Novel Pitolisant-Derived Sulfonyl Compounds for Alzheimer Disease
Abstract
:1. Introduction
2. Results
2.1. Chemistry
2.2. Biological Evaluation
2.2.1. Acetylcholinesterase Inhibition
2.2.2. Acetylcholine Release
2.2.3. In Vitro Blood-Brain Barrier Permeation Assay (PAMPA-BBB Assay)
2.2.4. Novel Object Recognition Test (NORT)
2.2.5. ADME Properties Prediction
3. Discussion
4. Materials and Methods
4.1. Chemistry
4.2. Biological Evaluation
4.2.1. Acetylcholinesterase Activity
4.2.2. In Vitro ACh Release
4.2.3. In Vitro Blood-Brain Barrier Permeation Assay
4.2.4. Cognitive Evaluation: Novel Object Recognition Test
4.2.5. ADME Prediction Properties
4.2.6. Data Analysis
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Comp. | Structure | MW (g/mol) | H3R IC50 (μM) | AChE Inhibition (%) ± SEM |
---|---|---|---|---|
1 | 284 | 0.25 | I | |
2 | 298 | 0.13 | 37.06 ± 4.02 | |
3 | 300 | 0.40 | I | |
4 | 445 | 0.40 | 20.82 ± 4.98 | |
5 | 453 | 0.08 | 25.22 ± 7.70 | |
6 | 446 | 0.50 | 29.91 ± 3.63 | |
7 | 493 | 0.50 | 37.02 ± 4.61 | |
8 | 507 | 0.50 | 30.17 ± 4.86 |
Compound | PAMPA-BBB Assay | |
---|---|---|
Pe (×10−6 cm/s) | Classification | |
2 | 2.23 ± 0.31 | CNS +/− |
6 | 0.32 ± 0.01 | CNS − |
7 | 0.47 ± 0.06 | CNS − |
Locomotor Activity | Discrimination Index (%) | |
---|---|---|
SALINE | 20,397.14 ± 1590.99 | 51.88 ± 1.34 |
GAL | 18,785.69 ± 1597.80 | 50.21 ± 5.52 |
SCOP | 21,676.27 ± 1871.73 | 54.58 ± 2.54 |
2 | 20,036.75 ± 2200.76 | 52.07 ± 2.37 |
SCOP + GAL | 19,806.37 ± 2050.06 | 51.77 ± 3.15 |
SCOP + 2 | 21,487.37 ± 1531.95 | 50.61 ± 2.92 |
Absorption | ||||||||
---|---|---|---|---|---|---|---|---|
Ref. | Molecular Weight (g/mol) | Log P | H-Bond Donor | H-Bond Acceptor | Lipinski Violation | GI Absorption | Water Solubility | Caco2 |
2 | 298.40 | 1.589 | 1 | 4 | 0 | 91.4% | −1.418 | 0.875 |
7 | 507.22 | 4.719 | 2 | 5 | 1 | 88.5 | −4.748 | 0.632 |
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Share and Cite
Pérez-Silanes, S.; Martisova, E.; Moreno, E.; Solas, M.; Plano, D.; Sanmartin, C.; Ramírez, M.J. Novel Pitolisant-Derived Sulfonyl Compounds for Alzheimer Disease. Int. J. Mol. Sci. 2024, 25, 799. https://doi.org/10.3390/ijms25020799
Pérez-Silanes S, Martisova E, Moreno E, Solas M, Plano D, Sanmartin C, Ramírez MJ. Novel Pitolisant-Derived Sulfonyl Compounds for Alzheimer Disease. International Journal of Molecular Sciences. 2024; 25(2):799. https://doi.org/10.3390/ijms25020799
Chicago/Turabian StylePérez-Silanes, Silvia, Eva Martisova, Esther Moreno, Maite Solas, Daniel Plano, Carmen Sanmartin, and María Javier Ramírez. 2024. "Novel Pitolisant-Derived Sulfonyl Compounds for Alzheimer Disease" International Journal of Molecular Sciences 25, no. 2: 799. https://doi.org/10.3390/ijms25020799