Tetrahydro-3-benzazepines with fluorinated side chains as NMDA and σ1 receptor antagonists: Synthesis, receptor affinity, selectivity and antiallodynic activity
| Autor: | Marta Pujol, Francisco R. Nieto, Eva Ayet, Bernhard Wünsch, Simone Thum, Simon M. Ametamey, Dirk Schepmann |
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| Rok vydání: | 2019 |
| Předmět: |
Pharmacology
0303 health sciences Benzazepines 010405 organic chemistry Stereochemistry Ligand Organic Chemistry Ether General Medicine 01 natural sciences 0104 chemical sciences 03 medical and health sciences chemistry.chemical_compound chemistry Drug Discovery Side chain Moiety NMDA receptor Receptor Selectivity 030304 developmental biology |
| Zdroj: | European Journal of Medicinal Chemistry. 177:47-62 |
| ISSN: | 0223-5234 |
| DOI: | 10.1016/j.ejmech.2019.05.034 |
| Popis: | 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 (Ki(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 (Ki(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. |
| Databáze: | OpenAIRE |
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