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-phenylc...
| Autores: | ; ; |
|---|---|
| Tipo de documento: | Artículo |
| Fecha de publicación: | 2025 |
| País: | España |
| Institución: | Universidad Complutense de Madrid (UCM) |
| Repositorio: | Docta Complutense |
| Lenguaje: | Inglés |
| OAI Identifier: | oai:docta.ucm.es:20.500.14352/118846 |
| Acceso en línea: | https://hdl.handle.net/20.500.14352/118846 |
| Nivel de acceso: | Acceso abierto |
| Palabra clave: | 576 Ligands Phenyls Plasma Selectivity Substituents Ciencias Biomédicas 24 Ciencias de la Vida |
| _version_ | 1878740068783357952 |
|---|---|
| author | Bagám, Andrea |
| author2 | Morales García, José Ángel Escolano, Carmen |
| author2_role | author author |
| author_browse | Bagám, Andrea Escolano, Carmen Morales García, José Ángel |
| author_facet | Bagám, Andrea Morales García, José Ángel Escolano, Carmen |
| author_role | author |
| collection | Docta Complutense |
| description | 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. |
| eu_rights_str_mv | openAccess |
| format | article |
| id | ES_ccf2f424d76d2931d2b76bb64f7a346b |
| institution | Universidad Complutense de Madrid (UCM) |
| instname_str | Universidad Complutense de Madrid (UCM) |
| language | eng |
| network_acronym_str | ES |
| network_name_str | España |
| oai_identifier_str | oai:docta.ucm.es:20.500.14352/118846 |
| publishDate | 2025 |
| publishDateSort | 2025 |
| publisher | American Chemical Society |
| publisherStr | American Chemical Society |
| reponame_str | Docta Complutense |
| spelling | Discovery of (3-Phenylcarbamoyl-3,4-dihydro-2H-pyrrol-2-yl)phosphonates as Imidazoline I2 Receptor Ligands with Anti-Alzheimer and Analgesic Properties Bagám, Andrea Morales García, José Ángel Escolano, Carmen 576 Ligands Phenyls Plasma Selectivity Substituents Ciencias Biomédicas 24 Ciencias de la Vida 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. American Chemical Society https://hdl.handle.net/20.500.14352/118846 |
| spellingShingle | Discovery of (3-Phenylcarbamoyl-3,4-dihydro-2H-pyrrol-2-yl)phosphonates as Imidazoline I2 Receptor Ligands with Anti-Alzheimer and Analgesic Properties Bagám, Andrea 576 Ligands Phenyls Plasma Selectivity Substituents Ciencias Biomédicas 24 Ciencias de la Vida |
| title | Discovery of (3-Phenylcarbamoyl-3,4-dihydro-2H-pyrrol-2-yl)phosphonates as Imidazoline I2 Receptor Ligands with Anti-Alzheimer and Analgesic Properties |
| title_full | Discovery of (3-Phenylcarbamoyl-3,4-dihydro-2H-pyrrol-2-yl)phosphonates as Imidazoline I2 Receptor Ligands with Anti-Alzheimer and Analgesic Properties |
| title_fullStr | Discovery of (3-Phenylcarbamoyl-3,4-dihydro-2H-pyrrol-2-yl)phosphonates as Imidazoline I2 Receptor Ligands with Anti-Alzheimer and Analgesic Properties |
| title_full_unstemmed | Discovery of (3-Phenylcarbamoyl-3,4-dihydro-2H-pyrrol-2-yl)phosphonates as Imidazoline I2 Receptor Ligands with Anti-Alzheimer and Analgesic Properties |
| title_short | Discovery of (3-Phenylcarbamoyl-3,4-dihydro-2H-pyrrol-2-yl)phosphonates as Imidazoline I2 Receptor Ligands with Anti-Alzheimer and Analgesic Properties |
| title_sort | Discovery of (3-Phenylcarbamoyl-3,4-dihydro-2H-pyrrol-2-yl)phosphonates as Imidazoline I2 Receptor Ligands with Anti-Alzheimer and Analgesic Properties |
| topic | 576 Ligands Phenyls Plasma Selectivity Substituents Ciencias Biomédicas 24 Ciencias de la Vida |
| topic_facet | 576 Ligands Phenyls Plasma Selectivity Substituents Ciencias Biomédicas 24 Ciencias de la Vida |
| url | https://hdl.handle.net/20.500.14352/118846 |