Replacement of benzylic hydroxy group by vinyl or hydroxymethyl moiety at the 3-benzazepine scaffold retaining GluN2B affinity

Since overactivation of NMDA receptors is associated with neurodegenerative disorders, the design and development of subunit-selective NMDA receptor antagonists are of great interest. In order to avoid the formation of quinone-like intermediates as starting point for degradation the benzylic OH group of the lead compounds 2 was replaced by an electron rich vinyl or homologous hydroxymethyl moiety. The Bi(OTf)₃ catalyzed intramolecular Friedel-Crafts alkylation of 9a represents the key step in the synthesis of 1-vinyl substituted tetrahydro-3-benzazepine 10. Ozonolysis of 10 and subsequent reduction led to the hydroxymethyl derivative 14. The GluN2B affinities of the methyl ethers 2a, 3a and 4a and phenols 2b and 3b are very similar, respectively. It can be concluded that the ifenprodil binding site of GluN2B subunit containing NMDA receptors well tolerates a vinyl or hydroxymethyl moiety instead of the benzylic OH group. However, the selectivity has to improved, since the σ₁ affinity of the new ligands is higher than their GluN2B affinity.