Trinitrophenyl-substituted nucleotides are potent antagonists selective for P2X1, P2X3, and heteromeric P2X2/3 receptors.
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 alpha,beta-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 microM) had no effect. Thus, we have identified a structural motif that confers antagonist action at P2X receptors that contain P2X1 or P2X3 subunits (the alpha,beta-methylene-ATP-sensitive subclass).
Virginio
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Geneva Biomedical Research Institute, Glaxo Wellcome Research and Development, Geneva, 1228 Switzerland.
Robertson
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Surprenant
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North
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D000818:Animals; D004305:Dose-Response Relationship, Drug; D006801:Humans; D009705:Nucleosides / Q000494:pharmacology*; D058919:Purinergic P2 Receptor Antagonists; D051381:Rats; D018048:Receptors, Purinergic P2 / Q000737:chemistry; D013329:Structure-Activity Relationship; D014301:Trinitrobenzenes / Q000494:pharmacology*
D009705:Nucleosides; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2; D014301:Trinitrobenzenes