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Seven PPADS (Pyridoxal‐5′‐Phosphate 6‐Azophenyl 2′,4′‐DiSulfonate) analogs were investigated at Group 1 P2X receptors expressed in Xenopus oocytes. All seven analogs potently inhibited P2X1(IC50range, 5–32 nM) and P2X3(IC50range, 22–345 nM), the two Group I P2X receptor subtypes. Analogs showed greater inhibitory activity where the pyridoxal moiety of PPADS contained a 5′‐phosphonate group, rather than a 5′‐phosphate group. Analogs also showed greater potency where disulfonate groups were removed from, or substituted at, the azophenyl moiety. The most active analog was MRS 2257 (pyridoxal‐5′‐phosphonate 6‐azophenyl 3′,5′‐bismethylenephosphonate) at P2X1(IC50, 5 nM) and P2X3(IC50, 22 nM) receptors, being 14‐fold and 10‐fold more potent than PPADS itself. MRS 2257 produced a nonsurmountable inhibition when tested against a range of ATP concentrations, although blockade was reversed by about 85% after 20 minutes of washout. TNP‐ATP and Ip5I were equipotent with MRS 2257 at P2X1receptors, whereas TNP‐ATP was 64‐fold more potent than MRS 2257 at P2X3receptors. In conclusion, the PPADS template can be altered at the pyridoxal and phenyl moieties to produce P2X1and P2X3receptor antagonists showing higher potency and greater degree of reversibility than the parent compound at these Group I P2X receptors. Drug Dev. Res. 53:281–291, 2001. © 2001 Wiley‐Liss, Inc.