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

Abstract

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 (K_i(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 (K_i(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.