Selective NR1/2B N-methyl-D-aspartate receptor antagonists among indole-2-carboxamides and benzimidazole-2-carboxamides.

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.

• Authors: István Borza, Eva Bozó, Gizella Barta-Szalai, Csilla Kiss, Gábor Tárkányi, Adám Demeter, Tamás Gáti, Viktor Háda, Sándor Kolok, Anikó Gere, László Fodor, József Nagy, Kornél Galgóczy, Ildikó Magdó, Béla Agai, József Fetter, Ferenc Bertha, György M Keserü, Csilla Horváth, Sándor Farkas, István Greiner, György Domány
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 50 Issue 5 Pg. 901-14 (Mar 08 2007) ISSN: 0022-2623 [Print] United States
• PMID: 17290978 (Publication Type: Journal Article)

Chemical References

• (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

Topics

• Analgesics (chemical synthesis, chemistry, pharmacology)
• Animals
• Benzimidazoles (chemical synthesis, chemistry, pharmacology)
• Calcium (metabolism)
• Cells, Cultured
• In Vitro Techniques
• Indoles (chemical synthesis, chemistry, pharmacology)
• Intracellular Space (metabolism)
• Male
• Mice
• Models, Molecular
• Pain Measurement
• Patch-Clamp Techniques
• Piperazines (chemical synthesis, chemistry, pharmacology)
• Prosencephalon (cytology, metabolism)
• Quantitative Structure-Activity Relationship
• Radioligand Assay
• Rats
• Rats, Wistar
• Receptors, N-Methyl-D-Aspartate (antagonists & inhibitors)