Effect of plasma protein binding on in vivo activity and brain penetration of glycine/NMDA receptor antagonists

…, S Grimwood, R Hargreaves, C Hurley…

文献索引：Rowley, Michael; Kulagowski, Janusz J.; Watt, Alan P.; Rathbone, Denise; Stevenson, Graeme I.; Carling, Robert W.; Baker, Raymond; Marshall, George R.; Kemp, John A.; Foster, Alan C.; Grimwood, Sarah; Hargreaves, Richard; Hurley, Catherine; Saywell, Kay L.; Tricklebank, Mark D.; Leeson, Paul D. Journal of Medicinal Chemistry, 1997 , vol. 40, # 25 p. 4053 - 4068

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被引用次数: 135

摘要

A major issue in designing drugs as antagonists at the glycine site of the NMDA receptor has been to achieve good in vivo activity. A series of 4-hydroxyquinolone glycine antagonists was found to be active in the DBA/2 mouse anticonvulsant assay, but improvements in in vitro affinity were not mirrored by corresponding increases in anticonvulsant activity. Here we show that binding of the compounds to plasma protein limits their brain penetration. ...