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

Mohamad Wessam Alnouri; Stephan Jepards; Alessandro Casari; Anke C Schiedel; Sonja Hinz; Christa E Müller

doi:10.1007/s11302-015-9460-9

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.

Authors

Mohamad Wessam Alnouri¹, Stephan Jepards, Alessandro Casari, Anke C Schiedel, Sonja Hinz, Christa E Müller

Affiliation

¹ Pharma Center Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, University of Bonn, An der Immenburg 4, D-53121, Bonn, Germany, wessam.alnouri@uni-bonn.de.

Abstract

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

Substances

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