Design,Synthesis, and Biological Evaluation of 3‐Benzazepin‐1‐ols as NR2B‐Selective NMDA Receptor Antagonists |
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Authors: | Bastian Tewes Dr Bastian Frehland Dirk Schepmann Dr Kai‐Uwe Schmidtke Thomas Winckler Prof Dr Bernhard Wünsch Prof Dr |
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Affiliation: | 1. Institut für Pharmazeutische und Medizinische Chemie der Westf?lischen Wilhelms‐Universit?t Münster, Hittorfstra?e 58–62, 48149 Münster (Germany), Fax: (+49)?251‐8332144;2. Institut für Pharmazie der Friedrich‐Schiller‐Universit?t Jena, Semmelweisstra?e 10, 07743 Jena (Germany) |
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Abstract: | Cleavage and reconstitution of a bond in the piperidine ring of ifenprodil ( 1 ) leads to 7‐methoxy‐2,3,4,5‐tetrahydro‐1H‐3‐benzazepin‐1‐ols, a novel class of NR2B‐selective NMDA receptor antagonists. The secondary amine 7‐methoxy‐2,3,4,5‐tetrahydro‐1H‐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, Ki=5.4 nM ) and the conformationally restricted 4‐phenylcyclohexyl derivative 31 (Ki=10 nM ) represent the most potent NR2B ligands of this series. Whereas 13 shows excellent selectivity, the 4‐phenylcyclohexyl derivative 31 also interacts with σ1 (Ki=33 nM ) and σ2 receptors (Ki=82 nM ). In the excitotoxicity assay the phenylbutyl derivative 13 inhibits the glutamate‐induced cytotoxicity with an IC50 value of 360 nM , indicating that 13 is an NMDA antagonist. |
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Keywords: | 3‐benzazepines functional activity medicinal chemistry NR2B‐selective NMDA antagonists structure– affinity relationships |
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