Selective NR1/2B N-Methyl-D-aspartate Receptor Antagonists among Indole-2-carboxamides and Benzimidazole-2-carboxamides
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文摘
(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 ofthe NMDA receptor. To establish the structure-activity relationship (SAR) and to attempt the improvementof the ADME properties of the lead, a series of compounds were prepared and tested. Several derivativesshowed low nanomolar activity both in the binding and in the functional assay. In a formalin-inducedhyperalgesia 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 developedbased on binding data of a series of indole- and benzimidazole-2-carboxamides.