4-Substituted-kynurenic acid derivatives: A novel class of NMDA receptor glycine site antagonists

A series of 4-substituted-kynurenic acid derivatives possessing several different substituents at C4-position which are consisted of both a flexible propyloxy chain and an adjunct several type of carbonyl groups has been synthesized and evaluated for theirin vitro antagonist activity at the glycine site on the NMDA receptor. Of them, N-benzoylthiourea15c and N-phenylthiourea15a were found to have the bestin vitro binding affinity with IC(50) of 3.95 and 6.04 muM, respectively. On the other hand, in compounds12a approximately c and13 the displacement of a thiourea group to an amide or a carbamate caused a significant decrease of thein vitro binding affinity. In the SAR study of the 4-substituted kynurenic acid derivatives, it was realized that the terminal substitution pattern on a flexible C4-propyloxy chain of kynurenic acid nucleus significantly influences on the binding affinity for glycine site; the binding affinity to the NMDA receptor might be increased by the introduction of a suitable electron rich substituent at C4 of kynurenic acid nucleus.