Exploring the Potential of Coumarin Derivatives on Serotonin Receptors 5-HT1A and 5HT2A
Abstract
1. Introduction
2. Results and Discussion
2.1. Chemistry
2.2. Pharmacology
2.3. ADMET and Molecular Docking Studies
3. Materials and Methods
3.1. Experimental Section
3.1.1. Chemical Compounds
3.1.2. General Procedure for Preparing Compounds 1–14
General Procedure for Preparing Intermediate Derivatives IIa–IIg
General Procedure for Preparing Derivatives 1–14
6-Acetyl-7-(2-hydroxy-3-(4-(2-methoxyphenyl)piperazin-1-yl)propoxy)-4-methyl-2H-chromen-2-one (1)
6-Acetyl-7-(2-hydroxy-3-(4-(3-methoxyphenyl)piperazin-1-yl)propoxy)-4-methyl-2H-chromen-2-one (2)
4-(2-Hydroxy-3-(4-(2-methoxyphenyl)piperazin-1-yl)propoxy)-2H-chromen-2-one (3)
4-(2-Hydroxy-3-(4-(3-methoxyphenyl)piperazin-1-yl)propoxy)-2H-chromen-2-one (4)
5-(2-Hydroxy-3-(4-(2-methoxyphenyl)piperazin-1-yl)propoxy)-4,7-dimethyl-2H-chromen-2-one (5)
5-(2-Hydroxy-3-(4-(3-methoxyphenyl)piperazin-1-yl)propoxy)-4,7-dimethyl-2H-chromen-2-one (6)
6-Acetyl-5-(2-hydroxy-3-(4-(2-methoxyphenyl)piperazin-1-yl)propoxy)-4,7-dimethyl-2H-chromen-2-one (7)
6-Acetyl-5-(2-hydroxy-3-(4-(3-methoxyphenyl)piperazin-1-yl)propoxy)-4,7-dimethyl-2H-chromen-2-one (8)
7-(2-Hydroxy-3-(4-(2-methoxyphenyl)piperazin-1-yl)propoxy)-4-methyl-2H-chromen-2-one (9)
7-(2-Hydroxy-3-(4-(3-methoxyphenyl)piperazin-1-yl)propoxy)-4-methyl-2H-chromen-2-one (10)
8-Acetyl-7-(2-hydroxy-3-(4-(2-methoxyphenyl)piperazin-1-yl)propoxy)-4-methyl-2H-chromen-2-one (11)
8-Acetyl-7-(2-hydroxy-3-(4-(3-methoxyphenyl)piperazin-1-yl)propoxy)-4-methyl-2H-chromen-2-one (12)
7-(2-Hydroxy-3-(4-(2-methoxyphenyl)piperazin-1-yl)propoxy)-2H-chromen-2-one (13)
7-(2-Hydroxy-3-(4-(3-methoxyphenyl)piperazin-1-yl)propoxy)-2H-chromen-2-one (14)
3.1.3. Biological Assays
Membrane Preparation
Competitive Binding Assays
Antagonist Activity at 5-HT1A Receptors
3.1.4. Theoretical Methodology
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Compound | 5-HT1A Ki (nM, 95% CI) | 5-HT1A IC50 (µM, 95% CI) | 5-HT2A Ki (nM, 95% CI) |
---|---|---|---|
1 | 243 (136–437) | 331 (55–1985) | 1846 (1126–10,440) |
2 | 196 (134–288) | 59 (18–160) | 83 (30–229) |
3 | 243 (159–372) | 68 (37–129) | 4006 (1832–8761) |
4 | 190 (118–307) | 10 (0.49–23) | 315 (131–760) |
5 | 90 (54–150) | 14.7 (7.1–30) | 1182 (516–2806) |
6 | 176 (97–319) | 6.5 (2.5–17.3) | 662 (320–1373) |
7 | 90 (56–147) | 2.4 (0.58–9.8) | 4150 (2276–7568) |
8 | 1776 (354–8916) | 16.2 (6.2–42.7) | 115 (36–367) |
9 | 245 (143–419) | 2.4 (0.7–7.9) | 291 (134–629) |
10 | 87 (53–142) | 89.5 (30.2–265) | 260 (111–607) |
11 | 96 (50–183) | 0.043 (0.014–0.137) | 6157 (3184–11,910) |
12 | 264 (162–432) | 6.1 (1.76–21.5) | 67 (26–169) |
13 | 222 (124–396) | 1.43 (0.63–32.6) | 18 (6–61) |
14 | 135 (85–216) | 112 (48.9–256.3) | 68 (41–113) |
8-OH-DPAT | 0.68 (0.45–1.02) | - | - |
Ketanserin | - | - | 0.56 (0.23–1.36) |
WAY-100635 | 0.0043 (0.00186–0.0075) |
Compound | MW a | Dipole b | vol c | SASA d | dHB e | aHB f | logP g | metab h | Ro3 i | Ro5 j | pKa k | LD50 l |
---|---|---|---|---|---|---|---|---|---|---|---|---|
1 | 466.5 | 7.1 | 777.6 | 1426.2 | 1 | 10.7 | 2.36 | 6 | 0 | 0 | 8.97 | 500 |
2 | 466.5 | 3.7 | 764.7 | 1418.1 | 1 | 10.7 | 2.30 | 5 | 0 | 0 | 8.97 | 550 |
3 | 410.5 | 3.5 | 705.7 | 1270.5 | 1 | 8.7 | 2.77 | 5 | 0 | 0 | 9.05 | 1100 |
