2-Methyltetrahydro-3-benzazepin-1-ols – The missing link in SAR of GluN2B selective NMDA receptor antagonists. Issue 2 (15th January 2018)

• Record Type: Journal Article
• Authors: Dey, Sougata; Schepmann, Dirk; Wünsch, Bernhard
• Is Part Of: Bioorganic & medicinal chemistry. Volume 26:Issue 2(2018)
• Page Start: 501
• Page End: 508
• Publication Date: 2018-01-15
• Subjects: 2-Methyltetrahydro-3-benzazepin-1-ol -- NMDA receptor -- GluN2B selective NMDA receptor antagonist -- Intramolecular Friedel-Crafts acylation -- N-Triflyl deprotection -- Radioligand receptor binding studies -- GluN2B affinity, pharmacophore based docking studies; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2017.12.010
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: The NMDA receptor containing GluN2B subunits represents a promising target for the development of drugs for the treatment of various neurological disorders including neurodegenerative diseases. In order to study the role of CH3 and OH moieties trisubstituted tetrahydro-3-benzazepines 4 were designed as missing link between tetra- and disubstituted 3-benzazepines 2 and 5 . The synthesis of 4 comprises eight reaction steps starting from alanine. The intramolecular Friedel-Crafts acylation to obtain the ketone 12 and the base-catalyzed elimination of trifluoromethanesulfinate (CF3 SO2 − ) followed by NaBH4 reduction represent the key steps. The GluN2B affinity of the cis -configured 3-benzazepin-1-ol cis -4a with a 4-phenylbutyl side chain ( K i = 252 nM) is considerably lower than the GluN2B affinity of ( R, R )-2 (Ki = 17 nM) indicating the importance of the phenolic OH moiety for the interaction with the receptor protein. Introduction of an additional CH3 moiety in 2-position led to a slight decrease of GluN2B affinity as can be seen by comparing the affinity data of cis- 4a and 5 . The homologous phenylpentyl derivative cis- 4b shows the highest GluN2B affinity ( K i = 56 nM) of this series of compounds. According to docking studies cis -4a adopts the same binding mode as the cocrystallized ligand ifenprodil-keto 1A and 5 at the interface of the GluN2B and GluN1a subunits. The same crucial H-bonds are formed between the C(O)NH2 moiety of Gln110 within the GluN2B subunit and the protonated amino moiety and the OH moiety of ( R, R )- cis -4a .