Identification of Novel Positive Allosteric Modulators of Neurotrophin Receptors for the Treatment of Cognitive Dysfunction
Abstract
:1. Introduction
2. Materials and Methods
2.1. Materials
2.2. Animal Welfare
2.3. TrkA PathHunter® Cell-Based Assay and High Throughput Screening
2.4. Immunoprecipitation and Kinase Activity Assay of Hemagglutinin (HA)-Tagged Full Length TrkA
2.5. Affinity Labeling and Immuno Precipitation/Streptavidin Adsorption
2.6. Surface Plasmon Resonance Studies
2.7. Long Term Potentiation and Electrophysiology
2.8. In Vivo Microdialysis
2.9. Western Blot Analysis
2.10. Morris Water Maze
2.11. Passive Avoidance
2.12. Novel Object Recognition
2.13. Statistical Analysis
3. Results
3.1. Screening and in Vitro Characterization
3.2. Mechanism of Action Studies
3.3. Facilitation of Long-Term Potentiation in Rat Hippocampal Slices
3.4. Microdialysis
3.5. In Vivo Behavioral Cognitive Models
4. Discussion
5. Patents
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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TrkA | TrkB | TrkC | IGF1R | FGFR1 | ||||||
---|---|---|---|---|---|---|---|---|---|---|
EC50 | Effect | EC50 | Effect | EC50 | Effect | EC50 | Effect | EC50 | Effect | |
ACD855 | 1.9 | 144% | 3.2 | 319% | 0.8 | 56% | 0.9 | 25% | 0.8 | 44% |
ACD856 | 0.38 | 185% | 0.29 | 176% | 0.33 | 328% | 0.25 | 104% | 0.19 | 117% |
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Dahlström, M.; Madjid, N.; Nordvall, G.; Halldin, M.M.; Vazquez-Juarez, E.; Lindskog, M.; Sandin, J.; Winblad, B.; Eriksdotter, M.; Forsell, P. Identification of Novel Positive Allosteric Modulators of Neurotrophin Receptors for the Treatment of Cognitive Dysfunction. Cells 2021, 10, 1871. https://doi.org/10.3390/cells10081871
Dahlström M, Madjid N, Nordvall G, Halldin MM, Vazquez-Juarez E, Lindskog M, Sandin J, Winblad B, Eriksdotter M, Forsell P. Identification of Novel Positive Allosteric Modulators of Neurotrophin Receptors for the Treatment of Cognitive Dysfunction. Cells. 2021; 10(8):1871. https://doi.org/10.3390/cells10081871
Chicago/Turabian StyleDahlström, Märta, Nather Madjid, Gunnar Nordvall, Magnus M. Halldin, Erika Vazquez-Juarez, Maria Lindskog, Johan Sandin, Bengt Winblad, Maria Eriksdotter, and Pontus Forsell. 2021. "Identification of Novel Positive Allosteric Modulators of Neurotrophin Receptors for the Treatment of Cognitive Dysfunction" Cells 10, no. 8: 1871. https://doi.org/10.3390/cells10081871