Synthesis and pharmacological evaluation of fluorinated benzo[7]annulen-7-amines as GluN2B-selective NMDA receptor antagonists

J Labelled Comp Radiopharm. 2019 Jun 30;62(8):354-379. doi: 10.1002/jlcr.3718.

Abstract

Because of their neuroprotective potential, GluN2B-selective ligands are of great interest for the treatment of various neurological and neurodegenerative disorders. Fluorinated benzo[7]annulen-7-amines, capable for PET, were synthesized by combining fluorinated phenylalkylamines with differently substituted ketones. Relationships between substitution pattern and GluN2B affinity as well as selectivity towards σ1 and σ2 receptors were investigated. Two promising ligands (18a and 20c) were selected for further pharmacological evaluation. Besides a slight serotonin transporter (SERT), norepinephrine transporter (NET), and hERG affinity, they did not show interaction with other targets. Furthermore, the pKa value of a set fluorinated ligands, bearing the fluorine atom in different positions, was determined.

Keywords: GluN2B subunit; NMDA receptor; PET; benzo[7]annulen-7-amines; fluorinated side chains; receptor selectivity; structure affinity relationships.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amines / chemical synthesis*
  • Amines / chemistry
  • Amines / metabolism
  • Amines / pharmacology*
  • Chemistry Techniques, Synthetic
  • Halogenation*
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors*
  • Receptors, N-Methyl-D-Aspartate / metabolism
  • Substrate Specificity

Substances

  • Amines
  • NR2B NMDA receptor
  • Receptors, N-Methyl-D-Aspartate