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Design, Synthesis, and Biological Evaluation of 3‐Benzazepin‐1‐ols as NR2B‐Selective NMDA Receptor Antagonists
Author(s) -
Tewes Bastian,
Frehland Bastian,
Schepmann Dirk,
Schmidtke KaiUwe,
Winckler Thomas,
Wünsch Bernhard
Publication year - 2010
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.201000005
Subject(s) - chemistry , nmda receptor , ifenprodil , stereochemistry , amine gas treating , derivative (finance) , selectivity , sigma receptor , glutamate receptor , receptor , biochemistry , organic chemistry , financial economics , economics , catalysis
Cleavage and reconstitution of a bond in the piperidine ring of ifenprodil ( 1 ) leads to 7‐methoxy‐2,3,4,5‐tetrahydro‐1 H ‐3‐benzazepin‐1‐ols, a novel class of NR2B‐selective NMDA receptor antagonists. The secondary amine 7‐methoxy‐2,3,4,5‐tetrahydro‐1 H ‐3‐benzazepin‐1‐ol ( 12 ), which was synthesized in six steps starting from 2‐phenylethylamine 3 , represents the central building block for the introduction of several N‐linked residues. A distance of four methylene units between the basic nitrogen atom and the phenyl residue in the side chain results in high NR2B affinity. The 4‐phenylbutyl derivative 13 (WMS‐1405, K i =5.4 n M ) and the conformationally restricted 4‐phenylcyclohexyl derivative 31 ( K i =10 n M ) represent the most potent NR2B ligands of this series. Whereas 13 shows excellent selectivity, the 4‐phenylcyclohexyl derivative 31 also interacts with σ 1 ( K i =33 n M ) and σ 2 receptors ( K i =82 n M ). In the excitotoxicity assay the phenylbutyl derivative 13 inhibits the glutamate‐induced cytotoxicity with an IC 50 value of 360 n M , indicating that 13 is an NMDA antagonist.