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Medicinal Chemistry of the A3 Adenosine Receptor

  • Kenneth A. Jacobson
  • Dilip K. Tosh
  • Zhan-Guo Gao
  • Jinha Yu
  • Rama R. Suresh
  • Harsha Rao
  • Romeo Romagnoli
  • Pier Giovanni Baraldi
  • Mojgan Aghazadeh Tabrizi
Chapter
Part of the The Receptors book series (REC, volume 34)

Abstract

Numerous structure-activity relationship (SAR) studies of ligands of the A3 adenosine receptor (AR) have generated selective agonists, antagonists, partial agonists, and allosteric modulators. The efficacy of nucleoside agonists may be reduced, while retaining affinity, by successive structural changes. Subnanomolar affinity and selectivity of >10,000-fold have been achieved for various compound classes, but often with a pronounced species dependence, especially for diverse heterocyclic antagonists. Two prototypical A3AR agonists, IB-MECA and Cl-IB-MECA, are being evaluated clinically for treating autoimmune inflammatory disorders and liver diseases. The design of A3AR orthosteric ligands is now largely guided by computational approaches, in which the receptor is modeled by homology to X-ray structures of the A2AAR and other G protein-coupled receptors (GPCRs). Thus, we have amassed a large body of data concerning the relationship of receptor structure and function and have supported many of the hypotheses generated with experimental data.

Keywords

A3 adenosine receptors A3 agonists A3 antagonists A3 allosteric modulators Structure-activity relationship 

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Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • Kenneth A. Jacobson
    • 1
  • Dilip K. Tosh
    • 2
  • Zhan-Guo Gao
    • 2
  • Jinha Yu
    • 2
  • Rama R. Suresh
    • 1
  • Harsha Rao
    • 1
  • Romeo Romagnoli
    • 3
  • Pier Giovanni Baraldi
    • 3
  • Mojgan Aghazadeh Tabrizi
    • 3
  1. 1.Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of HealthBethesdaUSA
  2. 2.Molecular Recognition Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of HealthBethesdaUSA
  3. 3.Department of Chemical and Pharmaceutical SciencesUniversity of FerraraFerraraItaly

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