Synthesis, Biological Evaluation, and Docking Studies of Antagonistic Hydroxylated Arecaidine Esters Targeting mAChRs
Abstract
:1. Introduction
2. Results and Discussion
2.1. Chemistry
2.2. Physicochemical Properties
2.3. Biological Evaluation
2.4. Molecular Docking Studies
3. Materials and Methods
3.1. Chemistry
3.1.1. General Considerations
3.1.2. Synthetic Procedures for Precursors (6a, 6c, 13b)
3.1.3. General Procedure for the EDC-Mediated Esterification of Arecaidine (8a−c, 9a−c, 15a−c, 16a−c, 21, 25, 27)
3.1.4. General Procedure for the TBAF-Mediated TBS Deprotection of Arecaidine Esters (10a−c, 17b, 18b, 22)
3.2. High-Throughput HPLC-logD
3.3. Biological Evaluation
3.3.1. Materials and Methods
3.3.2. Cell Culture
3.3.3. Cell Viability (MTT Assay)
3.3.4. Radioligand Binding Experiments
3.3.5. Fluo-4 Calcium Assay for Agonist-Antagonist Discrimination
3.3.6. Data Analysis and Statistics
3.4. Molecular Docking
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Cmpd. | HPLC-logD | CNS MPO Score 1 |
---|---|---|
8a | 0.79 ± 0.01 | 5.71 |
8b | 0.87 ± 0.01 | 5.70 |
8c | 1.03 ± 0.04 | 5.70 |
10b | 2.6 ± 0.1 | 5.20 |
10c | 2.8 ± 0.2 | 5.20 |
17b | 2.69 ± 0.01 | 4.83 |
18b | 1.57 ± 0.04 | 5.72 |
22 | 0.92 ± 0.08 | 5.75 |
25 | 2.69 ± 0.01 | 5.34 |
27 | 2.69 ± 0.01 | 5.03 |
DPMA | 3.32 ± 0.04 2 | 4.16 |
Affinity: Ki ± SD (nM) | x-Fold Selectivity for hM1 vs. hMx 1 | ||||||||
---|---|---|---|---|---|---|---|---|---|
Cmpd. | hM1 | hM2 | hM3 | hM4 | hM5 | hM2 | hM3 | hM4 | hM5 |
8c | 525 ± 36 | >1000 2 | 663 ± 56 | 697 ± 132 | 417 ± 73 | >1.9 | 1.3 | 1.3 | 0.8 |
10b | 12.5 ± 0.8 | 198 ± 35 | 70.4 ± 1.8 | 32.3 ± 3.8 | 49.1 ± 8.5 | 15.8 | 5.6 | 2.6 | 3.9 |
10c | 74.0 ± 3.2 | 980 ± 32 | 150 ± 26 | 93 ± 23 | 72 ± 13 | 13.2 | 2.0 | 1.3 | 1.0 |
17b | 5.5 ± 0.5 | 172 ± 20 | 20.4 ± 1.2 | 18.4 ± 5.8 | 11.0 ± 1.5 | 31.3 | 3.7 | 3.3 | 2.0 |
18b | 259 ± 75 | >1000 3 | 188 ± 18 | 634 ± 90 | 90 ± 27 | >3.7 | 0.7 | 2.4 | 0.35 |
25 | 231 ± 60 | >1000 3 | 283 ± 20 | 217 ± 23 | 284 ± 62 | >4.3 | 1.2 | 0.9 | 1.2 |
DPMA | 3.1 ± 0.5 4 | 110 ± 39 4 | 56 ± 22 4 | 16 ± 4 4 | 14 ± 1 4 | 35.5 | 18.1 | 5.2 | 4.5 |
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Kilian, J.; Millard, M.; Ozenil, M.; Krause, D.; Ghaderi, K.; Holzer, W.; Urban, E.; Spreitzer, H.; Wadsak, W.; Hacker, M.; et al. Synthesis, Biological Evaluation, and Docking Studies of Antagonistic Hydroxylated Arecaidine Esters Targeting mAChRs. Molecules 2022, 27, 3173. https://doi.org/10.3390/molecules27103173
Kilian J, Millard M, Ozenil M, Krause D, Ghaderi K, Holzer W, Urban E, Spreitzer H, Wadsak W, Hacker M, et al. Synthesis, Biological Evaluation, and Docking Studies of Antagonistic Hydroxylated Arecaidine Esters Targeting mAChRs. Molecules. 2022; 27(10):3173. https://doi.org/10.3390/molecules27103173
Chicago/Turabian StyleKilian, Jonas, Marlon Millard, Marius Ozenil, Dominik Krause, Khadija Ghaderi, Wolfgang Holzer, Ernst Urban, Helmut Spreitzer, Wolfgang Wadsak, Marcus Hacker, and et al. 2022. "Synthesis, Biological Evaluation, and Docking Studies of Antagonistic Hydroxylated Arecaidine Esters Targeting mAChRs" Molecules 27, no. 10: 3173. https://doi.org/10.3390/molecules27103173