Abstract
(4-Benzylpiperidine-1-yl)-(6-hydroxy-1H-indole-2-yl)-methanone (6a) derived from (E)-1-(4-benzylpiperidin-1-yl)-3-(4-hydroxy-phenyl)-propenone (5) was identified as a potent NR2B subunit-selective antagonist of the NMDA receptor. To establish the structure-activity relationship (SAR) and to attempt the improvement of the ADME properties of the lead, a series of compounds were prepared and tested. Several derivatives showed low nanomolar activity both in the binding and in the functional assay. In a formalin-induced hyperalgesia model in mice, 6a and (4-benzylpiperidine-1-yl)-[5(6)-hydroxy-1H-benzimidazol-2-yl]-methanone (60a) were as active as besonprodil (2) after oral administration. A CoMSIA model was developed based on binding data of a series of indole- and benzimidazole-2-carboxamides.
MeSH terms
-
Analgesics / chemical synthesis*
-
Analgesics / chemistry
-
Analgesics / pharmacology
-
Animals
-
Benzimidazoles / chemical synthesis*
-
Benzimidazoles / chemistry
-
Benzimidazoles / pharmacology
-
Calcium / metabolism
-
Cells, Cultured
-
In Vitro Techniques
-
Indoles / chemical synthesis*
-
Indoles / chemistry
-
Indoles / pharmacology
-
Intracellular Space / metabolism
-
Male
-
Mice
-
Models, Molecular
-
Pain Measurement
-
Patch-Clamp Techniques
-
Piperazines / chemical synthesis*
-
Piperazines / chemistry
-
Piperazines / pharmacology
-
Prosencephalon / cytology
-
Prosencephalon / metabolism
-
Quantitative Structure-Activity Relationship
-
Radioligand Assay
-
Rats
-
Rats, Wistar
-
Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors*
Substances
-
(4-benzylpiperidin-1-yl)-(5(6)-hydroxy-1H-benzimidazol-2-yl)methanone
-
(4-benzylpiperidin-1-yl)-(6-hydroxy-1H-indol-2-yl)methanone
-
Analgesics
-
Benzimidazoles
-
Indoles
-
NR1 NMDA receptor
-
NR2B NMDA receptor
-
Piperazines
-
Receptors, N-Methyl-D-Aspartate
-
Calcium