Profiling at recombinant homomeric and heteromeric rat P2X receptors identifies the suramin analogue NF449 as a highly potent P2X sub(1) receptor antagonist

• Published in: Neuropharmacology 2005-03, Vol.48 (3), p.461-468
• Main Authors: Rettinger, J, Braun, K, Hochmann, H, Kassack, MU, Ullmann, H, Nickel, P, Schmalzing, G, Lambrecht, G
• Format: Article
• Language: English
• ISSN: 0028-3908
• DOI: 10.1016/j.neuropharm.2004.11.003

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 ) (carbonylimino)))tetrakis-benzene-1,3-disulfonic acid (NF449) with respect to its potency to antagonize ATP or alpha beta -methyleneadenosine 5'-trisphosphate-induced inward currents of homomeric rat P2X sub(1)-P2X sub(4) receptors or heteromeric P2X sub(1+5) and P2X sub(2+3) receptors, respectively. NF449 most potently blocked P2X sub(1) and P2X sub(1 +5) receptors with IC sub(50) values of 0.3 nM and 0.7 nM, respectively. Three to four orders of magnitude higher NF449 concentrations were required to block homomeric P2X sub(3) or heteromeric P2X sub(2+3) receptors (IC sub(50) 1.8 and 0.3 mu M, respectively). NF449 was least potent at homomeric P2X sub(2) receptors (IC sub(50) 47 mu M) and homomeric P2X sub(4) receptors (IC sub(50) > 300 mu M). Altogether, these results characterize NF449 as the so far most potent and selective antagonist of receptors incorporating the P2X sub(1) subunit such as the P2X sub(1) homomer and the P2X sub(1+5) heteromer.