Structural highlights
FunctionP2RX3_HUMAN Receptor for ATP that acts as a ligand-gated ion channel. Publication Abstract from PubMedThe P2X3 receptor (P2X3R), an ATP-gated cation channel predominantly expressed in C- and Adelta-primary afferent neurons, has been proposed as a drug target for neurological inflammatory diseases, e.g., neuropathic pain, and chronic cough. Aiming to develop novel, selective P2X3R antagonists, tetrazolopyrimidine-based hit compound 9 was optimized through structure-activity relationship studies by modifying the tetrazole core as well as side chain substituents. The optimized antagonist 26a, featuring a cyclopropane-substituted triazolopyrimidine core, displayed potent P2X3R-antagonistic activity (IC(50) = 54.9 nM), 20-fold selectivity versus the heteromeric P2X2/3R, and high selectivity versus other P2XR subtypes. Noncompetitive P2X3R blockade was experimentally confirmed by calcium influx assays. Cryo-electron microscopy revealed that 26a stabilizes the P2X3R in its desensitized state, acting as a molecular barrier to prevent ions from accessing the central pore. In vivo studies in a rat neuropathic pain model (spinal nerve ligation) showed dose-dependent antiallodynic effects of 26a, thus presenting a novel, promising lead structure. Discovery of Triazolopyrimidine Derivatives as Selective P2X3 Receptor Antagonists Binding to an Unprecedented Allosteric Site as Evidenced by Cryo-Electron Microscopy.,Kim GR, Kim S, Kim YO, Han X, Nagel J, Kim J, Song DI, Muller CE, Yoon MH, Jin MS, Kim YC J Med Chem. 2024 Aug 22;67(16):14443-14465. doi: 10.1021/acs.jmedchem.4c01214. , Epub 2024 Aug 5. PMID:39102524[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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