TY - JOUR
T1 - Design, Synthesis, Pharmacological Evaluation and Docking Studies of GluN2B-Selective NMDA Receptor Antagonists with a Benzo[7]annulen-7-amine Scaffold
AU - Gawaskar, Sandeep
AU - Temme, Louisa
AU - Schreiber, Julian A.
AU - Schepmann, Dirk
AU - Bonifazi, Alessandro
AU - Robaa, Dina
AU - Sippl, Wolfgang
AU - Strutz-Seebohm, Nathalie
AU - Seebohm, Guiscard
AU - Wünsch, Bernhard
N1 - Publisher Copyright:
© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
PY - 2017/8/8
Y1 - 2017/8/8
N2 - 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-5H-benzo[7]annulen-7-amines with a 2-NO2 (7 c), 2-Cl (15 c), or 2-OBn group (22 c) show very high GluN2B affinity (Ki=1.6–3.6 nm). 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 (Ki=3.6 nm). 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 (Ki=28 and 21 nm, 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.
AB - 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-5H-benzo[7]annulen-7-amines with a 2-NO2 (7 c), 2-Cl (15 c), or 2-OBn group (22 c) show very high GluN2B affinity (Ki=1.6–3.6 nm). 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 (Ki=3.6 nm). 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 (Ki=28 and 21 nm, 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.
KW - docking studies
KW - GluN2B antagonists
KW - NMDA receptors
KW - selectivity
KW - structure–affinity relationships
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U2 - 10.1002/cmdc.201700311
DO - 10.1002/cmdc.201700311
M3 - Article
C2 - 28749574
AN - SCOPUS:85026430618
SN - 1860-7179
VL - 12
SP - 1212
EP - 1222
JO - ChemMedChem
JF - ChemMedChem
IS - 15
ER -