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

Abstract

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.

Design, Synthesis, Pharmacological Evaluation and Docking Studies of GluN2B‐Selective NMDA Receptor Antagonists with a Benzo[7]annulen‐7‐amine Scaffold

“…In as econd functional assay,t he cytoprotectivee ffect of the GluN2B antagonists 7c, 15 c, 16 c, 16 d and 22 c was recorded and compared with the cytoprotective effect of 1.I nt his assay mouse fibroblast L(tkÀ)c ells stably transfectedw ithG luN1a/ GluN2B-subunit-containing NMDA receptors were incubated with glutamate and glycine, which results in cell death.T he protectiveeffects of the test compound in the presence of glutamateand glycine was measured. [18,30] In accordance with the resultso ft he electrophysiological assay,t he high-affinity ligands 7c, 15 c,a nd 22 c even at the high concentrations of 10 and 100 mm could not protect the cells against the cytotoxic effects of glutamate and glycine. (Figure 5, Table 2).…”

Synthesis and Pharmacological Evaluation of Enantiomerically Pure GluN2B Selective NMDA Receptor Antagonists

“…Both the phenol rac-3 and the methyl ether rac-4 revealed high selectivity against ap anel of selected receptors, ion channels, and enzymes. [14][15][16] In in vivo experiments with mice racemic phenol rac-3 was well tolerated, and showeda nalgesic activity in the formalin assay. [15] Furthermore, promising properties of phenol rac-3 were found during treatment of immunemediated and inflammatoryC NS diseases.…”

Fluorinated GluN2B Receptor Antagonists with a 3‐Benzazepine Scaffold Designed for PET Studies

“…HPLC method for determinationofpurity 7-(Benzyloxy)-3-tosyl-2,3,4,5-tetrahydro-3-benzazepin-1-one (7) and 9-hydroxy-3-tosyl-2,3,4,5-tetrahydro-3-benzazepin-1-one (8):T he acid 6 (1.0 g, 2.28 mmol, 1.0 equiv) was dissolved in CH 2 Cl 2 (80 mL) and the solution was cooled to À15 8C. C 27 7-(Benzyloxy)-1-fluoro-3-(4-phenylbutyl)-2,3,4,5-tetrahydro-1H-3benzazepine (13):D AST (0.08 mL, 0.61 mmol, 4.2 equiv) was dissolved under N 2 atmosphere in absolute CH 2 Cl 2 (10 mL) at À78 8C. Afterward SnCl 4 (1.0 mL, 8.55 mmol, 3.75 equiv) was slowly added and the solution was stirred for 18 h at À15 8C.…”

“…[25] At first, toluenesulfonylated (tosylated) glycine ester [26] was alkylated with benzyloxy-substituted 2-phenylethanol 4 under Mitsunobu conditions. [27] After saponification of the methyl ester 5,v ariousr eaction conditions were tried to perform the intramolecular Friedel-Crafts acylationo fc arboxylic acid 6.T reatment of acid 6 with trifluoroacetic anhydride for 30 min and subsequent addition of SnCl 4 afforded am ixture of 3-benzazepinones 7 and 8 in 39 %y ield. During formation of the regioisomer with adjacent carbonyla nd benzyloxy moieties, unexpected cleavage of the benzyle ther was observedl eading to phenol 8.A fter reduction of the mixture of ketones 7 and 8 with NaBH 4 ,a lcohols 9 and 10 were separatedb yf lash chromatography.T he benzyl ether 9,w hich is the key intermediate of this study,h ad already been prepared by cleavage of the methoxy analogue of benzyle ther 7 with AlCl 3 and subsequentb enzylation of the resultingp henol.…”

“…The residue was purified by flash column chromatography (1 = 2cm, l = 15 cm, v = 10 mL, cyclohexane/ ethyl acetate = 2:1+ 1% N,N-dimethylethanamine) to yield 12.C olorless oil, yield 207 mg (92 %). C 27 7-(Benzyloxy)-1-fluoro-3-(4-phenylbutyl)-2,3,4,5-tetrahydro-1H-3benzazepine (13):D AST (0.08 mL, 0.61 mmol, 4.2 equiv) was dissolved under N 2 atmosphere in absolute CH 2 Cl 2 (10 mL) at À78 8C. As olution of 12 (58.1 mg, 0.14 mmol, 1equiv) in CH 2 Cl 2 (1 mL) was added.…”