Discovery of (3-Phenylcarbamoyl-3,4-dihydro-2H-pyrrol-2-yl) phosphonates as Imidazoline I2 receptor ligands with anti-Alzheimer and analgesic properties

Bagán, AndreaLópez Ruiz, AlbaAbás Prades, SòniaRuiz Cantero, M. CarmenVasilopoulou, FoteiniTaboada Jara, TeresaGriñán Ferré, ChristianPallàs, MercèMuguruza Millán, CarolinaDíez Alarcia, RebecaCallado Hernando, Luis FelipeEntrena Fernández, José ManuelCobos del Moral, Enrique JoséPérez Fernández, BelénMorales García, José A.Molins, EliesJonghe, Steven DeDaelemans, DirkBrea Floriani, José ManuelVal García, CristinaLoza García, María IsabelHernández Hernández, ElenaGarcía Sevilla, Jesús A.García-Fuster, M. JuliaDíaz Navarro, CaridadFernández Godino, RosarioGenilloud, OlgaBeljkaš, MilanOljačić, SlavicaNikolic, KatarinaEscolano Mirón, Carmen2026-01-292026-01-292025-01-17Andrea Bagán, Alba López-Ruiz, Sònia Abás, M. Carmen Ruiz-Cantero, Foteini Vasilopoulou, Teresa Taboada-Jara, Christian Griñán-Ferré, Mercè Pallàs, Carolina Muguruza, Rebeca Diez-Alarcia, Luis F. Callado, José M. Entrena, Enrique J. Cobos, Belén Pérez, José A. Morales-García, Elies Molins, Steven De Jonghe, Dirk Daelemans, José Brea, Cristina Val, M. Isabel Loza, Elena Hernández-Hernández, Jesús A. García-Sevilla, M. Julia García-Fuster, Caridad Díaz, Rosario Fernández-Godino, Olga Genilloud, Milan Beljkaš, Slavica Oljačić, Katarina Nikolic, and Carmen Escolano. 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 2025 68 (3), 2551-2573 DOI: 10.1021/acs.jmedchem.4c01644https://hdl.handle.net/10347/45592Imidazoline 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 therapeuticseng© 2025 The Authors. Published by American Chemical Society. This publication is licensed under CC-BY 4.0Attribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/LigandsPhenylsPlasmaSelectivitySubstituentsDiscovery of (3-Phenylcarbamoyl-3,4-dihydro-2H-pyrrol-2-yl) phosphonates as Imidazoline I2 receptor ligands with anti-Alzheimer and analgesic propertiesjournal article10.1021/acs.jmedchem.4c016441520-4804open access