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The Suramin Analog 4,4',4'',4'''-(Carbonylbis(imino-5,1,3-benzenetriylbis (carbonylimino)))tetra-kis-benzenesulfonic Acid (NF110) Potently Blocks P2X₃ Receptors: Subtype Selectivity Is Determined by Location of Sulfonic Acid Groups

Molecular Pharmacology, RWTH Aachen University, Aachen, Germany (R.H., G.S.); Max-Planck-Institute of Biophysics, Frankfurt am Main, Germany (J.R.); Rudolf-Boehm Institute for Pharmacology and Toxicology, University of Leipzig, Leipzig, Germany (Z.G., P.I.); Department of Pharmaceutical Chemistry, University of Bonn, Bonn, Germany (S.M., M.U.K.); and Department of Pharmacology, University of Frankfurt, Frankfurt am Main, Germany (G.L.)

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 >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 (K_i 36 nM) and displayed the following unique selectivity profile among suramin derivatives: P2X₂₊₃ = P2X₃ > P2X₁ > P2X₂ >> P2X₄ > P2X₇. The usefulness of NF110 as a P2X₃ receptor antagonist in native tissues could be demonstrated by showing that NF110 blocks -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.

Received for publication January 17, 2006.

Accepted for publication March 21, 2006.

Address correspondence to: Dr. Günther Schmalzing, Department of Molecular Pharmacology, University Hospital of RWTH Aachen University, Wendlingweg 2, 52074 Aachen, Germany. E-mail: gschmalzing{at}ukaachen.de

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