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Research ArticleArticle

Molecular Determinants of Potent P2X2 Antagonism Identified by Functional Analysis, Mutagenesis, and Homology Docking

Christian Wolf, Christiane Rosefort, Ghada Fallah, Matthias U. Kassack, Alexandra Hamacher, Mandy Bodnar, Haihong Wang, Peter Illes, Achim Kless, Gregor Bahrenberg, Günther Schmalzing and Ralf Hausmann
Molecular Pharmacology April 2011, 79 (4) 649-661; DOI: https://doi.org/10.1124/mol.110.068700
Christian Wolf
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Christiane Rosefort
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Ghada Fallah
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Matthias U. Kassack
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Alexandra Hamacher
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Mandy Bodnar
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Haihong Wang
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Peter Illes
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Achim Kless
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Gregor Bahrenberg
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Günther Schmalzing
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Ralf Hausmann
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Abstract

P2X2 receptors are members of the ATP-gated P2X family of cation channels, and they participate in neurotransmission in sympathetic ganglia and interneurons. Here, we identified 7,7′-(carbonylbis(imino-3,1-phenylenecarbonylimino-3,1-(4-methyl-phenylene)carbonylimino))bis(1-methoxy-naphthalene-3,6-disulfonic acid) tetrasodium salt (NF770) as a nanomolar-potent competitive P2X2 receptor antagonist within a series of 139 suramin derivatives. Three structural determinants contributed to the inhibition of P2X2 receptors by NF770: 1) a “large urea” structure with two symmetric phenylenecarbonylimino groups; 2) attachment of the naphthalene moiety in position 7,7′; and 3) the specific position of two sulfonic acid groups (3,3′; 6,6′) and of one methoxy group (1,1′) at the naphthalene moiety. This structure-activity relationship was interpreted using a rat P2X2 homology model based on the crystal structure of the closed zebrafish P2X4 receptor. Docking of the suramin derivatives into the modeled ATP-binding pocket provides a uniform explanation for the observed differences in inhibitory potencies. Changes in the chemical structure that increase the inhibitory potency of the suramin derivatives improved the spatial orientation within the ATP-binding pocket to allow for stronger polar interactions of functional groups with Gly72, Glu167, or Arg290. Gly72 is responsible for the orientation of the methoxy group close to Arg290 or Glu167. Combined mutational and functional analysis confirmed that residues Gly72 and Glu167 are as important for ATP binding as Arg290, the ATP-binding role of which has been shown in previous studies. The in silico prediction of Gly72 and Glu167 as ATP-binding residues strongly supports the validity of our homology docking.

Footnotes

  • ↵Embedded Image The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.

  • This work was supported by the Deutsche Forschungsgemeinschaft [Grants Schm 536/8-1/2 (to G.S.), Schm 536/8-2 (to R.H.), Graduiertenkolleg GRK677 (to M.U.K.)].

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    doi:10.1124/mol.110.068700.

  • ABBREVIATIONS:

