title: 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.
authors.affiliation: Institut für Pharmazeutische und Medizinische Chemie der Universität, Münster, Corrensstraße 48, 48149 Münster (Germany).
authors.forename: Andre
authors.initials: A
authors.lastname: Benner
authors.forename: Alessandro
authors.initials: A
authors.lastname: Bonifazi
authors.forename: Chikako
authors.initials: C
authors.lastname: Shirataki
authors.forename: Louisa
authors.initials: L
authors.lastname: Temme
authors.forename: Dirk
authors.initials: D
authors.lastname: Schepmann
authors.forename: Wilma
authors.initials: W
authors.lastname: Quaglia
authors.forename: Osami
authors.initials: O
authors.lastname: Shoji
authors.forename: Yoshihito
authors.initials: Y
authors.lastname: Watanabe
authors.forename: Constantin
authors.initials: C
authors.lastname: Daniliuc
authors.forename: Bernhard
authors.initials: B
authors.lastname: Wünsch
mesh_terms: D000818:Animals; D001552:Benzazepines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001567:Benzocycloheptenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D001552:Benzazepines; D001567:Benzocycloheptenes; C121001:NR2B NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate
keywords: GluN2B; NDMA receptors; benzo[7]annulenamines; cytoprotective activity; selectivity; structure-affinity relationships