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 in | European journal of medicinal chemistry Vol. 177; pp. 47 - 62 |
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Main Authors | , , , , , , |
Format | Journal Article |
Language | English |
Published |
ISSY-LES-MOULINEAUX
Elsevier
01.09.2019
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Subjects | |
Online Access | Get full text |
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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. |
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ISSN: | 0223-5234 1768-3254 |
DOI: | 10.1016/j.ejmech.2019.05.034 |