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Tetrahydro-3-benzazepines with fluorinated side chains as NMDA and σ1 receptor antagonists: Synthesis, receptor affinity, selectivity and antiallodynic activity.
Journal article

Tetrahydro-3-benzazepines with fluorinated side chains as NMDA and σ1 receptor antagonists: Synthesis, receptor affinity, selectivity and antiallodynic activity.

  • Thum S Institut für Pharmazeutische und Medizinische Chemie der Universität Münster, Corrensstraße 48, D-48149 Münster, Germany.
  • Schepmann D Institut für Pharmazeutische und Medizinische Chemie der Universität Münster, Corrensstraße 48, D-48149 Münster, Germany.
  • Ayet E Esteve Pharmaceuticals S.A, Baldiri Reixach 4-8, 08028 Barcelona, Spain.
  • Pujol M Esteve Pharmaceuticals S.A, Baldiri Reixach 4-8, 08028 Barcelona, Spain.
  • Nieto FR Department of Pharmacology and Institute of Neuroscience, School of Medicine and Biomedical Research Center, University of Granada, Avenida de la Investigación 11, 18016 Granada, Spain.
  • Ametamey SM Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH Zurich, Zurich, Switzerland.
  • Wünsch B Institut für Pharmazeutische und Medizinische Chemie der Universität Münster, Corrensstraße 48, D-48149 Münster, Germany; Cells-in-Motion Cluster of Excellence (EXC 1003-CiM), Westfälische Wilhelms-Universität Münster, Germany. Electronic address: wuensch@uni-muenster.de.
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  • 2019-05-27
Published in:
  • European journal of medicinal chemistry. - 2019
Antiallodynic activity
Fluorinated side chain
GluN2B subunit selective NMDA receptor antagonist
NMDA receptor
PET
Receptor selectivity
Structure activity relationships
Tetrahydro-3-benzazepines
σ(1) receptor selectivity
Analgesics
Animals
Benzazepines
Dose-Response Relationship, Drug
Excitatory Amino Acid Antagonists
Female
Humans
Hyperalgesia
Ligands
Mice
Microsomes, Liver
Molecular Structure
Piperidines
Rats
Receptors, N-Methyl-D-Aspartate
Receptors, sigma
Stereoisomerism
Structure-Activity Relationship
English The class of tetrahydro-1H-3-benzazepines was systematically modified in 1-, 3- and 7-position. In particular, a F-atom was introduced in β- or γ-position of the 4-phenylbutyl side chain in 3-position. Ligands with the F-atom in γ-position possess higher GluN2B affinity than analogs bearing the F-atom in β-position. This effect was attributed to the reduced basicity of β-fluoro amines. 3-Benzazepines with a benzylic OH moiety show moderate GluN2B affinity, but considerable selectivity over the σ2 receptor. However, removal of the benzylic OH moiety led to increased GluN2B affinity, but reduced GluN2B/σ2 selectivity. With respect to GluN2B affinity the phenol 17b with a γ-fluorophenylbutyl moiety in 3-position represents the most interesting fluorinated ligand (Ki(GluN2B) = 16 nM). Most of the synthesized ligands reveal either similar GluN2B and σ1 affinity or higher σ1 affinity than GluN2B affinity. The methyl ether 16b shows high σ1 affinity (Ki(σ1) = 6.6 nM) and high selectivity over a broad panel of receptors and transporters. The high antiallodynic activity in the mouse capsaicin assay proved the σ1 antagonistic activity of 16b.
Language
  • English
Open access status
closed
Identifiers
Persistent URL
https://sonar.ch/global/documents/60278
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