GluN2B‐Selective N‐Methyl‐d‐aspartate (NMDA) Receptor Antagonists Derived from 3‐Benzazepines: Synthesis and Pharmacological Evaluation of Benzo[7]annulen‐7‐amines

Abstract

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, Ki =10 nM) and 2-methoxy-N-methyl-N-(3-phenylpropyl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-amine (23 a, Ki =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.

Design, Synthesis, Pharmacological Evaluation and Docking Studies of GluN2B‐Selective NMDA Receptor Antagonists with a Benzo[7]annulen‐7‐amine Scaffold

“…Previous studies have shown that ap henylpropylamino group at 7-position is responsible for high GluN2B affinity. [20] To analyze the effects of various substituents at the 2-position, the phenylpropylamino moiety at the 7-position was kept almost un- Figure 2. Conformational restriction approach,starting from 2 to obtain benzo [7]annulen-7-amines 5c-7c.…”

“…5c [20] OCH 3 3-10 6c [21] H3-16 AE 40% 150 27 AE 12 7a [22] NO 2 1-7.6 AE 0.7 6% 21 AE 616 AE 2 7b [22] NO 2 2-3.3 AE 1.0 8% 20 AE 544 AE 25 7c [22] NO 2 3-1.6 AE 0.9 3% 18 AE 511 AE 4 7d [22] NO 2 other bindings ite at the same target protein. In ac ompetition assay with the radioligand [ 3 H](+)-MK-801 [24,25] the synthesized benzo [7]annulen-7-amines did not show any interaction with the PCP binding site.…”

“…Unexpectedly,r emoval of the methoxy substituent at 2-position (6c)r etained high GluN2B affinity (K i = 16 nm)a nd introduction of a nitro group at 2-position (7c)i ncreased the GluN2B affinity 10fold (K i = 1.6 nm). [20][21][22] This report is devoted to explore the effecto fv arious 2-substitutents on the GluN2B affinity and functional activity of benzo [7]annulen-7-amines taking variations of the N-substituents into account as well. The interactions of potent GluN2B selec- tive ligands with the GluN2B binding site will be analyzed on the molecular level by docking studies using the reported Xray crystal structure analysis.…”

Synthesis and pharmacological evaluation of fluorinated benzo[7]annulen‐7‐amines as GluN2B‐selective NMDA receptor antagonists

“…By a conformational restriction approach on the prototypical ligand ifenprodil ( 1 ), we obtained tetrahydro‐3‐benzazepines (including the recently reported [ 11 C]Me‐NB1 [ 11 C] 2 ) as well as benzo[7]annulen‐7‐amines ( 4 ) derived from Ro 25‐6981 ( 3 ) in a similar manner (Figure ) . Ligands of both compound classes possess high binding affinity towards the GluN2B subunit …”

Synthesis, GluN2B affinity and selectivity of benzo[7]annulen-7-amines

“…20 Stimulated by the high GluN2B affinity of 5, the pharmacological properties of various benzo [7]annulenamines 6 without a benzylic OH-moiety should be investigated. 21 Moreover, in the first series of ligands 6 the methoxy group in 2-position of 4 and 5 should be removed to analyze the contribution of this substituent to the GluN2B affinity and selectivity.…”