Modification of the 4-phenylbutyl side chain of potent 3-benzazepine-based GluN2B receptor antagonists. Issue 16 (15th August 2019)

• Record Type: Journal Article
• Authors: Wagner, Marina; Schepmann, Dirk; Ametamey, Simon M.; Wünsch, Bernhard
• Is Part Of: Bioorganic & medicinal chemistry. Volume 27:Issue 16(2019)
• Page Start: 3559
• Page End: 3567
• Publication Date: 2019-08-15
• Subjects: Glutamate receptors -- NMDA receptor -- GluN2B antagonists -- Ifenprodil binding site -- 3-Benzazepines -- Arylbutynyl analogs -- Structure-affinity relationships -- Selectivity; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2019.06.035
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: Excitotoxicity driven by overactivation of NMDA receptors represents a major mechanism of acute and chronic neurological and neurodegenerative disorders. Negative allosteric modulators interacting with the ifenprodil binding site of the NMDA receptor are able to interrupt this ongoing neurodamaging process. Starting from the potent 3-benzazepine-1, 7-diol4a novel NMDA receptor antagonists were designed by modification of the N-(4-phenylbutyl) side chain. With respect to developing novel fluorinated PET tracers, regioisomeric fluoroethoxy derivatives11, 12, 14, and15 were synthesized. Analogs19 and20 with various heteroaryl moieties at the end of the N-side chain were prepared by Sonogashira reaction and nucleophilic substitution. The fluoroethyl triazole37 was obtained by 1, 3-dipolar cycloaddition. In several new ligands, the flexibility of the (hetero)arylbutyl side chain was restricted by incorporation of a triple bond. The affinity towards the ifenprodil binding site was tested in an established competition assay using [ 3 H]ifenprodil as radioligand. Introduction of a fluoroethoxy moiety at the terminal phenyl ring, replacement of the terminal phenyl ring by a heteroaryl ring and incorporation of a triple bond into the butyl spacer led to considerable reduction of GluN2B affinity. The phenol15 ( Ki = 193 nM) bearing a p -fluoroethoxy moiety at the terminal phenyl ring represents the most promising GluN2B ligand of this series of compounds. With exception of15 showing moderate σ2 affinity ( K i = 79 nM), the interaction of synthesized 3-benzazepines towards the PCP binding site of the NMDA receptor, σ1 and σ2 receptors was rather low (Ki > 100 nM).