title: Profiling at recombinant homomeric and heteromeric rat P2X receptors identifies the suramin analogue NF449 as a highly potent P2X1 receptor antagonist.
abstract: 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 alphabeta-methyleneadenosine 5'-trisphosphate-induced inward currents of homomeric rat P2X(1)-P2X(4) receptors or heteromeric P2X(1 + 5) and P2X(2+3) receptors, respectively. NF449 most potently blocked P2X(1) and P2X(1 + 5) receptors with IC(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(3) or heteromeric P2X(2 + 3) receptors (IC(50) 1.8 and 0.3 microM, respectively). NF449 was least potent at homomeric P2X(2) receptors (IC(50) 47 microM) and homomeric P2X(4) receptors (IC(50) > 300 microM). Altogether, these results characterize NF449 as the so far most potent and selective antagonist of receptors incorporating the P2X(1) subunit such as the P2X(1) homomer and the P2X(1 + 5) heteromer.
authors.affiliation: Department of Molecular Pharmacology, Medical School of the Technical University of Aachen, Wendlingweg 2, D-52074 Aachen, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Rettinger
authors.forename: Kirsten
authors.initials: K
authors.lastname: Braun
authors.forename: Henrike
authors.initials: H
authors.lastname: Hochmann
authors.forename: Matthias U
authors.initials: MU
authors.lastname: Kassack
authors.forename: Heiko
authors.initials: H
authors.lastname: Ullmann
authors.forename: Peter
authors.initials: P
authors.lastname: Nickel
authors.forename: Günther
authors.initials: G
authors.lastname: Schmalzing
authors.forename: Günter
authors.initials: G
authors.lastname: Lambrecht
mesh_terms: D000818:Animals; D001557:Benzenesulfonates / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D058919:Purinergic P2 Receptor Antagonists; D051381:Rats; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D058469:Receptors, Purinergic P2X; D013498:Suramin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D014982:Xenopus laevis
chemical_list: C110258:4,4,',4'',4'''-(carbonylbis(imino-5,1,3-benzenetriylbis(carbonylimino)))tetrakis(benzene-1,3-disulfonate); D001557:Benzenesulfonates; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2; D058469:Receptors, Purinergic P2X; D013498:Suramin