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TitleDiscovery of Triazolopyrimidine Derivatives as Selective P2X3 Receptor Antagonists Binding to an Unprecedented Allosteric Site as Evidenced by Cryo-Electron Microscopy.
Journal, issue, pagesJ Med Chem, Vol. 67, Issue 16, Page 14443-14465, Year 2024
Publish dateAug 22, 2024
AuthorsGa-Ram Kim / Subin Kim / Yeo-Ok Kim / Xuehao Han / Jessica Nagel / Jihyun Kim / Dahin Irene Song / Christa E Müller / Myung-Ha Yoon / Mi Sun Jin / Yong-Chul Kim /
PubMed AbstractThe P2X3 receptor (P2X3R), an ATP-gated cation channel predominantly expressed in C- and Aδ-primary afferent neurons, has been proposed as a drug target for neurological inflammatory diseases, e.g., ...The P2X3 receptor (P2X3R), an ATP-gated cation channel predominantly expressed in C- and Aδ-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 was optimized through structure-activity relationship studies by modifying the tetrazole core as well as side chain substituents. The optimized antagonist , featuring a cyclopropane-substituted triazolopyrimidine core, displayed potent P2X3R-antagonistic activity (IC = 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 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 , thus presenting a novel, promising lead structure.
External linksJ Med Chem / PubMed:39102524
MethodsEM (single particle)
Resolution2.61 Å
Structure data

60647

9ik1

EMDB-60647, PDB-9ik1:
Cryo-EM structure of the human P2X3 receptor-compound 26a complex
Method: EM (single particle) / Resolution: 2.61 Å

Chemicals

PDB-1l2m:
Minimized Average Structure of the N-terminal, DNA-binding domain of the replication initiation protein from a geminivirus (Tomato yellow leaf curl virus-Sardinia)

ChemComp-ATP:
ADENOSINE-5'-TRIPHOSPHATE / ATP, energy-carrying molecule*YM

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

ChemComp-MG:
Unknown entry

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / P2X3 receptor / compound 26a / Cryo-EM

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