Tricyclic Quinoxalinediones, Aza-kynurenic Acids, and Indole-2- Carboxylic Acids as In Vivo Active NMDA-Glycine Antagonists

Abstract

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.

Drug Design, in Vitro Pharmacology, and Structure−Activity Relationships of 3-Acylamino-2-aminopropionic Acid Derivatives, a Novel Class of Partial Agonists at the Glycine Site on the N-Methyl-d-aspartate (NMDA) Receptor Complex

“…In particular, glycine has been shown to be a mandatory coagonist necessary for the opening of NMDA receptor ion channels. , The glycine recognition site, located on the NR1 subunit of the NMDA receptor complex, can be distinguished from the inhibitory glycine receptor by its insensitivity to strychnine. It has attracted considerable interest as a potential drug target, as an alternative to the NMDA recognition site itself. ,, A great number of glycine site antagonists from different structural classes have been described in recent years. − However, serious side effects (e.g., memory impairment, neurotoxic or psychotomimetic effects) have been observed with the use of competitive or channel blocking NMDA receptor antagonists in animal models and/or in human clinical trials . Since glycine is an obligatory coagonist, one would expect the same to happen from an antagonist blocking the glycine site.…”

“…1,4,5 A great number of glycine site antagonists from different structural classes have been described in recent years. [6][7][8][9][10][11][12][13][14][15][16][17] However, serious side effects (e.g., memory impairment, neurotoxic or psychotomimetic effects) have been observed with the use of competitive or channel blocking NMDA receptor antagonists in animal models and/or in human clinical trials. 18 Since glycine is an obligatory coagonist, one would expect the same to happen from an antagonist blocking the glycine site.…”

Synthesis of 3,4-dihydro-2H-1,2-benzothiazine-3-carboxylic acid 1,1-dioxides and their evaluation as ligands for NMDA receptor glycine binding site

“…The presence of a co-agonist, which binds to a specific strychnine-insensitive glycine binding site (glycine B) of the NMDA receptor, is necessary for ion channel activity 5 . Therefore, the glycine binding site was perceived as a unique pharmacological target and several highly potent glycine binding site antagonists have been discovered [6][7][8] . As, unsurprisingly, glycine B antagonist pharmacophore 9 does not look like a brain penetrant, this was one of the reasons for low efficacy in vivo.…”