Discovery and Structure Relationships of Salicylanilide Derivatives as Potent, Non-acidic P2X1 Receptor Antagonists
| Autor: | Sabrina Densborn, Sonja Hinz, Ralf Schmid, Aliaa Abdelrahman, Claudia Spanier, Christa E. Müller, Younis Baqi, Djamil Azazna, Eduardo Fuentes, Maoqun Tian |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Blood Platelets
Platelet Aggregation Purinergic P2X Receptor Antagonists Allosteric regulation Drug Evaluation Preclinical Molecular Dynamics Simulation Pharmacology Salicylanilides 01 natural sciences Cell Line Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound Allosteric Regulation Drug Discovery Extracellular Humans Protein Isoforms Binding site Receptor IC50 Ion channel 030304 developmental biology 0303 health sciences Binding Sites Trifluoromethyl Chemistry 0104 chemical sciences Receptors Purinergic P2X1 Salicylanilide 010404 medicinal & biomolecular chemistry Astrocytes Molecular Medicine Calcium Collagen |
| Zdroj: | Journal of Medicinal Chemistry. 63:6164-6178 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/acs.jmedchem.0c00435 |
| Popis: | Antagonists for the ATP-gated ion channel receptor P2X1 have potential as antithrombotics and for treating hyperactive bladder and inflammation. In this study, salicylanilide derivatives were synthesized based on a screening hit. P2X1 antagonistic potency was assessed in 1321N1 astrocytoma cells stably transfected with the human P2X1 receptor by measuring inhibition of the ATP-induced calcium influx. Structure-activity relationships were analyzed, and selectivity versus other P2X receptor subtypes was assessed. The most potent compounds, N-[3,5-bis(trifluoromethyl)phenyl]-5-chloro-2-hydroxybenzamide (1, IC50 0.0192 μM) and N-[3,5-bis(trifluoromethyl)phenyl]-4-chloro-2-hydroxybenzamide (14, IC50 0.0231 μM), displayed >500-fold selectivity versus P2X2 and P2X3, and 10-fold selectivity versus P2X4 and P2X7 receptors, and inhibited collagen-induced platelet aggregation. They behaved as negative allosteric modulators, and molecular modeling studies suggested an extracellular binding site. Besides selective P2X1 antagonists, compounds with ancillary P2X4 and/or P2X7 receptor inhibition were discovered. These compounds represent the first potent, non-acidic, allosteric P2X1 receptor antagonists reported to date. |
| Databáze: | OpenAIRE |
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