A series of tricyclic indole-2-carboxylic acid derivatives were synthesized and evaluated by the radioligand binding assay and the anticonvulsant effects in the mouse NMDA-induced seizure model. Among them, derivatives of 3S-(-)-4 such as 3a, 3f, and 3g which had certain zwitterionic anilides showed high affinity to the NMDA-glycine binding site. The absolute configuration of 3S-(-)-4 was confirmed by X-ray crystallographic analysis. In particular, 3g (SM-31900) was found to be a highly active glycine antagonist for both in vitro and in vivo assays (K(i) = 1.0 +/- 0.1 nM, ED(50) = 2.3 mg/kg, iv) and also showed high selectivity for the glycine site. In addition, 3g was soluble enough in aqueous media (>10 mg/mL at pH 7.4) to use for medications by intravenous injection.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1021/jm020239l | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Tricyclic quinoxalinediones, aza-kynurenic acids, and indole-2-carboxylic acids as in vivo active NMDA-glycine antagonists.
Curr Top Med Chem
August 2006
Drug Research Division and Technology Research and Development Center, Dainippon Sumitomo Pharma Co., Ltd., Konohana-Ku, Osaka, Japan.
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.
View Article and Find Full Text PDFTricyclic indole-2-carboxylic acids: highly in vivo active and selective antagonists for the glycine binding site of the NMDA receptor.
J Med Chem
February 2003
Research Division, Sumitomo Pharmaceuticals Co., Ltd, 1-98 Kasugadenaka 3-chome, Konohana-ku, Osaka 554-0022, Japan.
A series of tricyclic indole-2-carboxylic acid derivatives were synthesized and evaluated by the radioligand binding assay and the anticonvulsant effects in the mouse NMDA-induced seizure model. Among them, derivatives of 3S-(-)-4 such as 3a, 3f, and 3g which had certain zwitterionic anilides showed high affinity to the NMDA-glycine binding site. The absolute configuration of 3S-(-)-4 was confirmed by X-ray crystallographic analysis.
View Article and Find Full Text PDFSynthesis of tricyclic indole-2-carboxylic [correction of caboxylic] acids as potent NMDA-glycine antagonists.
J Org Chem
May 2001
Research Division, Sumitomo Pharmaceuticals Co., Ltd, 1-98 Kasugadenaka 3-chome, Konohana-ku, Osaka 554-0022, Japan.
The practical synthesis of a series of tricyclic indole-2-carboxylic acids, 7-chloro-3-arylaminocarbonylmethyl-1,3,4,5-tetrahydrobenz[cd]indole-2-carboxylic acids, as a new class of potent NMDA-glycine antagonists is described. The synthetic route to the key intermediate 12a comprises a regioselective iodination of 4-chloro-2-nitrotoluene, modified Reissert indole synthesis, Jeffery's Heck-type reaction with allyl alcohol, Wittig-Horner-Emmons reaction, and iodination at the indole C-3 position. The key step in the route is an intramolecular cyclization of 12a to give the tricyclic indole structure.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!