This review article describes the development of in vivo active antagonists for the glycine binding site of the NMethyl- D-Aspartate (NMDA) receptor. There were several difficulties in identifying a class of antagonists with in vivo efficacy and only a few compounds succeeded in emerging with activity in vivo. A series of tricyclic quinoxalinediones was highly potent glycine antagonists in vitro and the derivatives having a zwitterionic moiety including SM-18400 indeed showed in vivo activity. Similarly, tricyclic indole-2-carboxylic acids having a zwitterionic moiety such as SM- 31900 were also active in vivo. In fact, SM-18400 and SM-31900 exhibited efficacy in several animal stroke models using intravenous infusion protocols. The practical syntheses of SM-18400 and SM-31900 as well as the novel synthesis of moderately active glycine antagonists, tricyclic azakynurenic acids, were also developed.
Keywords: N-Methyl-D-Aspartate, NMDA-glycine antagonist, SM-18400, SM-31900, tricyclic quinoxalinedione, tricyclic indole-2-carboxylic acid
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