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

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-ph...

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Detalles Bibliográficos
Autores: Bagán, Andrea, López Ruiz, Alba, Abás, Sònia, Ruiz Cantero, M. Carmen, Vasilopoulou, Foteini, Taboada Jara, Teresa, Griñán Ferré, Christian, Pallàs, Mercè, Muguruza, Carolina, Diez Alarcia, Rebeca, Callado, Luis F., Entrena, José M., Cobos, Enrique J., Pérez, Belén, Morales García, José A., Molins, Elies, De Jonghe, Steven, Daelemans, Dirk, Brea, José, Val, Cristina, Loza, M. Isabel, Hernández Hernández, Elena, García Sevilla, Jesús A., García Fuster, M Julia, Díaz, Caridad, Fernández Godino, Rosario, Genilloud, Olga, Beljkaš, Milan, Oljačić, Slavica, Nikolic, Katarina, Escolano, Carmen
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2025
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/392338
Acceso en línea:http://hdl.handle.net/10261/392338
https://api.elsevier.com/content/abstract/scopus_id/85215605747
Access Level:acceso abierto
Palabra clave:Imidazoline
Binding sites
Clinical pharmacology
Central sensitization
Descripción
Sumario: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.

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