Interactions of Flavones and Other Phytochemicals with Adenosine Receptors

  • Kenneth A. Jacobson
  • Stefano Moro
  • John A. Manthey
  • Patrick L. West
  • Xiao-duo Ji
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 505)


Dietary flavonoids have varied effects on animal cells, such as inhibition of platelet binding and aggregation, inhibition of inflammation, and anticancer properties, but the mechanisms of these effects remain largely unexplained. Adenosine receptors are involved in the homeostasis of the immune, cardiovascular, and central nervous systems, and adenosine agonists/antagonists exert many similar effects. The affinity of flavonoids and other phytochemicals to adenosine receptors suggests that a wide range of natural substances in the diet may potentially block the effects of endogenous adenosine. We used competitive radioligand binding assays to screen flavonoid libraries for affinity and a computational CoMFA analysis of flavonoids to compare steric and electrostatic requirements for ligand recognition at three subtypes of adenosine receptors. Flavone derivatives, such as galangin, were found to bind to three subtypes of adenosine receptors in the µM range. Pentamethylmorin (Ki 2.65 µM) was 14- to 17-fold selective for human A3, receptors than for A1, and A2A receptors. An isoflavone, genistein, was found to bind to A1, receptors. Aurones, such as hispidol (Ki 350 nM) are selective A1, receptor antagonists, and, like genistein, are present in soy. The flavones, chemically optimized for receptor binding, have led to the antagonist, MRS 1067 (3,6-dichloro-2’-(isopropoxy)-4’-methylflavone), which is 200-fold more selective for human A3 than A1, receptors. Adenosine receptor antagonism, therefore, may be important in the spectrum of biological activities reported for the flavonoids.


Adenosine Receptor Adenosine Receptor Antagonist Endogenous Adenosine Comparative Molecular Field Analysis Structure Activity Relationship 
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Copyright information

© Springer Science+Business Media New York 2002

Authors and Affiliations

  • Kenneth A. Jacobson
    • 1
  • Stefano Moro
    • 1
    • 2
  • John A. Manthey
    • 3
  • Patrick L. West
    • 1
  • Xiao-duo Ji
    • 1
  1. 1.Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes, Digestive and Kidney DiseasesNational Institutes of HealthBethesdaUSA
  2. 2.Pharmaceutical Science DepartmentUniversity of PadovaItaly
  3. 3.U.S. Department of Agriculture, Agricultural Research ServiceU.S. Citrus and Subtropical Products LaboratoryWinter HavenUSA

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