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The distribution of the P2X
7 receptor in inf
lammatory ce
lls suggests that P2X
7 antagonists have a significantro
le to p
lay in the treatment of inf
lammatory disease. We conducted a natura
l product high-throughputscreening campaign to discover P2X
7 receptor antagonists. The Austra
lian marine sponge
Stylissa flabellatayie
lded two new bisimidazo-pyrano-imidazo
le bromopyrro
le ether a
lka
loids, sty
lissadines A (IC
50 0.7
M) and B (IC
50 1.8
M), as the specific bioactive constituents. The compounds inhibit BzATP-mediatedpore formation in THP-1 ce
lls. A
lso present in this extract was considerab
le nonspecific bioactivity inthe hemeo
lysin specificity assay. A new pyrro
le-imidazo
le a
lka
loid, konbu'acidin B, and the knownpyrro
le-imidazo
le a
lka
loids 4,5-dibromopa
lau'amine and massadine were a
lso iso
lated and had nonspecificactivity. ROESY and proton coup
ling constant data indicated that the stereochemistry at C12, C17, andC20 in 4,5-dibromopa
lau'amine shou
ld be revised to 12
R, 17
S, 20
S. By ana
logy, the re
lativestereochemistry of pa
lau'amine, 4-bromopa
lau'amine, sty
loguanidine, 3-bromosty
loguanidine, and 2,3-dibromosty
loguanidine shou
ld a
lso be revised to 12
R, 17
S, 20
S. Sty
lissadines A and B are the mostpotent natura
l product P2X
7 antagonists to be iso
lated to date and provide a nove
l c
lass of P2X
7 receptorinhibitors. They are a
lso the first examp
les of tetrameric pyrro
le-imidazo
le a
lka
loids.