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Design, Synthesis, Pharmacological Evaluation and Docking Studies of GluN2B‐Selective NMDA Receptor Antagonists with a Benzo[7]annulen‐7‐amine Scaffold
Author(s) -
Gawaskar Sandeep,
Temme Louisa,
Schreiber Julian A.,
Schepmann Dirk,
Bonifazi Alessandro,
Robaa Dina,
Sippl Wolfgang,
StrutzSeebohm Nathalie,
Seebohm Guiscard,
Wünsch Bernhard
Publication year - 2017
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201700311
Subject(s) - moiety , chemistry , stereochemistry , nmda receptor , amine gas treating , docking (animal) , receptor , biochemistry , medicine , nursing , organic chemistry
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.