support of the Unit of Excellence “UNETE” from the University of Granada (reference UCEPP2017-05). M.B., S.O., and K.N. acknowledge the Ministry of Science, Technological Development and Innovation, Republic of Serbia through two Grant Agreements with University of Belgrade-Faculty of Pharmacy No. 451-03-65/2024-03/200161 and No. 451-03-66/2024-03/200161. A.L. thanks to Grant PRE2022-105091 funded by MICIU/AEI/10.13039/501100011033.en
dc.identifier.citationBagán, 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., et al. (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. https://doi.org/10.1021/ACS.JMEDCHEM.4C01644
dc.identifier.doi10.1021/ACS.JMEDCHEM.4C01644
dc.identifier.eissn1520-4804
dc.identifier.issn0022-2623
dc.identifier.urihttp://hdl.handle.net/20.500.14454/2277
dc.language.isoeng
dc.publisherAmerican Chemical Society
dc.rights© 2025 The Authors. Published by American Chemical Society
dc.titleDiscovery of (3-Phenylcarbamoyl-3,4-dihydro-2H-pyrrol-2-yl)phosphonates as Imidazoline I2 Receptor Ligands with Anti-Alzheimer and Analgesic Propertiesen
dc.typejournal article
dcterms.accessRightsopen access
oaire.citation.titleJournal of Medicinal Chemistry
oaire.licenseConditionhttps://creativecommons.org/licenses/by/4.0/
oaire.versionVoR
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