GluN2B-selective N-methyl-d-aspartate (NMDA) receptor antagonists derived from 3-benzazepines: Synthesis and pharmacological evaluation of benzo[7]annulen-7-amines

Given their high neuroprotective potential, ligands that block GluN2B-containing N-methyl-D-aspartate (NMDA) receptors by interacting with the ifenprodil binding site located on the GluN2B subunit are of great interest for the treatment of various neuronal disorders. In this study, a novel class of GluN2B-selective NMDA receptor antagonists with the benzo[7]annulene scaffold was prepared and pharmacologically evaluated. The key intermediate, N-(2-methoxy-5-oxo-6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-yl)acetamide (11), was obtained by cyclization of 3-acetamido-5-(3-methoxyphenyl)pentanoic acid (10 b). The final reaction steps comprise hydrolysis of the amide, reduction of the ketone, and reductive alkylation, leading to cis- and trans-configured 7-(ω-phenylalkylamino)benzo[7]annulen-5-ols. High GluN2B affinity was observed with cis-configured γ-amino alcohols substituted with a 3-phenylpropyl moiety at the amino group. Removal of the benzylic hydroxy moiety led to the most potent GluN2B antagonists of this series: 2-methoxy-N-(3- phenylpropyl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-amine (20 a, K _i=10 nM) and 2-methoxy-N-methyl-N-(3-phenylpropyl)-6,7,8,9- tetrahydro-5H-benzo[7]annulen-7-amine (23 a, K_i=7.9 nM). The selectivity over related receptors (phencyclidine binding site of the NMDA receptor, σ₁ and σ₂ receptors) was recorded. In a functional assay measuring the cytoprotective activity of the benzo[7]annulenamines, all tested compounds showed potent NMDA receptor antagonistic activity. Cytotoxicity induced via GluN2A subunit-containing NMDA receptors was not inhibited by the new ligands. Benzylic OH not essential! A 10- to 11-step synthesis was performed to obtain cis- and trans-configured tetrahydrobenzo[7]annulenes with a 5-hydroxy moiety and various phenylalkylamino moieties at the 7-position. High affinity toward GluN2B-containing N-methyl-D-aspartate (NMDA) receptors was observed for cis-configured 3-phenylpropylamines. Unexpectedly, removal of the benzylic hydroxy group led to the most potent GluN2B antagonists of this series.