Cangrelor (ARC69931MX) produces global inhibition of human platelet function by increasing cAMP levels through a Gi‐independent mechanism.

Abstract

The recent use of antagonists against the P2Y1 and P2Y12 ADP receptors has significantly contributed to the characterization of ADP signaling in human platelets. Specifically, the results have suggested that while P2Y1 activation can initiate platelet aggregation, P2Y12 signaling accounts for the bulk of the ADP‐mediated effects. On this basis, efforts have focused on the development of a new class of P2Y12 antagonists (separate from clopidogrel and ticlopidine) as potential antithrombotic agents. The present work examined the molecular mechanisms by which one such adenosine‐based P2Y12 antagonist, i.e., Cangrelor (ARC69931MX), inhibits human platelet activation. It was found that the ability of ARC69931MX to block aggregation was associated with significant increases in platelet cAMP levels. It was also found that this elevation of cAMP did not require Gi signaling or even P2Y12 receptors, but was mediated through a separate G protein‐coupled pathway, presumably involving Gs. However, additional experiments revealed that ARC69931MX does not increase cAMP through activation of known platelet Gs‐coupled receptors, i.e., A2a, IP, DP or EP2. Collectively, these findings provide evidence that ARC69931MX interacts with an unidentified platelet G protein‐coupled receptor that stimulates substantial cAMP elevation and significant inhibition of platelet function through a P2Y12‐independent mechanism.