Selectivity is species-dependent: Characterization of standard agonists and antagonists at human, rat, and mouse adenosine receptors

Purinergic Signal. 2015 Sep;11(3):389-407. doi: 10.1007/s11302-015-9460-9. Epub 2015 Jul 1.


Adenosine receptors (ARs) have emerged as new drug targets. The majority of data on affinity/potency and selectivity of AR ligands described in the literature has been obtained for the human species. However, preclinical studies are mostly performed in mouse or rat, and standard AR agonists and antagonists are frequently used for studies in rodents without knowing their selectivity in the investigated species. In the present study, we selected a set of frequently used standard AR ligands, 8 agonists and 16 antagonists, and investigated them in radioligand binding studies at all four AR subtypes, A1, A2A, A2B, and A3, of three species, human, rat, and mouse. Recommended, selective agonists include CCPA (for A1AR of rat and mouse), CGS-21680 (for A2A AR of rat), and Cl-IB-MECA (for A3AR of all three species). The functionally selective partial A2B agonist BAY60-6583 was found to additionally bind to A1 and A3AR and act as an antagonist at both receptor subtypes. The antagonists PSB-36 (A1), preladenant (A2A), and PSB-603 (A2B) displayed high selectivity in all three investigated species. MRS-1523 acts as a selective A3AR antagonist in human and rat, but is only moderately selective in mouse. The comprehensive data presented herein provide a solid basis for selecting suitable AR ligands for biological studies.

Publication types

  • Comparative Study

MeSH terms

  • Adenosine A1 Receptor Agonists / metabolism
  • Adenosine A1 Receptor Agonists / pharmacology
  • Adenosine A1 Receptor Antagonists / metabolism
  • Adenosine A1 Receptor Antagonists / pharmacology
  • Adenosine A2 Receptor Agonists / metabolism
  • Adenosine A2 Receptor Agonists / pharmacology
  • Adenosine A2 Receptor Antagonists / metabolism
  • Adenosine A2 Receptor Antagonists / pharmacology
  • Adenosine A3 Receptor Agonists / metabolism
  • Adenosine A3 Receptor Agonists / pharmacology
  • Adenosine A3 Receptor Antagonists / metabolism
  • Adenosine A3 Receptor Antagonists / pharmacology
  • Animals
  • Arrestin / metabolism
  • Binding, Competitive / drug effects
  • CHO Cells
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Cricetinae
  • Cricetulus
  • Cyclic AMP / metabolism
  • DNA, Complementary / drug effects
  • DNA, Complementary / genetics
  • Humans
  • Mice
  • Rats
  • Receptor, Adenosine A2A / drug effects
  • Receptor, Adenosine A2A / genetics
  • Receptor, Adenosine A2A / metabolism
  • Receptor, Adenosine A2B / drug effects
  • Receptor, Adenosine A2B / genetics
  • Receptor, Adenosine A2B / metabolism
  • Receptors, Purinergic P1 / drug effects*
  • Receptors, Purinergic P1 / genetics
  • Receptors, Purinergic P1 / metabolism
  • Species Specificity
  • Structure-Activity Relationship


  • Adenosine A1 Receptor Agonists
  • Adenosine A1 Receptor Antagonists
  • Adenosine A2 Receptor Agonists
  • Adenosine A2 Receptor Antagonists
  • Adenosine A3 Receptor Agonists
  • Adenosine A3 Receptor Antagonists
  • Arrestin
  • DNA, Complementary
  • Receptor, Adenosine A2A
  • Receptor, Adenosine A2B
  • Receptors, Purinergic P1
  • Cyclic AMP