TY - JOUR
T1 - Discovery and Structure Relationships of Salicylanilide Derivatives as Potent, Non-acidic P2X1 Receptor Antagonists
AU - Tian, Maoqun
AU - Abdelrahman, Aliaa
AU - Baqi, Younis
AU - Fuentes, Eduardo
AU - Azazna, Djamil
AU - Spanier, Claudia
AU - Densborn, Sabrina
AU - Hinz, Sonja
AU - Schmid, Ralf
AU - Müller, Christa E.
N1 - Funding Information:
We thank Marion Schneider for LCMS analyses, and Sabine Terhart-Krabbe and Annette Reiner for NMR spectra. Duncan Crawford and Tocris are gratefully acknowledged for providing their compound library. This study was supported by the BMBF (German Federal Ministry for Education and Research) within the BioPharma initiative “Neuroallianz”. Y.B. is grateful for support by the Arab-German Young Academy of Sciences and Humanities (AGYA). E.F. thanks CONICYT/FONDECYT no. 1180427 for support.
Publisher Copyright:
© 2020 American Chemical Society.
PY - 2020/6/11
Y1 - 2020/6/11
N2 - 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.
AB - 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.
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U2 - 10.1021/acs.jmedchem.0c00435
DO - 10.1021/acs.jmedchem.0c00435
M3 - Article
C2 - 32345019
AN - SCOPUS:85086346825
SN - 0022-2623
VL - 63
SP - 6164
EP - 6178
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 11
ER -