論文

査読有り
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
  • Andre Benner
  • ,
  • Alessandro Bonifazi
  • ,
  • Chikako Shirataki
  • ,
  • Louisa Temme
  • ,
  • Dirk Schepmann
  • ,
  • Wilma Quaglia
  • ,
  • Osami Shoji
  • ,
  • Yoshihito Watanabe
  • ,
  • Constantin Daniliuc
  • ,
  • Bernhard Wuensch

9
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
DOI
https://doi.org/10.1002/cmdc.201300547
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/24677663
Web of Science
https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=JSTA_CEL&SrcApp=J_Gate_JST&DestLinkType=FullRecord&KeyUT=WOS:000333749200011&DestApp=WOS_CPL
ID情報
  • DOI : 10.1002/cmdc.201300547
  • ISSN : 1860-7179
  • eISSN : 1860-7187
  • PubMed ID : 24677663
  • Web of Science ID : WOS:000333749200011

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