Adenosine A2A receptor agonists with potent antiplatelet activity

被引:18
作者
Fuentes, Eduardo [1 ,2 ]
Fuentes, Manuel [1 ]
Caballero, Julio [3 ]
Palomo, Ivan [1 ]
Hinz, Sonja [4 ]
El-Tayeb, Ali [4 ]
Mueller, Christa E. [4 ]
机构
[1] Univ Talca, Platelet Res Lab, Dept Clin Biochem & Immunohematol, Fac Hlth Sci,Interdisciplinary Excellence Res Pro, Talca, Chile
[2] Univ Talca, Nucleo Cient Multidisciplinario, Talca, Chile
[3] Univ Talca, CBSM, Talca, Chile
[4] Univ Bonn, PharmaCtr Bonn, Pharmaceut Inst, Pharmaceut Chem 1, Bonn, Germany
关键词
Adenosine A(2A) receptor; antiplatelet activity; cAMP; docking; platelet; radioligand binding; PERCUTANEOUS CORONARY INTERVENTION; RESIDUAL PLATELET REACTIVITY; CLOPIDOGREL; THERAPY; ANTAGONISTS; DRUGS; DESENSITIZATION; CLASSIFICATION; IDENTIFICATION; DERIVATIVES;
D O I
10.1080/09537104.2017.1306043
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
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 mu mol/L) and platelet P-selectin cell-surface localization (EC50 0.062 +/- 0.2 mu mol/L), and to increase intraplatelets cAMP levels (EC50 0.24 +/- 0.01 mu mol/L). The compound was more active than CGS21680 (EC50 0.97 +/- 0.07 mu mol/L) and equipotent to NECA (EC50 0.31 +/- 0.05 mu mol/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 -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.
引用
收藏
页码:292 / 300
页数:9
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