Adenosine A_2A receptor agonists with potent antiplatelet activity

Abstract

Selected adenosine A_2A receptor agonists (PSB-15826, PSB-12404, and PSB-16301) have been evaluated as new antiplatelet agents. In addition, radioligand-binding studies and receptor-docking experiments were performed in order to explain their differential biological effects on a molecular level. Among the tested adenosine derivatives, PSB-15826 was the most potent compound to inhibit platelet aggregation (EC₅₀ 0.32 ± 0.05 µmol/L) and platelet P-selectin cell-surface localization (EC₅₀ 0.062 ± 0.2 µmol/L), and to increase intraplatelets cAMP levels (EC₅₀ 0.24 ± 0.01 µmol/L). The compound was more active than CGS21680 (EC₅₀ 0.97±0.07 µmol/L) and equipotent to NECA (EC₅₀ 0.31 ± 0.05 µmol/L) in platelet aggregation induced by ADP. In contrast to the results from cAMP assays, K_i values determined in radioligand-binding studies were not predictive of the A_2A agonists’ antiplatelet activity. Docking studies revealed the key molecular determinants of this new family of adenosine A_2A receptor agonists: differences in activities are related to π-stacking interactions between the ligands and the residue His264 in the extracellular loop of the adenosine A_2A receptor which may result in increased residence times. In conclusion, these results provide an improved understanding of the requirements of antiplatelet adenosine A_2A receptor agonists.

Keywords:

• Adenosine A_2A receptor
• antiplatelet activity
• cAMP
• docking
• platelet
• radioligand binding

Funding

This work was funded by FONDECYT Initiation from Eduardo Fuentes (grant number 11140142) and Interdisciplinary Excellence Research Program on Healthy Aging (grant number PIEI-ES).

Declaration of interest

The authors report no conflicts of interest.

Additional information

Funding

This work was funded by FONDECYT Initiation from Eduardo Fuentes (grant number 11140142) and Interdisciplinary Excellence Research Program on Healthy Aging (grant number PIEI-ES).