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GluN2B‐Selective N ‐Methyl‐ d‐ aspartate (NMDA) Receptor Antagonists Derived from 3‐Benzazepines: Synthesis and Pharmacological Evaluation of Benzo[7]annulen‐7‐amines
Author(s) -
Benner Andre,
Bonifazi Alessandro,
Shirataki Chikako,
Temme Louisa,
Schepmann Dirk,
Quaglia Wilma,
Shoji Osami,
Watanabe Yoshihito,
Daniliuc Constantin,
Wünsch Bernhard
Publication year - 2014
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201300547
Subject(s) - chemistry , stereochemistry , phencyclidine , nmda receptor , moiety , ifenprodil , receptor , biochemistry
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‐ m ethoxy‐5‐oxo‐6,7,8,9‐tetrahydro‐5 H ‐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‐5 H ‐benzo[7]annulen‐7‐amine ( 20 a , K i =10 n M ) and 2‐methoxy‐ N ‐methyl‐ N ‐(3‐phenylpropyl)‐6,7,8,9‐tetrahydro‐5 H ‐benzo[7]annulen‐7‐amine ( 23 a , K i =7.9 n M ). The selectivity over related receptors (phencyclidine binding site of the NMDA receptor, σ 1 and σ 2 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.