2014年4月
GluN2B-Selective N-Methyl-d-aspartate ( NMDA) Receptor Antagonists Derived from 3-Benzazepines: Synthesis and Pharmacological Evaluation of Benzo[7] annulen-7-amines
CHEMMEDCHEM
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- 巻
- 9
- 号
- 4
- 開始ページ
- 741
- 終了ページ
- 751
- 記述言語
- 英語
- 掲載種別
- 研究論文(学術雑誌)
- DOI
- 10.1002/cmdc.201300547
- 出版者・発行元
- WILEY-V C H VERLAG GMBH
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 (10b). The final reaction steps comprise hydrolysis of the amide, reduction of the ketone, and reductive alkylation, leading to cis- and trans-configured 7-(-phenylalkylamino)benzo[7]annulen-5-ols. High GluN2B affinity was observed with cis-configured -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 (20a, K-i=10nM) and 2-methoxy-N-methyl-N-(3-phenylpropyl)-6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-amine (23a, K-i=7.9nM). The selectivity over related receptors (phencyclidine binding site of the NMDA receptor, sigma(1) and sigma(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.
- リンク情報
- ID情報
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- DOI : 10.1002/cmdc.201300547
- ISSN : 1860-7179
- eISSN : 1860-7187
- PubMed ID : 24677663
- Web of Science ID : WOS:000333749200011