Selective NR1/2B N-Methyl-d-aspartate Receptor Antagonists among Indole-2-carboxamides and Benzimidazole-2-carboxamides

(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...

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Published in:Journal of medicinal chemistry 2007-03, Vol.50 (5), p.901-914
Main Authors: Borza, István, Bozó, Éva, Barta-Szalai, Gizella, Kiss, Csilla, Tárkányi, Gábor, Demeter, Ádám, Gáti, Tamás, Háda, Viktor, Kolok, Sándor, Gere, Anikó, Fodor, László, Nagy, József, Galgóczy, Kornél, Magdó, Ildikó, Ágai, Béla, Fetter, József, Bertha, Ferenc, Keserü, György M, Horváth, Csilla, Farkas, Sándor, Greiner, István, Domány, György
Format: Article
Language:English
Subjects:
Analgesics - chemical synthesis
Analgesics - chemistry
Analgesics - pharmacology
Animals
Benzimidazoles - chemical synthesis
Benzimidazoles - chemistry
Benzimidazoles - pharmacology
Biological and medical sciences
Calcium - metabolism
Cells, Cultured
Glutamatergic system (aspartate and other excitatory aminoacids)
In Vitro Techniques
Indoles - chemical synthesis
Indoles - chemistry
Indoles - pharmacology
Intracellular Space - metabolism
Male
Medical sciences
Mice
Models, Molecular
Neuropharmacology
Neurotransmitters. Neurotransmission. Receptors
Pain Measurement
Patch-Clamp Techniques
Pharmacology. Drug treatments
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
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Summary:(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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm060420k