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    Does the combination of optimal substitutions at the C2-, N5- and N8-positions of the pyrazolo-triazolo-pyrimidine scaffold guarantee selective modulation of the human A3 adenosine receptors?

    Access Status
    Fulltext not available
    Authors
    Cheong, S.
    Dolzhenko, Anton
    Paoletta, S.
    Lee, E.
    Kachler, S.
    Federico, S.
    Klotz, K.
    Dolzhenko, A.
    Spalluto, G.
    Moro, S.
    Pastorin, G.
    Date
    2011
    Type
    Journal Article
    
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    Citation
    Cheong, Siew and Dolzhenko, Anton and Paoletta, Silvia and Lee, Evelyn pei rong and Kachler, Sonja and Federico, Stephanie and Klotz, Karl-norbert and Dolzhenko, Anna and Spalluto, Giampiero and Moro, Stefano and Pastorin, Giorgia. 2011. Does the combination of optimal substitutions at the C2-, N5- and N8-positions of the pyrazolo-triazolo-pyrimidine scaffold guarantee selective modulation of the human A3 adenosine receptors?. Bioorganic & Medicinal Chemistry. 19 (20): pp. 6120-6134.
    Source Title
    Bioorganic & Medicinal Chemistry
    DOI
    10.1016/j.bmc.2011.08.026
    ISSN
    0968-0896
    School
    School of Pharmacy
    URI
    http://hdl.handle.net/20.500.11937/33279
    Collection
    • Curtin Research Publications
    Abstract

    In an attempt to study the optimal combination of a phenyl ring at the C2-position and different substituents at the N5- and N8-positions towards the selective modulation of human A3 adenosine receptors (hA3AR), we synthesized a new series of 2-para-(un)substituted-phenyl-pyrazolo-triazolo-pyrimidines bearing either a methyl or phenylethyl at N8 and chains of variable length at N5. Through biological evaluation, it was found that the majority of the compounds had good affinities towards the hA3AR in the low nanomolar range. Compound 16 possessed the best hA3AR affinity and selectivity profile (KihA3 = 1.33 nM; hA1/hA3 = 4880; hA2A/hA3 = 1100) in the present series of 2-(substituted)phenylpyrazolo-triazolo-pyrimidine derivatives. In addition to pharmacological characterization, a molecular modeling investigation on these compounds further elucidated the effect of different substituents at the pyrazolo-triazolo-pyrimidine scaffold on affinity and selectivity to hA3AR.

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