P2Y receptors in GtoPdb v.2021.3

P2Y receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on P2Y Receptors [3, 5, 192]) are activated by the endogenous ligands ATP, ADP, uridine triphosphate, uridine diphosphate and UDP-glucose. The relationship of many of the cloned receptors to endogenously expressed receptors is not yet established and so it might be appropriate to use wording such as 'uridine triphosphate-preferring (or ATP-, etc.) P2Y receptor' or 'P2Y1-like', etc., until further, as yet undefined, corroborative criteria can be applied [47, 110, 190, 383, 396]. Clinically used drugs acting on these receptors include the dinucleoside polyphosphate diquafosol, agonist of the P2Y2 receptor subtype, approved in Japan for the management of dry eye disease [241], and the P2Y12 receptor antagonists prasugrel, ticagrelor and cangrelor, all approved as antiplatelet drugs [53, 323].

P2Y receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

P2Y receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on P2Y Receptors [3, 5]) are activated by the endogenous ligands ATP, ADP, uridine triphosphate, uridine diphosphate and UDP-glucose. The relationship of many of the cloned receptors to endogenously expressed receptors is not yet established and so it might be appropriate to use wording such as 'uridine triphosphate-preferring (or ATP-, etc.) P2Y receptor' or 'P2Y1-like', etc., until further, as yet undefined, corroborative criteria can be applied [46, 109, 187, 375, 388].Clinically used drugs acting on these receptors include the dinucleoside polyphosphate diquafosol, agonist of the P2Y2 receptor subtype, approved in Japan for the management of dry eye disease [236], and the P2Y12 receptor antagonists prasugrel, ticagrelor and cangrelor, all approved as antiplatelet drugs [52, 316].

Uridine Triphosphate Thio-analogues Inhibit Platelet P2Y12 Receptors and Aggregation

Platelet P2Y12 is an important 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 P2Y12 but not P2Y1 receptors and antagonises 10 μM ADP-induced platelet aggregation in a concentration-dependent manner with an IC50 value of ~250 μM. An 8-fold higher platelet inhibitory activity was observed with a 2-thio analogue of UTP (2S-UTP), with an IC50 of 30 μM. The 4-thio analogue (4S-UTP) with an IC50 of 7.5 μM was 33-fold more effective. A 3-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 γ phosphate of the sugar moiety, which yields an enzymatically stable analogue. The interaction of UTP analogues with P2Y12 receptors was verified by P2Y12 receptor binding and cAMP assays. These novel data demonstrate for the first time that 2- and 4-thio analogues of UTP are potent P2Y12 receptor antagonists that may be useful for therapeutic intervention.

Uridine Triphosphate Thio-analogues Inhibit Platelet P2Y12 Receptors and Aggregation

Platelet P2Y12 is an important ADP receptor that is involved in agonists-induced platelet aggregation and is an important target for the development of anti-platelet aggregation drugs. Here the effects of thio-analogues of uridine triphosphate (UTP) on ADP-induced platelet aggregation are characterised. Using human platelet rich plasma we demonstrate that UTP inhibits P2Y12 but not P2Y1 receptors and antagonises ADP-induced platelet aggregation in a conc.-dependent manner with an IC50 value of ~250 mM against ADP (10 mM). An 8-fold increase in the platelet inhibitory activity was observed with 2-thio analogue of UTP (2S-UTP) with an IC50 value of 30 mM. A 33-fold increase in anti-platelet aggregation activity was observed with 4-thio analogue (4S-UTP) with an IC50 value of 7.5 mM. However, a 3-fold decrease in activity was observed by introducing an isobutyl group at the 4S- position. A complete loss in anti-platelet aggregation activity was observed with thio-modification of gamma phosphate of the sugar moiety which yields an enzymatically stable analogue. The interaction of UTP analogues with P2Y12 receptors was further verified by P2Y12 receptor binding assay and cAMP assay. The novel data demonstrate for the first time that 2- and 4-thio analogues of UTP are potent P2Y12 receptor antagonists that can be useful candidates for therapeutic intervention.