N-Skatyltryptamines—Dual 5-HT6R/D2R Ligands with Antipsychotic and Procognitive Potential
Abstract
:1. Introduction
2. Results
2.1. Chemistry
2.2. Structure–Affinity Relationship
2.3. Functional Assays toward 5-HT6R and D2R
2.4. Molecular Modeling
2.5. In Vitro ADMETox Studies
2.5.1. Permeability Assay
2.5.2. Metabolic Stability
2.5.3. CYP450 Inhibition
2.5.4. Hepatotoxicity
2.6. In Vivo Behavioral Tests
2.6.1. MK-801-Induced Hyperactivity in Mice
2.6.2. Novel Object Recognition (NOR) Test
2.6.3. Effect of Compound 15 and 18 on Spontaneous Activity of Mice
3. Discussion
4. Materials and Methods
4.1. Chemistry
4.2. In Vitro Pharmacology
4.2.1. Radioligand Binding Assay
4.2.2. D2R Functional Assay
4.2.3. 5-HT6R Functional Assays
4.3. Molecular Modeling
4.4. In Vitro ADMETox Studies
4.4.1. PAMPA
4.4.2. Metabolic Stability
4.4.3. CYP450 Inhibition
4.4.4. Hepatotoxicity Assay
4.5. Behavioral Tests
4.5.1. Novel Object Recognition Test
4.5.2. MK-801-Induced Hyperactivity
4.5.3. Locomotor Activity of Mice
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Conflicts of Interest
Sample Availability
References
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pKi [nM] | |||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|
ID | R1 | R2 | R3 | R4 | R5 | R6 | 5-HT1A | 5-HT2A | 5-HT6 | 5-HT7 | D2 |
Trp | H | H | H | - | - | - | 7.16 | 6.51 | 6.95 | 7.22 | <5.00 |
5-MeOTrp | MeO | H | H | - | - | - | 9.05 | 7.35 | 7.92 | 6.32 | 6.18 |
5-Cl-Trp | Cl | H | H | - | - | - | 8.80 | 7.50 | 8.42 | 8.80 | 6.61 |
1 | H | H | H | H | H | H | 6.82 | 8.70 | 7.76 | 5.54 | 7.22 |
2 | Me | H | H | H | H | H | 7.16 | 7.25 | 7.89 | 6.53 | <5.00 |
3 | OMe | H | H | H | H | H | 7.81 | 8.08 | 7.93 | 7.25 | 6.49 |
4 | Cl | H | H | H | H | H | n.d. | n.d. | 7.97 | n.d. | 6.61 |
5 | H | Cl | H | H | H | H | 6.48 | 6.93 | 7.78 | 5.80 | 7.81 |
6 | H | H | F | H | H | H | 6.56 | 7.42 | 7.77 | 5.99 | 6.53 |
7 | H | H | Cl | H | H | H | 6.29 | 7.20 | 7.88 | 5.60 | 5.93 |
8 | H | H | Br | H | H | H | 6.22 | 7.11 | 7.79 | 5.69 | 6.52 |
9 | H | H | H | OH | H | H | 6.54 | 6.71 | 6.65 | 6.29 | 6.12 |
10 | H | H | H | F | H | H | 7.31 | 6.46 | 7.39 | 6.32 | 6.07 |
11 | H | H | H | Cl | H | H | 7.17 | 6.49 | 7.29 | 6.42 | 6.68 |
12 | H | H | H | I | H | H | 7.31 | 6.63 | 7.34 | 6.29 | 6.68 |
13 | H | H | H | H | F | H | 6.87 | 6.59 | 7.65 | 5.74 | 7.52 |
14 | H | H | H | H | Cl | H | 6.97 | 7.33 | 8.05 | 5.80 | 7.91 |
15 | H | H | H | H | Br | H | 7.01 | 6.39 | 7.99 | 6.33 | 7.54 |
16 | H | H | H | H | H | F | 6.25 | 6.91 | 7.50 | 5.89 | 8.04 |
17 | H | H | H | H | H | Cl | 7.55 | 6.41 | 7.44 | 6.97 | 8.29 |
18 | H | H | H | H | H | Br | 7.52 | 6.40 | 7.35 | 6.88 | 8.26 |
19 | H | H | H | H | H | OBn | 7.13 | 6.64 | 7.52 | 5.95 | 6.39 |
