Inhibiting Acetylcholinesterase to Activate Pleiotropic Prodrugs with Therapeutic Interest in Alzheimer’s Disease
Abstract
:1. Introduction
2. Results
2.1. Chemistry
2.2. In Silico Results
2.3. In Vitro Results
2.3.1. AChE Inhibition and 5-HT4R Binding
2.3.2. Pharmacological Profile Results
2.3.3. Brain Penetration
2.3.4. AChE-Dependent Decarbamoylation
2.4. In Vivo Results
2.4.1. Pharmacological Screening
2.4.2. Spontaneous Locomotor Activity
2.4.3. Spontaneous Alternation Deficit
3. Discussion
4. Materials and Methods
4.1. Chemistry
4.1.1. General Methods
4.1.2. Synthesis of Compounds (11–18)
4.1.3. General Procedure for the Synthesis of Compounds (4–6)
4.1.4. General Procedure for the Synthesis of Compounds (7–9)
4.1.5. General Procedure for the Preparation of Fumarate Salts (19–20)
4.2. In Silico Study
4.3. Biological Evaluation
4.3.1. In Vitro Tests of AChE Inhibitory Activity
4.3.2. Kinetic Study for AChE Inhibition
4.3.3. Pharmacological Characterization of Drugs on Human 5-HT4R
4.3.4. Determination of cAMP Production
4.3.5. Parallel Artificial Membrane Permeability Assay
4.3.6. AChE-Dependent Decarbamoylation
4.3.7. In Vivo Biological Studies
5. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Sample Availability: Samples of all the synthesized compounds are available from the authors. |
Compound | X | R | (h)AChE IC50 (nM) or % Inhibition at 10−6 M | (h)5-HT4R Ki (nM) or % Inhibition at 10−8 M |
---|---|---|---|---|
Donepezil | - | - | 7.0 ± 1.5 | - |
Rivastigmine | - | - | 4.150 ± 160 1 | - |
RS67333 | - | - | - | 5.1 ± 0.5 2 |
4 | CH2 | OH | 148.6 ± 34.9 | 5.1 ± 1.1 |
7 | CH2 | OCON(Me)Et | 4151 ± 794 | 3% |
5 | O | OH | 11% | 0.6 ± 0.4 |
8 | O | OCON(Me)Et | 16,290 ± 240 | 23% |
6 | NH | OH | 4% | 5.8 ± 1.2 |
9 | NH | OCON(Me)Et | 10,077 ± 2,988 | 13% |
19 | CH2 | OH, fumaric salt | 72.0 ± 1.4 | 6.9 ± 1.2 |
20 | CH2 | OCON(Me)Et, fumaric salt | 6070 ± 404 | 16% |
Compound | Log(EC50) 1 | % Control Agonist Response 2 | Profile |
---|---|---|---|
RS67333 | −8.8 ± 0.2 | 48.7 ± 5.2 | Partial agonist |
19 | −9.90 ± 0.0 | 59.0 ± 3.9 | Partial agonist |
Compound | LogPe |
---|---|
Corticosterone | −4.84 ± 0.02 |
Theophylline | −6.52 ± 0.05 |
20 | −4.39 ± 0.12 |
Compound | Dose (mg/kg) | LD50 (mg/kg) | Symptoms (Subtoxic Doses) |
---|---|---|---|
20 | 1–10–100 | >100 | 1–10, no symptoms |
100, tremors, hypoactivity full recovery after 24h | |||
Amphetamine 1 | 2 | - | Hyperactivity, exophtalmy, irritability |
Chlorpromazine 1 | 10 | - | Hypoactivity, ataxia, sleep |
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Toublet, F.-X.; Lecoutey, C.; Lalut, J.; Hatat, B.; Davis, A.; Since, M.; Corvaisier, S.; Freret, T.; Sopkova de Oliveira Santos, J.; Claeysen, S.; et al. Inhibiting Acetylcholinesterase to Activate Pleiotropic Prodrugs with Therapeutic Interest in Alzheimer’s Disease. Molecules 2019, 24, 2786. https://doi.org/10.3390/molecules24152786
Toublet F-X, Lecoutey C, Lalut J, Hatat B, Davis A, Since M, Corvaisier S, Freret T, Sopkova de Oliveira Santos J, Claeysen S, et al. Inhibiting Acetylcholinesterase to Activate Pleiotropic Prodrugs with Therapeutic Interest in Alzheimer’s Disease. Molecules. 2019; 24(15):2786. https://doi.org/10.3390/molecules24152786
Chicago/Turabian StyleToublet, François-Xavier, Cédric Lecoutey, Julien Lalut, Bérénice Hatat, Audrey Davis, Marc Since, Sophie Corvaisier, Thomas Freret, Jana Sopkova de Oliveira Santos, Sylvie Claeysen, and et al. 2019. "Inhibiting Acetylcholinesterase to Activate Pleiotropic Prodrugs with Therapeutic Interest in Alzheimer’s Disease" Molecules 24, no. 15: 2786. https://doi.org/10.3390/molecules24152786
APA StyleToublet, F.-X., Lecoutey, C., Lalut, J., Hatat, B., Davis, A., Since, M., Corvaisier, S., Freret, T., Sopkova de Oliveira Santos, J., Claeysen, S., Boulouard, M., Dallemagne, P., & Rochais, C. (2019). Inhibiting Acetylcholinesterase to Activate Pleiotropic Prodrugs with Therapeutic Interest in Alzheimer’s Disease. Molecules, 24(15), 2786. https://doi.org/10.3390/molecules24152786