In:
ChemMedChem, Wiley, Vol. 12, No. 15 ( 2017-08-08), p. 1212-1222
Abstract:
Antagonists that selectively target GluN2B‐subunit‐containing N ‐methyl‐ d ‐aspartate (NMDA) receptors are of major interest for the treatment of various neurological disorders. In this study, relationships between variously substituted benzo[7]annulen‐7‐amines and their GluN2B affinity were investigated. 2‐Nitro‐5,6,8,9‐tetrahydrobenzo[7] annulen‐7‐one ( 8 ) represents the central building block for the introduction of various substituents at the 2‐position and various 7‐amino moieties. N ‐(3‐Phenylpropyl)‐6,7,8,9‐tetrahydro‐5 H ‐benzo[7]annulen‐7‐amines with a 2‐NO 2 ( 7 c ), 2‐Cl ( 15 c ), or 2‐OBn group ( 22 c ) show very high GluN2B affinity ( K i =1.6–3.6 n m ). Docking studies revealed the same binding poses for benzo[7]annulen‐7‐amines and ifenprodil at the interface of GluN1b and GluN2B subunits. The large 2‐OBn moiety of 22 c occupies a previously unrecognized subpocket, which explains its high GluN2B affinity ( K i =3.6 n m ). In two‐electrode voltage clamp experiments and cytoprotection assays, the high‐affinity GluN2B ligands 7 c , 15 c , and 22 c could not inhibit the glutamate‐/glycine‐evoked current and cytotoxic effects. However, the analogous phenols 16 c ((3‐phenylpropyl)amino moiety) and 16 d ((4‐phenylbutyl)amino moiety) with 10‐fold lower GluN2B affinity ( K i =28 and 21 n m , respectively) showed promising inhibition of glutamate‐/glycine‐evoked effects in both assays. The presence of a phenolic hydroxy group seems to be essential for inducing conformational changes of the receptor protein, which finally results in closure of the ion conduction pathway.
Type of Medium:
Online Resource
ISSN:
1860-7179
,
1860-7187
DOI:
10.1002/cmdc.201700311
Language:
English
Publisher:
Wiley
Publication Date:
2017
detail.hit.zdb_id:
2209649-8
SSG:
15,3
Bookmarklink