Actions of ticagrelor, prasugrel, and clopidogrel mediated by P2Y₁₂ and adenosine. Ticagrelor acts directly and via an active metabolite (TAM) with both noncompetitive antagonism of activation by ADP and inverse agonism at P2Y₁₂. In addition, ticagrelor and TAM weakly inhibit ENT1 leading to increased extracellular adenosine that acts via adenosine receptors such as A₁ and A_2A receptors, the latter mediating platelet inhibition. The prodrugs prasugrel and clopidogrel produce active metabolites that bind irreversibly to P2Y₁₂ with noncompetitive antagonism of ADP binding. Adenosine triphosphate (ATP) and ADP released from platelet dense granules are degraded to adenosine via platelet surface CD39 (ectonucleoside triphosphate diphosphohydrolase-1) and CD73 (5′-nucleotidase). Activation of P2Y₁₂ by ADP leads to activation of the G_αi and inhibition of adenylate cyclase (AC) with consequent fall in cyclic adenosine monophosphate (cAMP), which leads to reduced activity of protein kinase A (PKA) and consequent phosphorylation of VASP (VASP-P). Conversely, activation of A_2A receptors by adenosine and prostacyclin receptor (IP) by endothelium-derived prostacyclin leads to activation of the stimulatory G protein α subunit (G_αs) and activation of AC. The balance of platelet activation and its inhibition regulated via AC and other intracellular signaling pathways modulates the affinity of glycoprotein IIb/IIIa complex (αIIbβ3) for fibrinogen and consequent platelet-platelet aggregation.