D-DOPA Is a Potent, Orally Bioavailable, Allosteric Inhibitor of Glutamate Carboxypeptidase II
Abstract
1. Introduction
2. Materials and Methods
2.1. Reagents and Chemicals
2.2. GCPII Activity Assay
2.3. Metabolic Stability Assays
2.4. Pharmacokinetic Studies in Mice
2.5. Bioanalysis in Plasma and Brain
2.6. D-DOPA Target Engagement Studies
2.7. D-DOPA Mode of Inhibition Studies
3. Results and Discussion
3.1. IC50 of Catechol-Based Scaffolds
3.2. In Vitro Metabolic Stability of Caffeic Acid, L-DOPA, and D-DOPA
3.3. Bioanalytical Methods for Caffeic Acid, L-DOPA, and D-DOPA
3.4. Initial Pharmacokinetic Studies of Caffeic Acid, L-DOPA, and D-DOPA in Mice
3.5. Pharmacokinetic and Target Engagement Studies of D-DOPA + Sodium Benzoate in Mice
3.6. Characterization of D-DOPA’s Mode of GCPII Inhibition
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 | Structure | IC50 (μM) | Compound | Structure | IC50 (μM) |
---|---|---|---|---|---|
1 (L-DOPA) | 0.6 | 6 | 20 | ||
2 (Tyr) | 100 | 7 (Dopamine) | >100 | ||
3 | >100 | 8 | 4 | ||
4 | >100 | 9 (Caffeic Acid) | 0.3 | ||
5 | >100 | 10 (D-DOPA) | 0.2 |
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Gori, S.S.; Thomas, A.G.; Pal, A.; Wiseman, R.; Ferraris, D.V.; Gao, R.-d.; Wu, Y.; Alt, J.; Tsukamoto, T.; Slusher, B.S.; et al. D-DOPA Is a Potent, Orally Bioavailable, Allosteric Inhibitor of Glutamate Carboxypeptidase II. Pharmaceutics 2022, 14, 2018. https://doi.org/10.3390/pharmaceutics14102018
Gori SS, Thomas AG, Pal A, Wiseman R, Ferraris DV, Gao R-d, Wu Y, Alt J, Tsukamoto T, Slusher BS, et al. D-DOPA Is a Potent, Orally Bioavailable, Allosteric Inhibitor of Glutamate Carboxypeptidase II. Pharmaceutics. 2022; 14(10):2018. https://doi.org/10.3390/pharmaceutics14102018
Chicago/Turabian StyleGori, Sadakatali S., Ajit G. Thomas, Arindom Pal, Robyn Wiseman, Dana V. Ferraris, Run-duo Gao, Ying Wu, Jesse Alt, Takashi Tsukamoto, Barbara S. Slusher, and et al. 2022. "D-DOPA Is a Potent, Orally Bioavailable, Allosteric Inhibitor of Glutamate Carboxypeptidase II" Pharmaceutics 14, no. 10: 2018. https://doi.org/10.3390/pharmaceutics14102018
APA StyleGori, S. S., Thomas, A. G., Pal, A., Wiseman, R., Ferraris, D. V., Gao, R.-d., Wu, Y., Alt, J., Tsukamoto, T., Slusher, B. S., & Rais, R. (2022). D-DOPA Is a Potent, Orally Bioavailable, Allosteric Inhibitor of Glutamate Carboxypeptidase II. Pharmaceutics, 14(10), 2018. https://doi.org/10.3390/pharmaceutics14102018