20 | OMe | H | H | H | H | Cl | 8.10 | 7.51 | 8.01 | 7.53 | 6.63 |
21 | OMe | H | H | H | Cl | H | 7.73 | 7.76 | 8.28 | 7.09 | 6.81 |
22 | H | Cl | H | H | H | Cl | 6.25 | 6.39 | 7.44 | 5.88 | 6.30 |
ID | R1 | R2 | R3 | R4 | R5 | R6 | 5-HT6 EC50 | 5-HT6 Kb | D2 Kb |
---|---|---|---|---|---|---|---|---|---|
[nM] | |||||||||
1 | H | H | H | H | H | H | n.d. | 151 | n.d. |
5 | H | Cl | H | H | H | H | 157 | 136 | 104 |
13 | H | H | H | H | F | H | n.d. | 30 | 91 |
14 | H | H | H | H | Cl | H | n.d. | 112 | 290 |
15 | H | H | H | H | Br | H | n.d. | 131 | 109 |
17 | H | H | H | H | H | Cl | n.d. | 234 | 215 |
18 | H | H | H | H | H | Br | 77 | 10,000 | 167 |
21 | OMe | H | H | H | H | Cl | 22 | 10,000 | n.d. |
22 | OMe | H | H | H | Cl | H | 26 | n.d. | n.d. |
Compound | PAMPA Pe * [10−6 cm/s] ± SD |
---|---|
Norfloxacin | 0.56 ± 0.13 |
Caffeine | 15.1 ± 0.40 |
5 | 7.09 ± 1.24 |
14 | 8.34 ± 1.33 |
15 | 2.42 ± 0.92 |
17 | 8.42 ± 0.27 |
18 | 3.90 ± 0.56 |
Compound | Molecular Mass (m/z) | Retention Time (min) | Molecular Mass of the Metabolite (m/z) | Metabolic Pathway |
---|---|---|---|---|
5 | 324.25 | 4.17 | M1 340.26 | hydroxylation |
14 | 324.31 | 4.054.38 | M1 340.26 M2 340.33 | hydroxylation hydroxylation |
15 | 370.13 | 4.124.34 | M1 386.15 M2 384.09 | hydroxylation hydroxylation |
17 | 324.25 | 3.954.27 | M1 340.26 M2 340.26 | hydroxylation hydroxylation |
18 | 368.14 | 4.004.27 | M1 384.09 M2 386.08 | hydroxylation hydroxylation |
Compounds | Doses (mg/kg) | Ambulation Scores ± SEM |
---|---|---|
NaCl | - | 100.0 ± 11.81 |
15 | 0.5 | 134.9 ± 11.13 |
15 | 1 | 124.7 ± 21.75 |
15 | 3 | 91.8 ± 24.61 |
NaCl | - | 100.0 ± 8.95 |
18 | 0.05 | 113.6 ± 34.00 |
18 | 0.1 | 131.8 ± 19.50 |
18 | 0.5 | 116.7 ± 13.23 |
18 | 1 | 85.31 ± 15.86 |
18 | 3 | 87.79 ± 20.89 |
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Hogendorf, A.; Hogendorf, A.S.; Kurczab, R.; Satała, G.; Szewczyk, B.; Cieślik, P.; Latacz, G.; Handzlik, J.; Lenda, T.; Kaczorowska, K.; et al. N-Skatyltryptamines—Dual 5-HT6R/D2R Ligands with Antipsychotic and Procognitive Potential. Molecules 2021, 26, 4605. https://doi.org/10.3390/molecules26154605
Hogendorf A, Hogendorf AS, Kurczab R, Satała G, Szewczyk B, Cieślik P, Latacz G, Handzlik J, Lenda T, Kaczorowska K, et al. N-Skatyltryptamines—Dual 5-HT6R/D2R Ligands with Antipsychotic and Procognitive Potential. Molecules. 2021; 26(15):4605. https://doi.org/10.3390/molecules26154605
Chicago/Turabian StyleHogendorf, Agata, Adam S. Hogendorf, Rafał Kurczab, Grzegorz Satała, Bernadeta Szewczyk, Paulina Cieślik, Gniewomir Latacz, Jadwiga Handzlik, Tomasz Lenda, Katarzyna Kaczorowska, and et al. 2021. "N-Skatyltryptamines—Dual 5-HT6R/D2R Ligands with Antipsychotic and Procognitive Potential" Molecules 26, no. 15: 4605. https://doi.org/10.3390/molecules26154605