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The distribution of the P2X₇ receptor in inflammatory cells suggests that P2X₇ antagonists have a significant role to play in the treatment of inflammatory disease. We conducted a natural product high-throughput screening campaign to discover P2X₇ receptor antagonists. The Australian marine sponge Stylissa flabellata yielded two new bisimidazo-pyrano-imidazole bromopyrrole ether alkaloids, stylissadines A (IC₅₀ 0.7 μM) and B (IC₅₀ 1.8 μM), as the specific bioactive constituents. The compounds inhibit BzATP-mediated pore formation in THP-1 cells. Also present in this extract was considerable nonspecific bioactivity in the hemeolysin specificity assay. A new pyrrole-imidazole alkaloid, konbu'acidin B, and the known pyrrole-imidazole alkaloids 4,5-dibromopalau'amine and massadine were also isolated and had nonspecific activity. ROESY and proton coupling constant data indicated that the stereochemistry at …