4 | 410.5 | 4.5 | 705.1 | 1273.8 | 1 | 8.7 | 2.78 | 5 | 0 | 0 | 9.05 | 550 |
5 | 438.5 | 6.7 | 753.1 | 1367.3 | 1 | 8.7 | 3.38 | 7 | 0 | 1 | 8.99 | 1100 |
6 | 438.5 | 7.6 | 761.9 | 1387.3 | 1 | 8.7 | 3.37 | 6 | 0 | 0 | 9.00 | 676 |
7 | 480.6 | 6.1 | 774.1 | 1433.4 | 1 | 10.7 | 2.76 | 7 | 0 | 1 | 8.99 | 500 |
8 | 480.6 | 8.7 | 763.9 | 1425.7 | 1 | 10.7 | 2.70 | 7 | 0 | 1 | 8.99 | 550 |
9 | 424.5 | 9.0 | 758.5 | 1356.8 | 1 | 8.7 | 3.17 | 6 | 0 | 0 | 8.97 | 1100 |
10 | 424.5 | 6.5 | 745.6 | 1348.7 | 1 | 8.7 | 3.11 | 5 | 0 | 0 | 8.97 | 1100 |
11 | 466.5 | 12.7 | 775.3 | 1420.3 | 1 | 10.7 | 2.52 | 6 | 0 | 0 | 8.97 | 550 |
12 | 466.5 | 10.0 | 762.4 | 1412.2 | 1 | 10.7 | 2.46 | 5 | 0 | 0 | 8.97 | 1000 |
13 | 410.5 | 8.7 | 733.7 | 1305.2 | 1 | 8.7 | 2.91 | 5 | 0 | 0 | 8.97 | 1100 |
14 | 410.5 | 6.1 | 720.7 | 1297.1 | 1 | 8.7 | 2.85 | 4 | 0 | 0 | 8.97 | 550 |
aripiprazole | 448.4 | 7.8 | 709 | 1318.3 | 1 | 6.25 | 4.43 | 5 | 0 | 0 | 7.39 | 800 |
ketanserin | 395.4 | 7.8 | 699.4 | 1235.5 | 1 | 7.5 | 2.93 | 3 | 0 | 0 | 6.45 | 790 |
8-OH-DPAT | 247.4 | 1 | 556.1 | 959.5 | 1 | 2.75 | 3.46 | 4 | 0 | 0 | 9.4 | 150 |
WAY100635 | 422.6 | 3.9 | 761.8 | 1413.2 | 0 | 8.25 | 3.95 | 6 | 0 | 0 | 6.34 | 874 |
5HT1A | 5HT2A | |||
---|---|---|---|---|
Compound | ΔG [kcal/mol] | Ki [nM] | ΔG [kcal/mol] | Ki [nM] |
1 | <−9.0 | >250 | −10.8 | 12.1 |
2 | −9.8 | 65.5 | −10.3 | 28.2 |
3 | <−9.0 | >250 | −11.0 | 8.6 |
4 | −9.6 | 91.9 | −10.7 | 14.3 |
5 | −9.4 | 128.7 | −10.7 | 14.3 |
6 | <−9.0 | >250 | −10.5 | 20.1 |
7 | −10.0 | 46.8 | −11.3 | 5.2 |
8 | <−9.0 | >250 | −10.9 | 10.2 |
9 | <−9.0 | >250 | −9.8 | 65.5 |
10 | −9.2 | 180.4 | −10.0 | 46.8 |
11 | −9.4 | 128.7 | −10.9 | 10.2 |
12 | −9.2 | 180.4 | −10.3 | 28.2 |
13 | <−9.0 | >250 | −9.7 | 77.6 |
14 | −9.5 | 108.8 | −9.8 | 65.5 |
aripiprazole | −9.5 | 108.8 | −9.9 | 55.4 |
ketanserin | −9.6 | - | −11.7 | 2.7 |
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Ostrowska, K.; Horosz, G.; Kruk, K.; Sieroń, B.; Leśniak, A.; Czartoryska, Z.; Bujalska-Zadrożny, M.; Milenkovic, D.; Trzaskowski, B. Exploring the Potential of Coumarin Derivatives on Serotonin Receptors 5-HT1A and 5HT2A. Int. J. Mol. Sci. 2025, 26, 1946. https://doi.org/10.3390/ijms26051946
Ostrowska K, Horosz G, Kruk K, Sieroń B, Leśniak A, Czartoryska Z, Bujalska-Zadrożny M, Milenkovic D, Trzaskowski B. Exploring the Potential of Coumarin Derivatives on Serotonin Receptors 5-HT1A and 5HT2A. International Journal of Molecular Sciences. 2025; 26(5):1946. https://doi.org/10.3390/ijms26051946
Chicago/Turabian StyleOstrowska, Kinga, Gabriela Horosz, Karolina Kruk, Bartłomiej Sieroń, Anna Leśniak, Zofia Czartoryska, Magdalena Bujalska-Zadrożny, Dejan Milenkovic, and Bartosz Trzaskowski. 2025. "Exploring the Potential of Coumarin Derivatives on Serotonin Receptors 5-HT1A and 5HT2A" International Journal of Molecular Sciences 26, no. 5: 1946. https://doi.org/10.3390/ijms26051946
APA StyleOstrowska, K., Horosz, G., Kruk, K., Sieroń, B., Leśniak, A., Czartoryska, Z., Bujalska-Zadrożny, M., Milenkovic, D., & Trzaskowski, B. (2025). Exploring the Potential of Coumarin Derivatives on Serotonin Receptors 5-HT1A and 5HT2A. International Journal of Molecular Sciences, 26(5), 1946. https://doi.org/10.3390/ijms26051946