Ticagrelor inverse agonist activity at the P2Y12 receptor is non‐reversible versus its endogenous agonist adenosine 5´‐diphosphate.

Background and Purpose: Ticagrelor is labelled as a reversible, direct‐acting platelet P2Y12 receptor (P2Y12R) 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 P2Y12R. Experimental Approach: Studies were performed in human platelets, with P2Y12R‐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 P2Y12R activation. Key Results: Initial studies revealed that a range of P2Y12R ligands, including ticagrelor, displayed inverse agonist activity at P2Y12R. Only ticagrelor was resistant to washout and, in human platelet and cell‐based assays, washing failed to reverse ticagrelor‐dependent inhibition of ADP‐stimulated P2Y12R function. The P2Y12R 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 P2Y12R than other P2Y12R ligands. Conclusion and Implications: Ticagrelor binding to P2Y12R is prolonged and more akin to that of an irreversible antagonist, especially versus the endogenous P2Y12R 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. [ABSTRACT FROM AUTHOR]