Tricyclic Indole-2-carboxylic Acids:  Highly in Vivo Active and Selective Antagonists for the Glycine Binding Site of the NMDA Receptor

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-(−)-<BO>4</BO> such as <BO>3a</BO>, <BO>3f</BO>, and <BO>3g</BO> which had certain zwitterionic anilides showed high affinity to the NMDA-glycine binding site. The absolute configuration of 3S-(−)-<BO>4</BO> was confirmed by X-ray crystallographic analysis. In particular, <BO>3g</BO> (SM-31900) was found to be a highly active glycine antagonist for both in vitro and in vivo assays (K<INF>i</INF> = 1.0 ± 0.1 nM, ED<INF>50</INF> = 2.3 mg/kg, iv) and also showed high selectivity for the glycine site. In addition, <BO>3g</BO> was soluble enough in aqueous media (>10 mg/mL at pH 7.4) to use for medications by intravenous injection.