Reactome | P2RY12 binds P2RY12 antagonists

P2RY12 binds P2RY12 antagonists

Stable Identifier

R-HSA-9611277

Type

Reaction [binding]

Species

Homo sapiens

Compartment

extracellular region, plasma membrane

ReviewStatus

5/5

Locations in the PathwayBrowser

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Signal Transduction (Homo sapiens)

- Signaling by GPCR (Homo sapiens)
  - GPCR ligand binding (Homo sapiens)
    - Class A/1 (Rhodopsin-like receptors) (Homo sapiens)
      - Nucleotide-like (purinergic) receptors (Homo sapiens)
        
        P2Y receptors (Homo sapiens)
        
        P2RY12 binds P2RY12 antagonists (Homo sapiens)

General

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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 Kubica, J, Kozinski, M, Navarese, EP, Tantry, U, Kubica, A, Siller-Matula, JM, Jeong, YH, Fabiszak, T, Andruszkiewicz, A, Gurbel, PA	Curr Med Res Opin	2014
28089137	A comparison of cangrelor, prasugrel, ticagrelor, and clopidogrel in patients undergoing percutaneous coronary intervention: A network meta-analysis Westman, PC, Lipinski, MJ, Torguson, R, 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 VAN Giezen, JJ, Nilsson, L, Berntsson, P, Wissing, BM, Giordanetto, F, Tomlinson, W, Greasley, PJ	J. Thromb. Haemost.	2009
26194851	Modeling ligand recognition at the P2Y12 receptor in light of X-ray structural information Paoletta, S, Sabbadin, D, von Kügelgen, I, Hinz, S, Katritch, V, Hoffmann, K, Abdelrahman, A, Straßburger, J, Baqi, Y, Zhao, Q, Stevens, RC, Moro, S, Müller, CE, Jacobson, KA	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 Hasegawa, M, Sugidachi, A, Ogawa, T, Isobe, T, Jakubowski, JA, Asai, F	Thromb. Haemost.	2005
27694321	Inverse agonism at the P2Y12 receptor and ENT1 transporter blockade contribute to platelet inhibition by ticagrelor Aungraheeta, R, Conibear, A, Butler, M, Kelly, E, Nylander, S, Mumford, A, Mundell, SJ	Blood	2016
11196645	Identification of the platelet ADP receptor targeted by antithrombotic drugs Hollopeter, G, Jantzen, HM, Vincent, D, Li, G, England, L, Ramakrishnan, V, Yang, RB, Nurden, P, Nurden, A, Julius, D, Conley, PB	Nature	2001
3304967	Ticlopidine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in platelet-dependent disease states Saltiel, E, Ward, A	Drugs	1987
23890048	Ticagrelor inhibits human platelet aggregation via adenosine in addition to P2Y12 antagonism Nylander, S, Femia, EA, Scavone, M, Berntsson, P, Asztély, AK, Nelander, K, Löfgren, L, Nilsson, RG, Cattaneo, M	J. Thromb. Haemost.	2013
26758983	Effects of P2Y12 receptor antagonists beyond platelet inhibition--comparison of ticagrelor with thienopyridines Nylander, S, Schulz, R	Br. J. Pharmacol.	2016
24414167	Characterization of the adenosine pharmacology of ticagrelor reveals therapeutically relevant inhibition of equilibrative nucleoside transporter 1 Armstrong, D, Summers, C, Ewart, L, Nylander, S, Sidaway, JE, VAN Giezen, JJ	J. Cardiovasc. Pharmacol. Ther.	2014
8720746	Ticlopidine. A review of its pharmacology, clinical efficacy and tolerability in the prevention of cerebral ischaemia and stroke Noble, S, Goa, KL	Drugs Aging	1996
12386137	Structure and stereochemistry of the active metabolite of clopidogrel Pereillo, JM, Maftouh, M, Andrieu, A, Uzabiaga, MF, Fedeli, O, Savi, P, Pascal, M, Herbert, JM, Maffrand, JP, Picard, C	Drug Metab. Dispos.	2002
15199474	P2Y12, a new platelet ADP receptor, target of clopidogrel Herbert, JM, Savi, P	Semin Vasc Med	2003