Datensatz

Zusammenfassung

P2X receptors are cation channels gated by extracellular ATP and related nucleotides. Because of the widespread distribution of P2X receptors and the high subtype diversity, potent and selective antagonists are needed to dissect their roles in intact tissues. Based on suramin as a lead compound, several derivates have been described that block recombinant P2X receptors with orders of magnitude higher potency than suramin. Here we characterized the suramin analogue 4,4′,4″,4‴-(carbonylbis(imino-5,1,3-benzenetriylbis(carbonylimino)))tetrakis-benzene-1,3-disulfonic acid (NF449) with respect to its potency to antagonize ATP or αβ-methyleneadenosine 5′-trisphosphate-induced inward currents of homomeric rat P2X₁–P2X₄ receptors or heteromeric P2X₁₊₅ and P2X₂₊₃ receptors, respectively. NF449 most potently blocked P2X₁ and P2X₁₊₅ receptors with IC₅₀ values of 0.3 nM and 0.7 nM, respectively. Three to four orders of magnitude higher NF449 concentrations were required to block homomeric P2X₃ or heteromeric P2X₂₊₃ receptors (IC₅₀ 1.8 and 0.3 μM, respectively). NF449 was least potent at homomeric P2X₂ receptors (IC₅₀ 47 μM) and homomeric P2X₄ receptors (IC50 > 300 μM). Altogether, these results characterize NF449 as the so far most potent and selective antagonist of receptors incorporating the P2X₁ subunit such as the P2X₁ homomer and the P2X₁₊₅ heteromer.