The potency of selatogrel, a reversible antagonist of the P2Y12 receptor, is affected by calcium concentration
Here, we report the in vitro characterization of the P2Y12 receptor antagonist selatogrel (ACT-246475). Binding studies with radiolabeled selatogrel demonstrated that selatogrel is a competitive antagonist of ADP binding to the P2Y12 receptor with a fast onset of action. Consequently, selatogrel was...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2022-01-01
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| Series: | Platelets |
| Subjects: | |
| Online Access: | http://dx.doi.org/10.1080/09537104.2020.1869711 |
| _version_ | 1797684110377877504 |
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| author | Martine Baumann Benoît Lack Isabelle Guillaumat Mark J. Murphy Markus A. Riederer |
| author_facet | Martine Baumann Benoît Lack Isabelle Guillaumat Mark J. Murphy Markus A. Riederer |
| author_sort | Martine Baumann |
| collection | DOAJ |
| description | Here, we report the in vitro characterization of the P2Y12 receptor antagonist selatogrel (ACT-246475). Binding studies with radiolabeled selatogrel demonstrated that selatogrel is a competitive antagonist of ADP binding to the P2Y12 receptor with a fast onset of action. Consequently, selatogrel was confirmed to be a potent inhibitor of P2Y12-mediated intra-platelet signaling and ADP-induced platelet activation. Characterization of selatogrel in platelet-rich plasma in vitro demonstrated that the mode of anti-coagulation affected the anti-platelet potency. Specifically, in platelet-rich plasma containing physiological calcium concentration (anticoagulated with a direct thrombin inhibitor), selatogrel achieved half-maximal inhibition of ADP-induced platelet aggregation at a 3-fold lower concentration than in conditions with low calcium concentration (anticoagulated with citrate). Furthermore, calcium-dependent reduction in selatogrel potency was observed in whole blood platelet aggregation using the VerifyNow™ system with a 3.7-fold potency loss in low calcium conditions. A comparable potency loss was also observed with the reversible P2Y12 receptor antagonists ticagrelor, cangrelor and elinogrel. Furthermore, receptor-binding experiments using radiolabeled selatogrel confirmed a 3-fold lowering of selatogrel binding affinity to the P2Y12 receptor in low calcium conditions. In conclusion, our data suggest that in low calcium conditions (i.e., citrate-anticoagulated blood), there is a risk of underestimating the potency of reversible P2Y12 receptor antagonists. To avoid overdosing, and a potential increase in bleeding risk, we propose that the ex vivo evaluation of reversible P2Y12 receptor antagonists should be performed with platelet assay systems containing physiological calcium concentration. |
| first_indexed | 2024-03-12T00:25:47Z |
| format | Article |
| id | doaj.art-021492ffe66347039fb420e397888fd0 |
| institution | Directory Open Access Journal |
| issn | 0953-7104 1369-1635 |
| language | English |
| last_indexed | 2024-03-12T00:25:47Z |
| publishDate | 2022-01-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Platelets |
| spelling | doaj.art-021492ffe66347039fb420e397888fd02023-09-15T10:38:09ZengTaylor & Francis GroupPlatelets0953-71041369-16352022-01-0133114715610.1080/09537104.2020.18697111869711The potency of selatogrel, a reversible antagonist of the P2Y12 receptor, is affected by calcium concentrationMartine Baumann0Benoît Lack1Isabelle Guillaumat2Mark J. Murphy3Markus A. Riederer4Idorsia Pharmaceuticals LtdIdorsia Pharmaceuticals LtdIdorsia Pharmaceuticals LtdIdorsia Pharmaceuticals LtdIdorsia Pharmaceuticals LtdHere, we report the in vitro characterization of the P2Y12 receptor antagonist selatogrel (ACT-246475). Binding studies with radiolabeled selatogrel demonstrated that selatogrel is a competitive antagonist of ADP binding to the P2Y12 receptor with a fast onset of action. Consequently, selatogrel was confirmed to be a potent inhibitor of P2Y12-mediated intra-platelet signaling and ADP-induced platelet activation. Characterization of selatogrel in platelet-rich plasma in vitro demonstrated that the mode of anti-coagulation affected the anti-platelet potency. Specifically, in platelet-rich plasma containing physiological calcium concentration (anticoagulated with a direct thrombin inhibitor), selatogrel achieved half-maximal inhibition of ADP-induced platelet aggregation at a 3-fold lower concentration than in conditions with low calcium concentration (anticoagulated with citrate). Furthermore, calcium-dependent reduction in selatogrel potency was observed in whole blood platelet aggregation using the VerifyNow™ system with a 3.7-fold potency loss in low calcium conditions. A comparable potency loss was also observed with the reversible P2Y12 receptor antagonists ticagrelor, cangrelor and elinogrel. Furthermore, receptor-binding experiments using radiolabeled selatogrel confirmed a 3-fold lowering of selatogrel binding affinity to the P2Y12 receptor in low calcium conditions. In conclusion, our data suggest that in low calcium conditions (i.e., citrate-anticoagulated blood), there is a risk of underestimating the potency of reversible P2Y12 receptor antagonists. To avoid overdosing, and a potential increase in bleeding risk, we propose that the ex vivo evaluation of reversible P2Y12 receptor antagonists should be performed with platelet assay systems containing physiological calcium concentration.http://dx.doi.org/10.1080/09537104.2020.1869711p2y12 receptor antagonistplatelet aggregationplatelet inhibition |
| spellingShingle | Martine Baumann Benoît Lack Isabelle Guillaumat Mark J. Murphy Markus A. Riederer The potency of selatogrel, a reversible antagonist of the P2Y12 receptor, is affected by calcium concentration Platelets p2y12 receptor antagonist platelet aggregation platelet inhibition |
| title | The potency of selatogrel, a reversible antagonist of the P2Y12 receptor, is affected by calcium concentration |
| title_full | The potency of selatogrel, a reversible antagonist of the P2Y12 receptor, is affected by calcium concentration |
| title_fullStr | The potency of selatogrel, a reversible antagonist of the P2Y12 receptor, is affected by calcium concentration |
| title_full_unstemmed | The potency of selatogrel, a reversible antagonist of the P2Y12 receptor, is affected by calcium concentration |
| title_short | The potency of selatogrel, a reversible antagonist of the P2Y12 receptor, is affected by calcium concentration |
| title_sort | potency of selatogrel a reversible antagonist of the p2y12 receptor is affected by calcium concentration |
| topic | p2y12 receptor antagonist platelet aggregation platelet inhibition |
| url | http://dx.doi.org/10.1080/09537104.2020.1869711 |
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