Enantiomerically Pure 2-Methyltetrahydro-3-benzazepin-1-ols Selectively Blocking GluN2B Subunit Containing N-Methyl-D-aspartate Receptors.

A chiral pool synthesis was developed to obtain all four stereoisomeric 2-methyl-3-(4-phenylbutyl)tetrahydro-3-benzazepin-1-ols 21, 31, and 32 in a seven- to eight-step sequence. The phenols 32 reveal slightly higher GluN2B affinity than the methyl ethers 21. The GluN2B affinity increases in the order (1R,2S) < (1S,2S) < (1S,2R) < (1R,2R). The stereoisomeric phenols (R,R)-32 and (S,R)-32 show the highest GluN2B affinity and the highest cytoprotective activity. Both compounds represent GluN2B selective allosteric NMDA receptor antagonists. Docking of the 3-benzazepin-1-ols into the ifenprodil binding site of the crystallized GluN1b/GluN2B N-terminal domains led to free binding energies, which correlate nicely with the experimentally determined GluN2B affinities. The similar GluN2B affinity of the stereoisomeric phenols (S,S)-32, (R,R)-32, and (S,R)-32 is explained by different binding modes of the 3-benzazepine scaffold. The benzyl ethers 31 reveal unexpectedly high GluN2B affinity but do not show cytoprotective effects. The additional benzyl moiety of 31 binds into a previously unrecognized lipophilic subpocket.