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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

  • Marvin Korff , Ruben Steigerwald , Elena Bechthold , Dirk Schepmann ORCID logo , Julian A. Schreiber ORCID logo , Sven G. Meuth ORCID logo , Guiscard Seebohm ORCID logo and Bernhard Wünsch ORCID logo EMAIL logo
Published/Copyright: October 10, 2022
Biological Chemistry
From the journal Biological Chemistry Volume 404 Issue 4

Abstract

GluN2B-NMDA receptors play a key role in several neurological and neurodegenerative disorders. In order to develop novel negative allosteric GluN2B-NMDA receptor modulators, the concept of conformational restriction was pursued, i.e. the flexible aminoethanol substructure of ifenprodil was embedded into a more rigid tetrahydro-3-benzazepine system. The resulting tetrahydro-3-benzazepine-1,7-diol (±)-2 (WMS-1410) showed promising receptor affinity in receptor binding studies (Ki = 84 nM) as well as pharmacological activity in two-electrode-voltage-clamp experiments (IC50 = 116 nM) and in cytoprotective assays (IC50 = 18.5 nM). The interactions of (R)-2 with the ifenprodil binding site of GluN2B-NMDA receptors were analyzed on the molecular level and the “foot-in-the-door” mechanism was developed. Due to promising pharmacokinetic parameters (logD7.4 = 1.68, plasma protein binding of 76–77%, sufficient metabolic stability) F-substituted analogs were prepared and evaluated as tracers for positron emission tomography (PET). Both fluorine-18-labeled PET tracers [18F]11 and [18F]15 showed high brain uptake, specific accumulation in regions known for high GluN2B-NMDA receptor expression, but no interactions with σ1 receptors. Radiometabolites were not observed in the brain. Both PET tracers might be suitable for application in humans.

Keywords: fluorine-18-labeled PET tracer; labeling of CNS regions in vivo; molecular interactions of 3-benzazepines with GluN2B-NMDA receptors; NMDA receptors with GluN2B subunit; pharmacokinetic properties; tetrahydro-3-benzazepinediols
Corresponding author: Bernhard Wünsch, Chemical Biology of Ion Channels (Chembion), Westfälische Wilhelms-Universität Münster, GRK 2515 Munster, Germany; and Westfälische Wilhelms-Universität Münster, Institut für Pharmazeutische und Medizinische Chemie, Corrensstraße 48, D-48149 Münster, Germany, E-mail:
Marvin Korff and Ruben Steigerwald contributed equally.

Funding source: Deutsche Forschungsgemeinschaft

  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), which is gratefully acknowledged.

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

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Received: 2022-07-06
Accepted: 2022-09-22
Published Online: 2022-10-10
Published in Print: 2023-03-28

© 2022 Walter de Gruyter GmbH, Berlin/Boston

Articles in the same Issue

  1. Frontmatter
  2. Highlight: Chemical Biology of Ion Channels
  3. Highlight: chemical biology of ion channels
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  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
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https://doi.org/10.1515/hsz-2022-0222
Keywords for this article
fluorine-18-labeled PET tracer; labeling of CNS regions in vivo; molecular interactions of 3-benzazepines with GluN2B-NMDA receptors; NMDA receptors with GluN2B subunit; pharmacokinetic properties; tetrahydro-3-benzazepinediols

Articles in the same Issue

  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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