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Furan
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27. Bensa, D.; Constantieux, T.; Rodriguez, J. Synthesis 2004, 923.
28. A2A binding assay: Membranes from HEK-293 cells expressing recombinant
human A2A receptor (0.04 mg/mL), yttrium oxide wheat germ-agglutinin-
coated SPA beads (4 mg/mL), 0.01 mg/mL adenosine deaminase and 2 nM
[3H]SCH58261 were incubated with test compounds (1% DMSO final) in 1ꢁ
PBS + 10 mM MgCl2 overnight following centrifugation at 1000 rpm for 2 min.
Signal was detected using the Viewlux CCD Imager. Assays were performed in
duplicate and compounds were tested at least two times. The data were fit to a
one-site competition binding model for IC50 determination using the program
GraphPad Prism (GraphPad Software, Inc., San Diego, CA) and Ki values were
calculated using the Cheng–Prusoff equation.30
29. A1 binding assay: Membranes from CHO-K1 cells expressing recombinant
human A1 receptor (0.04 mg/mL), wheat germ-agglutinin-coated SPA beads
(2 mg/mL), 0.01 mg/mL adenosine deaminase and 2 nM [3H]DPCPX were
incubated with test compounds (1% DMSO final) in 1ꢁ PBS + 10 mM MgCl2.
for 2 h following centrifugation at 1000 rpm for 1 min. Signal was detected
using the Microbeta Trilux. Assays were performed in duplicate and
compounds were tested at least two times. The data were fit to a one-site
competition binding model for IC50 determination using the program
GraphPad Prism (GraphPad Software, Inc., San Diego, CA) and Ki values were
calculated using the Cheng–Prusoff equation.30
Figure 4. Potential for alternative binding of 13d versus 7.
at R1 and the resulting pseudo symmetry of the molecule. The pres-
ence of the furan heterocycle within the 2-amino substituent may
allow the antagonist to adopt an alternative binding conformation
whereby the furfuryl heterocycle binds in the site adopted by the
4-furan group of the other analogs (Fig. 4).
In summary, potent small-molecule antagonists of the A2A
receptor displaying a good selectivity versus the A1 receptor have
been identified. Specifically, 7l is an A2A antagonist with a Ki of
12 nM and displays >500-fold binding selectivity versus A1. In
addition, 13d shows maintenance of good A2A binding activity
(Ki < 100 nM) with no associated A1 activity up to concentrations
of 10 lM. The results presented provide a low molecular weight
template for further development of an A2A antagonist.
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