Identification of a New Morpholine Scaffold as a P2Y12 Receptor Antagonist
Abstract
:1. Introduction
2. Results
2.1. High-Throughput Screening of Anti-Platelet Compounds
2.2. Anti-Platelet Activities of Selected Compounds
2.3. Binding Affinities of Identified Compounds for the Rhp2y12 Receptor
2.4. Comparison of the Pharmacological Characteristics of Compound E and Ticagrelor
2.5. Selectivity over P2Y1 and P2Y13 Receptors
2.6. Docking Study of Compound E to Human P2Y12 Receptor
3. Materials and Methods
3.1. Chemical Compounds
3.2. Platelet Preparation for Aggregation Studies
3.3. Light Transmission Aggregometry
3.4. Cell Culture
3.5. Human P2Y12 Receptor and P2Y13 Receptor-Binding Assay with [3H]2-Methylthioadp and [3H]ADP
3.6. Ca2+ Mobilization Assay
3.7. Molecular Modeling
3.8. Statistical Analysis
4. Discussion
Acknowledgments
Author Contributions
Conflicts of Interest
References
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Ligand | 20 μM ADP (IC50, μM) | Compounds | 20 μM ADP (IC50, μM) |
---|---|---|---|
ATP | 2.14 ± 0.51 | A | 8.04 ± 0.51 |
MRS2179 | 1.1 ± 0.01 | B | 9.49 ± 1.15 |
2-MeSAMP | 1.09± 0.16 | C | 4.03 ± 0.95 |
Ticagrelor | 0.32 ± 0.02 | D | 6.08 ± 0.11 |
E | 6.21 ± 0.71 | ||
F | 9.35 ± 2.19 |
Compounds | IC50 vs. [3H]-2-MeSADP (μM) | IC50 vs. [3H]ADP (μM) |
---|---|---|
A | >30 | >30 |
B | >30 | >30 |
C | >30 | >30 |
D | >30 | >30 |
E | 15.51 ± 2.24 | 8.33 ± 1.69 |
F | >30 | >30 |
Ligand | IC50 vs. [3H]-2-MeSADP (μM) | IC50 vs. [3H]ADP (μM) |
---|---|---|
2-MeSADP | 0.12 ± 0.02 | 17.22 ± 4.62 |
ADP | 24.78 ± 2.09 | 0.19 ± 0.10 |
Ticagrelor | 0.04 ± 0.02 | 8.40 ± 3.05 |
Compound E | 15.51 ± 2.24 | 8.33 ± 1.69 |
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Ahn, Y.H.; Lee, J.-Y.; Park, H.D.; Kim, T.H.; Park, M.C.; Choi, G.; Kim, S. Identification of a New Morpholine Scaffold as a P2Y12 Receptor Antagonist. Molecules 2016, 21, 1114. https://doi.org/10.3390/molecules21091114
Ahn YH, Lee J-Y, Park HD, Kim TH, Park MC, Choi G, Kim S. Identification of a New Morpholine Scaffold as a P2Y12 Receptor Antagonist. Molecules. 2016; 21(9):1114. https://doi.org/10.3390/molecules21091114
Chicago/Turabian StyleAhn, Young Ha, Joo-Youn Lee, Hee Dong Park, Tae Hun Kim, Min Chul Park, Gildon Choi, and Sunghoon Kim. 2016. "Identification of a New Morpholine Scaffold as a P2Y12 Receptor Antagonist" Molecules 21, no. 9: 1114. https://doi.org/10.3390/molecules21091114