Allosteric Modulation of A3 Adenosine Receptors by a Series of 3-(2-Pyridinyl)isoquinoline Derivatives

  1. Zhan-Guo Gao1,2,
  2. Jacqueline E. Van Muijlwijk-Koezen2,
  3. Aishe Chen1,
  4. Christa E. Müller3,
  5. Adriaan P. Ijzerman2 and
  6. Kenneth A. Jacobson1
  1. 1Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland (Z.-G.G., A.C., K.A.J.); 2Division of Medicinal Chemistry, Leiden/Amsterdam Center for Drug Research, Leiden University, Leiden, the Netherlands (Z.-G.G., J.E.V.M.-K., A.P.I.); and 3Pharmaceutical Institute, University of Bonn, Bonn, Germany (C.E.M.)
  1. Dr. K. A. Jacobson, Chief, Molecular Recognition Section, Bldg. 8A, Rm. B1A-19, NIH, NIDDK, LBC, Bethesda, MD 20892-0810. E-mail:kajacobs{at}helix.nih.gov

Abstract

Allosteric modulators of A1 and A2A adenosine receptors have been described; however, for the A3adenosine receptor, neither an allosteric site nor a compound with allosteric effects has been described. In this study, the allosteric modulation of human A3 adenosine receptors by a series of 3-(2-pyridinyl)isoquinoline derivatives was investigated by examining their effects on the dissociation of the agonist radioligand, [125I]N6-(4-amino-3-iodobenzyl)-5′-N-methylcarboxamidoadenosine (I-AB-MECA), from the receptor. Several 3-(2-pyridinyl)isoquinoline derivatives, including VUF5455, VUF8502, VUF8504, and VUF8507, slowed the dissociation of the agonist radioligand [125I]I-AB-MECA in a concentration-dependent manner, suggesting an allosteric interaction. These compounds had no effect on the dissociation of the radiolabeled antagonist [3H]PSB-11 from the A3 adenosine receptor, suggesting a selective enhancement of agonist binding. By comparison, compounds of similar structure (VUF8501, VUF8503, VUF8505), the classical adenosine receptor antagonist CGS15943 and the A1receptor allosteric enhancer PD81723 did not significantly influence the dissociation rate of [125I]I-AB-MECA. The effect of agonist on forskolin-induced cAMP production was significantly enhanced by VUF5455. When the subtype-selectivity of the allosteric enhancement was tested the compounds had no effect on the dissociation of either [3H]N6-[(R)-phenylisopropyl]adenosine from the A1 adenosine receptor or [3H]CGS21680 from the A2A adenosine receptor. Probing of structure-activity relationships suggested that a carbonyl group is essential for allosterism but preferred only for competitive antagonism. The presence of a 7-methyl group decreased the competitive binding affinity without a major loss of the allosteric enhancing activity, suggesting that the structural requirements for allosteric enhancement might be distinct from those for competitive antagonism.

Footnotes

  • Z.-G.G. received financial support from Gilead Sciences (Foster City, CA).

  • Abbreviations:
    GPCR
    G protein-coupled receptor
    I-AB-MECA
    N6-(4-amino-3-iodobenzyl)-5′-N-methylcarboxamidoadenosine
    R-PIA
    N6-[(R)-phenylisopropyl]adenosine
    CGS21680
    2-[p-(2-carboxyethyl)phenyl-ethylamino]-5′-N-ethylcarboxamidoadenosine
    BCA
    bicinchoninic acid
    CGS15943
    5-amino-9-chloro-2-(2-furyl)-1,2,4-triazolo[1,5-c]quinazoline
    CPA
    N6-cyclopentyladenosine
    NECA
    5′-N-ethylcarboxamidoadenosine
    HEK
    human embryonic kidney
    CHAPS
    3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfornate
    VUF5455
    4-methoxy-N-[7-methyl-3-(2-pyridinyl)-1-isoquinolinyl]benzamide
    VUF8502
    4-methyl-N-[3-(2-pyridinyl)-1-isoquinolinyl]benzamide
    VUF8504
    4-methoxy-N-[3-(2-pyridinyl)-1-isoquinolinyl]benzamide
    VUF8507
    N-[3-(2-pyridinyl)-1-isoquinolinyl]benzamide
    VUF8501
    N-[3-(2-pyridinyl)-1-isoquinolinyl]benzenecarboximidamide
    VUF8503
    4-methyl-N-[3-(2-pyridinyl)-1-isoquinolinyl]benzenecarboximidamide
    VUF8505
    4-methoxy-N-[3-(2-pyridinyl)-1-isoquinolinyl]benzenecarboximidamide
    PD81723
    2-amino-4,5-dimethyl-3-thienyl-[3-(trifluoromethyl)phenyl]methanone
    PSB-11
    8-ethyl-4-methyl-2-phenyl-(8R)-4,5,7,8-tetrahydro-1H-imidazo[2.1-i]purin-5-one
    • Received December 19, 2000.
    • Accepted August 6, 2001.
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  1. Molecular Pharmacology November 1, 2001 vol. 60 no. 5 1057-1063
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