Synthesis and Pharmacological Evaluation of Novel Non-nucleotide Purine Derivatives as P2X7 Antagonists for the Treatment of Neuroinflammation
| Autor: | Annette Nicke, Antonio M. G. de Diego, Ricardo de Pascual, Paloma Narros-Fernández, Javier Egea, Antonio G. García, Cristóbal de los Ríos, Francesco Calzaferri |
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| Přispěvatelé: | UAM. Departamento de Farmacología |
| Rok vydání: | 2021 |
| Předmět: |
Purine
Male Purinergic P2X Receptor Antagonists Medicina Interleukin-1beta Xenopus Anti-Inflammatory Agents Pharmacology 01 natural sciences Calcium in biology 03 medical and health sciences chemistry.chemical_compound Xenopus laevis Drug Discovery Animals Humans Nucleotide ATP Binding Cassette Transporter Subfamily B Member 1 Neuroinflammation 030304 developmental biology chemistry.chemical_classification Adenosine Triphosphatases 0303 health sciences biology Purinergic receptor Antagonist Xanthine biology.organism_classification 3. Good health 0104 chemical sciences Mice Inbred C57BL Molecular Docking Simulation 010404 medicinal & biomolecular chemistry HEK293 Cells chemistry Purines Macrophages Peritoneal Oocytes Molecular Medicine Receptors Purinergic P2X7 |
| Zdroj: | Journal of Medicinal Chemistry Biblos-e Archivo. Repositorio Institucional de la UAM instname |
| ISSN: | 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.0c02145 |
| Popis: | The ATP-gated P2X7 purinergic receptor (P2X7) is involved in the pathogenesis of many neurodegenerative diseases (NDDs). Several P2X7 antagonists have been developed, though none of them reached clinical trials for this indication. In this work, we designed and synthesized novel blood-brain barrier (BBB)-permeable derivatives as potential P2X7 antagonists. They comprise purine or xanthine cores linked to an aryl group through different short spacers. Compounds were tested in YO-PRO-1 uptake assays and intracellular calcium dynamics in a human P2X7-expressing HEK293 cell line, two-electrode voltage-clamp recordings in Xenopus laevis oocytes, and in interleukin 1β release assays in mouse peritoneal macrophages. BBB permeability was assessed by parallel artificial membrane permeability assays and P-glycoprotein ATPase activity. Dichloroarylpurinylethanones featured a certain P2X7 blockade, being compound 6 (2-(6-chloro-9H-purin-9-yl)-1-(2,4-dichlorophenyl)ethan-1-one), named ITH15004, the most potent, selective, and BBB-permeable antagonist. Compound 6 can be considered as a first non-nucleotide purine hit for future drug optimizations This work has been supported by the following grants: EU Horizon 2020 Research and Innovation Program under Marie Skłodowska-Curie, Grant Agreement N. 766124 to AGG and AN, and Ministerio de Economía y Competitividad, Spain, Grant Number SAF2016-78892R to AGG; Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) Project-ID: 335447717, SFB 1328 (TP15) to A.N.; Instituto de Salud Carlos III, Ministerio de Economía y Competitividad, Spain, Grant Numbers PI16/01041 and PI19/01724 (Cofunded by FEDER) to CdlR; Instituto de Salud Carlos III, Ministerio de Economía y Competitividad, Spain, Grant Numbers PI16/00735 and PI19/00082 (Co-funded by FEDER) to J.E. |
| Databáze: | OpenAIRE |
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