Startseite Lebenswissenschaften In vitro ADME characterization of a very potent 3-acylamino-2-aminopropionic acid-derived GluN2C-NMDA receptor agonist and its ester prodrugs
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In vitro ADME characterization of a very potent 3-acylamino-2-aminopropionic acid-derived GluN2C-NMDA receptor agonist and its ester prodrugs

  • Elena Bechthold , Lucie Grey ORCID logo , Emil Diamant , Judith Schmidt , Ruben Steigerwald , Fabao Zhao , Kasper B. Hansen , Lennart Bunch , Rasmus P. Clausen und Bernhard Wünsch ORCID logo EMAIL logo
Veröffentlicht/Copyright: 25. November 2022
Biological Chemistry
Aus der Zeitschrift Biological Chemistry Band 404 Heft 4

Abstract

The GluN2C subunit exists predominantly, but not exclusively in NMDA receptors within the cerebellum. Antagonists such as UBP1700 and positive allosteric modulators including PYD-106 and 3-acylamino-2-aminopropionic acid derivatives such as UA3-10 ((R)-2-amino-3-{[5-(2-bromophenyl)thiophen-2-yl]carboxamido}propionic acid) represent promising tool compounds to investigate the role of GluN2C-containing NMDA receptors in the signal transduction in the brain. However, due to its high polarity the bioavailability and CNS penetration of the amino acid UA3-10 are expected to be rather low. Herein, three ester prodrugs 12a–c of the NMDA receptor glycine site agonist UA3-10 were prepared and pharmacokinetically characterized. The esters 12a–c showed higher lipophilicity (higher logD7.4 values) than the acid UA3-10 but almost the same binding at human serum albumin. The acid UA3-10 was rather stable upon incubation with mouse liver microsomes and NADPH, but the esters 12a–c were fast hydrolyzed to afford the acid UA3-10. Incubation with pig liver esterase and mouse serum led to rapid hydrolysis of the esters 12a–c. The isopropyl ester 12c showed a promising logD7.4 value of 3.57 and the highest stability in the presence of pig liver esterase and mouse serum. These results demonstrate that ester prodrugs of UA3-10 can potentially afford improved bioavailability and CNS penetration.

Keywords: 3-acylamino-2-aminopropionic acid derivatives; GluN2C subtype-specific NMDA agonists; hydrolytic stability; in vitro ADME; physicochemical parameters; UA3-10
Corresponding author: Bernhard Wünsch, Westfälische Wilhelms-Universität Münster, GRK 2515, Chemical Biology of Ion Channels (Chembion), Corrensstraße 48, D-48149 Münster, Germany; and Westfälische Wilhelms-Universität Münster, Institut für Pharmazeutische und Medizinische Chemie, Corrensstraße 48, D-48149 Münster, Germany, E-mail:
Elena Bechthold and Lucie Grey contributed equally to this work.

Funding source: National Institutes of Health

Award Identifier / Grant number: [NS097536] to K.B.H.

Funding source: Deutsche Forschungsgemeinschaft

Award Identifier / Grant number: GRK 2515/1

  1. Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

  2. Research funding: This work was supported by the Research Training Group “Chemical biology of ion channels (Chembion)” funded by the Deutsche Forschungsgemeinschaft (DFG) [GRK 2515/1], which is gratefully acknowledged. The authors acknowledge financial support from the National Institutes of Health [NS097536] to K.B.H.

  3. Conflict of interest statement: The authors declare no conflicts of interest regarding this article.

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Supplementary Material

The online version of this article offers supplementary material (https://doi.org/10.1515/hsz-2022-0229).

Received: 2022-07-12
Accepted: 2022-11-01
Published Online: 2022-11-25
Published in Print: 2023-03-28

© 2022 Walter de Gruyter GmbH, Berlin/Boston

Artikel in diesem Heft

  1. Frontmatter
  2. Highlight: Chemical Biology of Ion Channels
  3. Highlight: chemical biology of ion channels
  4. The second PI(3,5)P2 binding site in the S0 helix of KCNQ1 stabilizes PIP2-at the primary PI1 site with potential consequences on intermediate-to-open state transition
  5. In vitro ADME characterization of a very potent 3-acylamino-2-aminopropionic acid-derived GluN2C-NMDA receptor agonist and its ester prodrugs
  6. A novel NMDA receptor test model based on hiPSC-derived neural cells
  7. Chemical, pharmacodynamic and pharmacokinetic characterization of the GluN2B receptor antagonist 3-(4-phenylbutyl)-2,3,4,5-tetrahydro-1H-3-benzazepine-1,7-diol – starting point for PET tracer development
  8. Characterization of Kv1.2-mediated outward current in TRIP8b-deficient mice
  9. Influence of inflammatory processes on thalamocortical activity
  10. NMDA receptors – regulatory function and pathophysiological significance for pancreatic beta cells
  11. The role of the Na+/Ca2+-exchanger (NCX) in cancer-associated fibroblasts
  12. Pancreatic KCa3.1 channels in health and disease
  13. Validation of TREK1 ion channel activators as an immunomodulatory and neuroprotective strategy in neuroinflammation
https://doi.org/10.1515/hsz-2022-0229
Schlagwörter für diesen Artikel
3-acylamino-2-aminopropionic acid derivatives; GluN2C subtype-specific NMDA agonists; hydrolytic stability; in vitro ADME; physicochemical parameters; UA3-10

Artikel in diesem Heft

  1. Frontmatter
  2. Highlight: Chemical Biology of Ion Channels
  3. Highlight: chemical biology of ion channels
  4. The second PI(3,5)P2 binding site in the S0 helix of KCNQ1 stabilizes PIP2-at the primary PI1 site with potential consequences on intermediate-to-open state transition
  5. In vitro ADME characterization of a very potent 3-acylamino-2-aminopropionic acid-derived GluN2C-NMDA receptor agonist and its ester prodrugs
  6. A novel NMDA receptor test model based on hiPSC-derived neural cells
  7. Chemical, pharmacodynamic and pharmacokinetic characterization of the GluN2B receptor antagonist 3-(4-phenylbutyl)-2,3,4,5-tetrahydro-1H-3-benzazepine-1,7-diol – starting point for PET tracer development
  8. Characterization of Kv1.2-mediated outward current in TRIP8b-deficient mice
  9. Influence of inflammatory processes on thalamocortical activity
  10. NMDA receptors – regulatory function and pathophysiological significance for pancreatic beta cells
  11. The role of the Na+/Ca2+-exchanger (NCX) in cancer-associated fibroblasts
  12. Pancreatic KCa3.1 channels in health and disease
  13. Validation of TREK1 ion channel activators as an immunomodulatory and neuroprotective strategy in neuroinflammation
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