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Vol. 53, Issue 6, 969-973, June 1998
Geneva Biomedical Research Institute, Glaxo Wellcome Research and
Development, Geneva, 1228 Switzerland (C.V., A.S., R.A.N.) and
Exploratory Chemistry, Glaxo Wellcome Research and Development,
Stevenage, SG1 2NY, United Kingdom (G.R.)
There are currently seven P2X receptor subunits (P2X1-7)
defined by molecular cloning. The functional identification of these
receptors has relied primarily on the potency of 
,
-methylene-ATP relative to that of ATP and on the kinetics of receptor
desensitization. In the present experiments we found that the
2',3'-O-(2,4,6-trinitrophenyl)-substituted analogs of ATP are selective
and potent antagonists at some but not all P2X receptors. The
trinitrophenyl analogs of ATP, ADP, AMP, and GTP produced a reversible
inhibition of ATP-evoked currents in human embryonic kidney 293 cells
expressing P2X1 receptors, P2X3 receptors, or
both P2X2 and P2X3 (heteromeric) receptors; IC50 values were close to 1 nM. These compounds
were at least 1000-fold less effective in blocking currents in cells
expressing P2X2, P2X4, or P2X7
receptors (P2X5 and P2X6 not tested). GTP, 2,4,6-trinitrophenol, and the 2',3'-trinitrophenyl analog of adenosine (0.1-10 µM) had no effect. Thus, we have identified a
structural motif that confers antagonist action at P2X receptors that
contain P2X1 or P2X3 subunits (the
,-methylene-ATP-sensitive subclass).
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