Ticagrelor inverse agonist activity at the P2Y₁₂ receptor is non-reversible versus its endogenous agonist adenosine...

Ticagrelor is labelled as a reversible, direct-acting platelet P2Y₁₂ receptor (P2Y₁₂ R) antagonist that is indicated clinically for the prevention of thrombotic events in patients with acute coronary syndrome (ACS). As with many antiplatelet drugs, ticagrelor therapy increases bleeding risk in patients, which may require platelet transfusion in emergency situations. The aim of this study was to further examine the reversibility of ticagrelor at the P2Y₁₂ R.

Studies were performed in human platelets, with P2Y₁₂ R-stimulated GTPase activity and platelet aggregation assessed. Cell-based bioluminescence resonance energy transfer (BRET) assays were undertaken to assess G protein-subunit activation downstream of P2Y₁₂ R activation.

Initial studies revealed that a range of P2Y₁₂ R ligands, including ticagrelor, displayed inverse agonist activity at P2Y₁₂ R. Only ticagrelor was resistant to washout and, in human platelet and cell-based assays, washing failed to reverse ticagrelor-dependent inhibition of ADP-stimulated P2Y₁₂ R function. The P2Y₁₂ R agonist 2MeSADP, which was also resistant to washout, was able to effectively compete with ticagrelor. In silico docking revealed that ticagrelor and 2MeSADP penetrated more deeply into the orthosteric binding pocket of the P2Y₁₂ R than other P2Y₁₂ R ligands.

Ticagrelor binding to P2Y₁₂ R is prolonged and more akin to that of an irreversible antagonist, especially versus the endogenous P2Y₁₂ R agonist ADP. This study highlights the potential clinical need for novel ticagrelor reversal strategies in patients with spontaneous major bleeding, and for bleeding associated with urgent invasive procedures.