Tricyclic quinoxalinediones, aza-kynurenic acids, and indole-2-carboxylic acids as in vivo active NMDA-glycine antagonists.
This review article describes the development of in vivo active antagonists for the glycine binding site of the N-Methyl-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.
Nagata
Ryu
R
Drug Research Division and Technology Research and Development Center, Dainippon Sumitomo Pharma Co., Ltd., Konohana-Ku, Osaka, Japan. ryu-nagata@ds-pharma.co.jp
Katayama
Seiji
S
Ohtani
Ken-Ichi
K
Tanaka
Hiroyasu
H
Shimago
Kozo
K
D002264:Carboxylic Acids; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007736:Kynurenic Acid / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D011810:Quinoxalines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018009:Receptors, Glycine / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D002264:Carboxylic Acids; D007211:Indoles; D011810:Quinoxalines; D018009:Receptors, Glycine; C058980:indole-2-carboxylic acid; D007736:Kynurenic Acid