    A-317491
    5-[[[(3-Phenoxyphenyl)methyl][(1S)-1,2,3,4-tetrahydro-1-naphthalenyl]amino]carbonyl]-1,2,4-benzenetricarboxylic acid sodium salt hydrate
    RO-3
    5-(2-isopropyl-4,5-dimethoxy-benzyl)-pyrimidine-2,4-diamine
    RO-4
    5-(5-iodo-2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine
    GSK314181A
    (adamantan-1-ylmethyl)-5-[(3R-amino-pyrrolidin-1-yl)methyl]-2-chloro-benzamide
    A-740003
    N-(1-{[(cyanoimino)(5-quinolinylamino)methyl]amino}-2,2-dimethylpropyl)-2-(3,4-dimethoxyphenyl)acetamide
    A-804598
    2-cyano-1-[(1S)-1-phenylethyl]-3-quinolin-5-ylguanidine
    PPADS
    pyridoxalphosphate-6-azophenyl-2′,4′-disulfonic acid
    TNP-ATP
    2′,3′-O-(2,4,6-trinitrophenyl)-ATP
    r
    rat
    zf
    zebrafish
    ORi
    oocyte Ringer solution
    αβ-meATP
    αβ-methylene-ATP
    TEVC
    two-electrode voltage-clamp
    PAGE
    polyacrylamide gel electrophoresis
    NF449
    4,4′,4″,4‴-(carbonylbis(imino-5,1,3-benzenetriyl-bis(carbonylimino)))tetrakisbenzene-1,3-disulfonic acid-octasodium salt
    NF110
    4,4′,4″,4‴-(carbonylbis(imino-5,1,3-benzenetriyl-bis(carbonylimino)))tetrakisbenzenesulfonic acid
    NF770
    7,7′-(carbonylbis(imino-3,1-phenylenecarbonylimino-3,1-(4-methyl-phenylene)carbonylimino))bis(1-methoxy-naphthalene-3,6-disulfonic acid) tetrasodium salt
    NF742
    8,8′-(carbonylbis(imino-3,1-phenylenecarbonylimino-3,1-(4-methyl-phenylene)carbonylimino))bis(1-methoxy-naphthalene-3,6-disulfonic acid) tetrasodium salt
    NF769
    7,7′-(carbonylbis(imino-3,1-(4-methyl-phenylene)carbonylimino))bis(1-methoxy-naphthalene-3,6-disulfonic acid) tetrasodium salt
    NF778
    6,6′-(carbonylbis(imino-3,1-phenylenecarbonylimino-3,1-(4-methyl-phenylene)carbonylimino))bis(1-methoxy-naphthalene-3,5-disulfonic acid) tetrasodium salt.
    NF127
    8,8′-(carbonylbis(imino-3,1-phenylenecarbonylimino-3,1-(4-ethylphenylene)-carbonylimino))bis(naphthalene-1,3,5-trisulfonic acid) hexasodium salt
    NF739
    8,8′-(carbonylbis(imino-3,1-(4-methylphenylene)carbonylimino))bis(1-methoxynaphthalene-3,6-disulfonic acid) tetrasodium salt
    NF776
    6,6′-(carbonylbis(imino-3,1-(4-methylphenylene)carbonylimino))bis(1-methoxynaphthalene-3,5-disulfonic acid) tetrasodium salt
    2D
    two-dimensional
    NF279
    8,8′-[carbonylbis(imino-4,1-phenylenecarbonylimino-4,1-phenylenecarbonylimino)]bis-1,3,5-naphthalenetrisulfonic acid hexasodium salt
    TM
    transmembrane
    RO-85
    1-methyl-3-phenyl-1H-thieno[2,3-c]pyrazole-5-carboxylic acid [(R)-2-(4-acetyl-piperazin-1-yl)-1-methyl-ethyl]-amide
    A-839977
    1-(2,3-dichlorophenyl)-N-[2-(pyridin-2-yloxy)benzyl]-1H-tetrazol-5-amine
    NF708
    3,3′-(carbonylbis(imino-3,1-phenylene)carbonylimino))bis(benzenephosphonic acid) tetrasodium salt
    NF739
    8,8′-(carbonylbis(imino-3,1-(4-methylphenylene)carbonylimino))bis(1-methoxynaphthalene-3,6-disulfonic acid)tetrasodium salt.

  • Received September 6, 2010.
  • Accepted December 29, 2010.
  • Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 79 (4)
Molecular Pharmacology
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1 Apr 2011
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Research ArticleArticle

Molecular Determinants of Potent P2X2 Antagonism Identified by Functional Analysis, Mutagenesis, and Homology Docking

Christian Wolf, Christiane Rosefort, Ghada Fallah, Matthias U. Kassack, Alexandra Hamacher, Mandy Bodnar, Haihong Wang, Peter Illes, Achim Kless, Gregor Bahrenberg, Günther Schmalzing and Ralf Hausmann
Molecular Pharmacology April 1, 2011, 79 (4) 649-661; DOI: https://doi.org/10.1124/mol.110.068700

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Research ArticleArticle

Molecular Determinants of Potent P2X2 Antagonism Identified by Functional Analysis, Mutagenesis, and Homology Docking

Christian Wolf, Christiane Rosefort, Ghada Fallah, Matthias U. Kassack, Alexandra Hamacher, Mandy Bodnar, Haihong Wang, Peter Illes, Achim Kless, Gregor Bahrenberg, Günther Schmalzing and Ralf Hausmann
Molecular Pharmacology April 1, 2011, 79 (4) 649-661; DOI: https://doi.org/10.1124/mol.110.068700
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