Discovery and Structure Relationships of Salicylanilide Derivatives as Potent, Non-acidic P2X1 Receptor Antagonists.

Abstract

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.

• Authors: Maoqun Tian, Aliaa Abdelrahman, Younis Baqi, Eduardo Fuentes, Djamil Azazna, Claudia Spanier, Sabrina Densborn, Sonja Hinz, Ralf Schmid, Christa E Müller
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 63 Issue 11 Pg. 6164-6178 (06 11 2020) ISSN: 1520-4804 [Electronic] United States
• PMID: 32345019 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Protein Isoforms
• Purinergic P2X Receptor Antagonists
• Receptors, Purinergic P2X1
• Salicylanilides
• Collagen
• Calcium

Topics

• Allosteric Regulation (drug effects)
• Astrocytes (cytology, drug effects, metabolism)
• Binding Sites
• Blood Platelets (cytology, drug effects, metabolism)
• Calcium (metabolism)
• Cell Line
• Collagen
• Drug Evaluation, Preclinical
• Humans
• Molecular Dynamics Simulation
• Platelet Aggregation (drug effects)
• Protein Isoforms (antagonists & inhibitors, metabolism)
• Purinergic P2X Receptor Antagonists (chemistry, metabolism, pharmacology)
• Receptors, Purinergic P2X1 (chemistry, metabolism)
• Salicylanilides (chemistry, metabolism, pharmacology)
• Structure-Activity Relationship