Tetrahydro-3-benzazepines with fluorinated side chains as NMDA and sigma(1) receptor antagonists: Synthesis, receptor affinity, selectivity and antiallodynic activity

The class of tetrahydro-1H-3-benzazepines was systematically modified in 1-, 3- and 7-position. In particular, a F-atom was introduced in beta- or gamma-position of the 4-phenylbutyl side chain in 3-position. Ligands with the F-atom in gamma-position possess higher GluN2B affinity than analogs beari...

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Published inEuropean journal of medicinal chemistry Vol. 177; pp. 47 - 62
Main Authors Thum, Simone, Schepmann, Dirk, Ayet, Eva, Pujol, Marta, Nieto, Francisco R., Ametamey, Simon M., Wuensch, Bernhard
Format Journal Article
LanguageEnglish
Published ISSY-LES-MOULINEAUX Elsevier 01.09.2019
Subjects
Chemistry, Medicinal
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Science & Technology
TARGET
GLUN2B SUBUNIT
ANALOGS
Tetrahydro-3-benzazepines
MODULATORS
Fluorinated side chain
GluN2B subunit selective NMDA receptor antagonist
IFENPRODIL
sigma receptor selectivity
NR2B
CHAPERONES
Structure activity relationships
PHARMACOLOGY
BIOLOGICAL EVALUATION
Receptor selectivity
Antiallodynic activity
NMDA receptor
BINDING
PET
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Summary:The class of tetrahydro-1H-3-benzazepines was systematically modified in 1-, 3- and 7-position. In particular, a F-atom was introduced in beta- or gamma-position of the 4-phenylbutyl side chain in 3-position. Ligands with the F-atom in gamma-position possess higher GluN2B affinity than analogs bearing the F-atom in beta-position. This effect was attributed to the reduced basicity of beta-fluoro amines. 3-Benzazepines with a benzylic OH moiety show moderate GIuN2B affinity, but considerable selectivity over the sigma(2) receptor. However, removal of the benzylic OH moiety led to increased GluN2B affinity, but reduced GluN2B/sigma(2) selectivity. With respect to GluN2B affinity the phenol 17b with a gamma-fluorophenylbutyl moiety in 3position represents the most interesting fluorinated ligand (K-i(GluN2B) = 16 nM). Most of the synthesized ligands reveal either similar GluN2B and sigma(1) affinity or higher sigma(1) affinity than GluN2B affinity. The methyl ether 16b shows high sigma(1) affinity (K-i(sigma(i))= 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 sigma(1) antagonistic activity of 16b. (C) 2019 Elsevier Masson SAS. All rights reserved.
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2019.05.034