Diclofenac and other non-steroidal anti-inflammatory drugs (NSAIDs) are competitive antagonists of the human P2X3 receptor

• DOI: 10.3389/fphar.2023.1120360
• Publication Date: 2023-03-16T04:28:43Z
• Authors: Laura Grohs; Linhan Cheng; Saskia Cönen; Bassam G. Haddad; Astrid Bülow; Idil Toklucu; Lisa Ernst; Jannis Körner; Günther Schmalzing; Angelika Lampert; Jan-Philipp Machtens; Ralf Hausmann
• Keywords: Diclofenac; Anti-inflammatory

Introduction: The P2X3 receptor (P2X3R), an ATP-gated non-selective cation channel of the P2X family, is expressed in sensory neurons and involved nociception. P2X3R inhibition was shown to reduce chronic neuropathic pain. In a previous screening 2000 approved drugs, natural products, bioactive substances, various non-steroidal anti-inflammatory drugs (NSAIDs) were found inhibit P2X3R-mediated currents. Methods: To investigate whether receptors contributes analgesic effect NSAIDs, we characterized potency selectivity NSAIDs at other P2XR subtypes using two-electrode voltage clamp electrophysiology. Results: We identified diclofenac as hP2X3R hP2X2/3R antagonist with micromolar (with IC 50 values 138.2 76.7 µM, respectively). A weaker hP2X1R, hP2X4R, hP2X7R by determined. Flufenamic acid (FFA) inhibited hP2X3R, rP2X3R, (IC 221 264.1 ∼900 respectively), calling into question its use ion blocker, when P2XR-mediated currents are under study. Inhibition or could be overcome prolonged ATP application increasing concentrations agonist α,β-meATP, respectively, indicating competition agonists. Molecular dynamics simulation showed that largely overlaps bound open state hP2X3R. Our results suggest competitive antagonism through which diclofenac, interacting residues ATP-binding site, left flipper, dorsal fin domains, inhibits gating conformational fixation flipper domains. summary, demonstrate human NSAIDs. Diclofenac proved most effective strong hP2X7R. Discussion: Considering their involvement nociception, rarely reached therapeutic range, may play minor role analgesia compared high-potency cyclooxygenase but explain known side taste disturbances caused diclofenac.