UMMS Affiliation
Center for Platelet Function Studies, Department of Pediatrics
Publication Date
2014-04-10
Document Type
Article
Subjects
Dinucleoside Phosphates; Humans; Platelet Aggregation; Platelet Function Tests; Purinergic P2Y Receptor Antagonists; Receptors, Purinergic P2Y1; Stereoisomerism
Disciplines
Cellular and Molecular Physiology | Hematology | Medical Pharmacology | Pharmacology
Abstract
BACKGROUND: Diadenosine tetraphosphate (Ap4A), a constituent of platelet dense granules, and its P1,P4-dithio and/or P2,P3-chloromethylene analogs, inhibit adenosine diphosphate (ADP)-induced platelet aggregation. We recently reported that these compounds antagonize both platelet ADP receptors, P2Y1 and P2Y12. The most active of those analogs, diadenosine 5',5''''-P1,P4-dithio-P2,P3-chloromethylenetetraphosphate, (compound 1), exists as a mixture of 4 stereoisomers.
OBJECTIVE: To separate the stereoisomers of compound 1 and determine their effects on platelet aggregation, platelet P2Y1 and P2Y12 receptor antagonism, and their metabolism in human plasma.
METHODS: We separated the 4 diastereomers of compound 1 by preparative reversed-phase chromatography, and studied their effect on ADP-induced platelet aggregation, P2Y1-mediated changes in cytosolic Ca2+, P2Y12-mediated changes in VASP phosphorylation, and metabolism in human plasma.
RESULTS: The inhibition of ADP-induced human platelet aggregation and human platelet P2Y12 receptor, and stability in human plasma strongly depended on the stereo-configuration of the chiral P1- and P4-phosphorothioate groups, the SPSP diastereomer being the most potent inhibitor and completely resistant to degradation in plasma, and the RPRP diastereomer being the least potent inhibitor and with the lowest plasma stability. The inhibitory activity of SPRP diastereomers depended on the configuration of the pseudo-asymmetric carbon of the P2,P3-chloromethylene group, one of the configurations being significantly more active than the other. Their plasma stability did not differ significantly, being intermediate to that of the SPSP and the RPRP diastereomers.
CONCLUSIONS: The presently-described stereoisomers have utility for structural, mechanistic, and drug development studies of dual antagonists of platelet P2Y1 and P2Y12 receptors.
Rights and Permissions
Copyright: © 2014 Chang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
DOI of Published Version
10.1371/journal.pone.0094780
Source
PLoS One. 2014 Apr 10;9(4):e94780. doi: 10.1371/journal.pone.0094780. eCollection 2014. Link to article on publisher's site
Journal/Book/Conference Title
PloS one
Related Resources
PubMed ID
24722456
Repository Citation
Chang H, Yanachkov IB, Dix EJ, Yanachkova M, Li Y, Barnard MR, Wright GE, Michelson AD, Frelinger AL. (2014). Antiplatelet activity, P2Y(1) and P2Y(1)(2) inhibition, and metabolism in plasma of stereoisomers of diadenosine 5',5'''-P(1) ,P(4)-dithio-P(2),P(3)-chloromethylenetetraphosphate. Open Access Articles. https://doi.org/10.1371/journal.pone.0094780. Retrieved from https://escholarship.umassmed.edu/oapubs/2542
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
Included in
Cellular and Molecular Physiology Commons, Hematology Commons, Medical Pharmacology Commons, Pharmacology Commons