PT - JOURNAL ARTICLE AU - Ralf Hausmann AU - Jürgen Rettinger AU - Zoltan Gerevich AU - Sabine Meis AU - Matthias U. Kassack AU - Peter Illes AU - Günter Lambrecht AU - Günther Schmalzing TI - The Suramin Analog 4,4′,4″,4″′-(Carbonylbis(imino-5,1,3-benzenetriylbis (carbonylimino)))tetra-kis-benzenesulfonic Acid (NF110) Potently Blocks P2X<sub>3</sub> Receptors: Subtype Selectivity Is Determined by Location of Sulfonic Acid Groups AID - 10.1124/mol.106.022665 DP - 2006 Jun 01 TA - Molecular Pharmacology PG - 2058--2067 VI - 69 IP - 6 4099 - http://molpharm.aspetjournals.org/content/69/6/2058.short 4100 - http://molpharm.aspetjournals.org/content/69/6/2058.full SO - Mol Pharmacol2006 Jun 01; 69 AB - We have previously identified the suramin analog 4,4′,4″,4″′-(carbonylbis(imino-5,1,3-benzenetriylbis(carbonylimino)))tetrakis-benzene-1,3-disulfonic acid (NF449) as a low nanomolar potency antagonist of recombinant P2X1 receptors. Here, we characterize, by two-electrode voltage-clamp electrophysiology, three isomeric suramin analogs designated para-4,4′,4″,4″″-(carbonylbis(imino-5,1,3-benzenetriylbis (carbonylimino)))tetrakis-benzenesulfonic acid (NF110), meta-(3,3′,3″,3″″-(carbonylbis(imino-5,1,3-benzenetriylbis (carbonylimino)))tetra-kis-benzenesulfonic acid (NF448), and ortho-(2,2′,2″,2″″-(carbonylbis(imino-5,1,3-benzenetriylbis (carbonylimino)))tetra-kis-benzenesulfonic acid (MK3) with respect to their potency in antagonizing rat P2X receptor-mediated inward currents in Xenopus laevis oocytes. Meta, para, and ortho refer to the position of the single sulfonic acid group relative to the amide bond linking the four symmetrically oriented benzenesulfonic acid moieties to the central, invariant suramin core. NF448, NF110, and MK3 were &gt;200-fold less potent in blocking P2X1 receptors than NF449, from which they differ structurally only by having one instead of two sulfonic acid residues per benzene ring. Although the meta- and ortho-isomers retained P2X1 receptor selectivity, the para-isomer NF110 exhibited a significantly increased activity at P2X3 receptors (Ki ∼ 36 nM) and displayed the following unique selectivity profile among suramin derivatives: P2X2+3 = P2X3 &gt; P2X1 &gt; P2X2 &gt;&gt; P2X4 &gt; P2X7. The usefulness of NF110 as a P2X3 receptor antagonist in native tissues could be demonstrated by showing that NF110 blocks αβ-methylene-ATP-induced currents in rat dorsal root ganglia neurons with similar potency as recombinant rat P2X3 receptors. Together, these data highlight the importance of both the number and exact location of negatively charged groups for P2X subtype potency and selectivity.