4-SUBSTITUTED-KYNURENIC ACID-DERIVATIVES - A NOVEL CLASS OF NMDA RECEPTOR GLYCINE SITE ANTAGONISTS

A series of 4-substituted-kynurenic acid derivatives possessing severa l different substituents at C4-position which are consisted of both a flexible propyloxy chain and an adjunct several type of carbonyl group s has been synthesized and evaluated for their in vitro antagonist act ivity at the glycine site on the NMDA receptor. Of them, N-benzoylthio urea 15c and N-phenylthiourea 15a were found to have the best in vitro binding affinity with IC50 of 3.95 and 6.04 mu M, respectively. On th e other hand, in compounds 12a similar to c and 13 the displacement of a thiourea group to an amide or a carbamate caused a significant decr ease of the in vitro binding affinity. In the SAR study of the 4-subst ituted kynurenic acid derivatives, it was realized that the terminal s ubstitution 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 kynu renic acid nucleus.