Platelet P2 receptors: old and new targets for antithrombotic drugs.
Platelets possess three P2 receptors for adenine nucleotides: P2Y1 and P2Y12, which interact with ADP, and P2X1, which interacts with ATP. The interaction of adenine nucleotides with their platelet receptors plays an important role in thrombogenesis. The thienopyridine ticlopidine, an antagonist of the platelet P2Y12 ADP receptor, reduces the incidence of vascular events in patients at risk, but it also has some important drawbacks: a relatively high incidence of toxic effects; delayed onset of action; high inter-individual variability in response. Another thienopyridine, clopidogrel, has superseded ticlopidine, because it is an efficacious antithrombotic drug and is less toxic than ticlopidine. However, the high inter-patient variability in response still remains an important issue. These drawbacks justify the continuing search for agents that can further improve the clinical outcome of patients with atherosclerosis through greater efficacy and/or safety. A new thienopyridyl compound prasugrel, which is characterized by higher potency and faster onset of action compared with clopidogrel, is currently under clinical evaluation. Two direct and reversible P2Y12 antagonists, cangrelor and AZD6140, have very rapid onset and reversal of platelet inhibition, which make them attractive alternatives to thienopyridines, especially when rapid inhibition of platelet aggregation or its quick reversal are required. Along with new P2Y12 antagonists, inhibitors of the other platelet receptor for ADP, P2Y1, and of the receptor for ATP, P2X1, are under development and may prove to be effective antithrombotic agents.
Cattaneo
Marco
M
Università degli Studi di Milano, Unità di Ematologia e Trombosi-Ospedale San Paolo, Via di Rudinì 820142 Milano, Italy. marco.cattaneo@unimi.it
D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D000249:Adenosine Monophosphate / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D000789:Angina, Unstable / Q000188:drug therapy; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects* / Q000502:physiology; D000077144:Clopidogrel; D003327:Coronary Disease / Q000188:drug therapy*; D003328:Coronary Thrombosis / Q000188:drug therapy; D004347:Drug Interactions; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D006801:Humans; D009203:Myocardial Infarction / Q000188:drug therapy; D010879:Piperazines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D000068799:Prasugrel Hydrochloride; D058919:Purinergic P2 Receptor Antagonists; D016032:Randomized Controlled Trials as Topic; D018048:Receptors, Purinergic P2 / Q000008:administration & dosage / Q000187:drug effects*; D058469:Receptors, Purinergic P2X; D013577:Syndrome; D013876:Thiophenes / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D000077486:Ticagrelor; D013988:Ticlopidine / Q000009:adverse effects / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use*
D005343:Fibrinolytic Agents; D010879:Piperazines; D010975:Platelet Aggregation Inhibitors; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2; D058469:Receptors, Purinergic P2X; D013876:Thiophenes; D000249:Adenosine Monophosphate; C117446:cangrelor; D000077144:Clopidogrel; D000068799:Prasugrel Hydrochloride; D000077486:Ticagrelor; D000241:Adenosine; D013988:Ticlopidine