P2RY12 binds P2RY12 antagonists

Stable Identifier
Reaction [binding]
Homo sapiens
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P2Y purinoceptor 12 (P2RY12) is found on the surface of blood platelet cells and is an important regulator in blood clotting. Platelets play a pivotal role in the pathogenesis of acute coronary syndrome (ACS), a leading cause of death in the world. ADP released from activated platelets bind to P2RY12, amplifying the initial platelet aggregation response. Pharmacological blockade of P2RY12 by P2RY12 antogonists represents an important target for the treatment and prevention of thrombosis (Hollopeter et al. 2001). P2RY12 antogonists include ticlopidine, clopidogrel, prasugrel and ticagrelor. Ticagrelor, unlike ticlopidine, clopidogrel and prasugrel, binds to the P2Y12R in a reversible manner (Van Giezen et al. 2009, Paoletta et al. 2015) and is also direct acting (the others are all prodrugs requiring metabolic activation (Nylander & Schulz 2016). Ticagrelor also inhibits adenosine uptake by equilibrative nucleoside transporter 1 (SLC29A1) on erythrocytes and other cells (Nylander et al. 2013, Armstrong et al. 2014 , Aungraheeta et al. 2016). Clopidogrel is used to reduce the risk of heart disease and stroke in those at high risk and together with aspirin following the placement of a coronary artery stent (Herbert & Savi 2003). Clopidogrel is a prodrug, the active metabolite, S-clopidogrel, is the only one of eight stereoisomers formed in the liver which possesses biological activity (Pereillo et al. 2002). Ticlopidine is a thienopyridine derivative which reduces the risk of reversible ischaemia and stroke in patients who have previously experienced a cerebral ischaemic episode (Noble & Goa 1996, Saltiel & Ward 1987). The active compound is believed to be a prodrug which is a potent inhibitor of platelet aggregation induced by ADP. The active form of prasugrel, R-138727, is a thienopyridine antiplatelet drug which binds to and irreversibly inhibits the platelet P2RY12 receptor. The (R, S)-isomer of R-138727 shows the most potent antiplatelet activity (Hasegawa et al. 2005). Cangrelor is a potent, direct-acting P2Y12 antagonist with rapid onset and quickly reversible action (Kubica et al. 2014). It is administered intravenously but despite its rapid platelet inhibition, the oral P2Y12 inhibitors ticagrelor and prasugrel have comparable clinical outcomes (Westman et al. 2017).

Literature References
PubMed ID Title Journal Year
24393016 Cangrelor: an emerging therapeutic option for patients with coronary artery disease

Kozinski, M, Kubica, A, Tantry, U, Fabiszak, T, Navarese, EP, Kubica, J, Gurbel, PA, Jeong, YH, Andruszkiewicz, A, Siller-Matula, JM

Curr Med Res Opin 2014
28089137 A comparison of cangrelor, prasugrel, ticagrelor, and clopidogrel in patients undergoing percutaneous coronary intervention: A network meta-analysis

Torguson, R, Westman, PC, Lipinski, MJ, Waksman, R

Cardiovasc Revasc Med 2017
19552634 Ticagrelor binds to human P2Y(12) independently from ADP but antagonizes ADP-induced receptor signaling and platelet aggregation

Tomlinson, W, Wissing, BM, Nilsson, L, VAN Giezen, JJ, Giordanetto, F, Berntsson, P, Greasley, PJ

J. Thromb. Haemost. 2009
26194851 Modeling ligand recognition at the P2Y12 receptor in light of X-ray structural information

Abdelrahman, A, Baqi, Y, Sabbadin, D, Paoletta, S, Zhao, Q, Moro, S, Hinz, S, Straßburger, J, von Kügelgen, I, Katritch, V, Jacobson, KA, Müller, CE, Hoffmann, K, Stevens, RC

J. Comput. Aided Mol. Des. 2015
16268477 Stereoselective inhibition of human platelet aggregation by R-138727, the active metabolite of CS-747 (prasugrel, LY640315), a novel P2Y12 receptor inhibitor

Jakubowski, JA, Hasegawa, M, Isobe, T, Ogawa, T, Sugidachi, A, Asai, F

Thromb. Haemost. 2005
27694321 Inverse agonism at the P2Y12 receptor and ENT1 transporter blockade contribute to platelet inhibition by ticagrelor

Conibear, A, Mundell, SJ, Mumford, A, Aungraheeta, R, Butler, M, Nylander, S, Kelly, E

Blood 2016
11196645 Identification of the platelet ADP receptor targeted by antithrombotic drugs

Vincent, D, Conley, PB, Yang, RB, Jantzen, HM, England, L, Li, G, Julius, D, Ramakrishnan, V, Nurden, A, Nurden, P, Hollopeter, G

Nature 2001
3304967 Ticlopidine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in platelet-dependent disease states

Ward, A, Saltiel, E

Drugs 1987
23890048 Ticagrelor inhibits human platelet aggregation via adenosine in addition to P2Y12 antagonism

Nilsson, RG, Asztély, AK, Nylander, S, Löfgren, L, Femia, EA, Berntsson, P, Scavone, M, Nelander, K, Cattaneo, M

J. Thromb. Haemost. 2013
26758983 Effects of P2Y12 receptor antagonists beyond platelet inhibition--comparison of ticagrelor with thienopyridines

Schulz, R, Nylander, S

Br. J. Pharmacol. 2016
24414167 Characterization of the adenosine pharmacology of ticagrelor reveals therapeutically relevant inhibition of equilibrative nucleoside transporter 1

Ewart, L, VAN Giezen, JJ, Summers, C, Armstrong, D, Sidaway, JE, Nylander, S

J. Cardiovasc. Pharmacol. Ther. 2014
8720746 Ticlopidine. A review of its pharmacology, clinical efficacy and tolerability in the prevention of cerebral ischaemia and stroke

Goa, KL, Noble, S

Drugs Aging 1996
12386137 Structure and stereochemistry of the active metabolite of clopidogrel

Uzabiaga, MF, Pereillo, JM, Pascal, M, Picard, C, Andrieu, A, Maffrand, JP, Maftouh, M, Fedeli, O, Herbert, JM, Savi, P

Drug Metab. Dispos. 2002
15199474 P2Y12, a new platelet ADP receptor, target of clopidogrel

Herbert, JM, Savi, P

Semin Vasc Med 2003
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