Journalartikel

Jahr der Veröffentlichung: 2017

Zeitschrift: International Journal of Molecular Sciences

Bandnummer: 18

Heftnummer: 2

eISSN: 1422-0067

Open Access Status: Gold

DOI Link: https://doi.org/10.3390/ijms18020269

Verlag: MDPI

Abstract: 
Platelet P2Y(12) is an important adenosine diphosphate (ADP) receptor that is involved in agonist-induced platelet aggregation and is a valuable target for the development of anti-platelet drugs. Here we characterise the effects of thio analogues of uridine triphosphate (UTP) on ADP-induced platelet aggregation. Using human platelet-rich plasma, we demonstrate that UTP inhibits P2Y(12) but not P2Y(1) receptors and antagonises 10 mu M ADP-induced platelet aggregation in a concentration-dependent manner with an IC50 value of 250 mu M. An eight-fold higher platelet inhibitory activity was observed with a 2-thio analogue of UTP (2S-UTP), with an IC50 of 30 mu M. The 4-thio analogue (4S-UTP) with an IC50 of 7.5 mu M was 33-fold more effective. A three-fold decrease in inhibitory activity, however, was observed by introducing an isobutyl group at the 4S- position. A complete loss of inhibition was observed with thio-modification of the phosphate of the sugar moiety, which yields an enzymatically stable analogue. The interaction of UTP analogues with P2Y(12) receptor was verified by P2Y(12) receptor binding and cyclic AMP (cAMP) assays. These novel data demonstrate for the first time that 2- and 4-thio analogues of UTP are potent P2Y(12) receptor antagonists that may be useful for therapeutic intervention.

Harvard-Zitierstil: Guenduez, D., Tanislav, C., Sedding, D., Parahuleva, M., Santoso, S., Troidl, C., et al. (2017) Uridine Triphosphate Thio Analogues Inhibit Platelet P2Y₁₂ Receptor and Aggregation, International Journal of Molecular Sciences, 18(2), Article 269. https://doi.org/10.3390/ijms18020269

APA-Zitierstil: Guenduez, D., Tanislav, C., Sedding, D., Parahuleva, M., Santoso, S., Troidl, C., Hamm, C., & Aslam, M. (2017). Uridine Triphosphate Thio Analogues Inhibit Platelet P2Y₁₂ Receptor and Aggregation. International Journal of Molecular Sciences. 18(2), Article 269. https://doi.org/10.3390/ijms18020269