Evidence for direct interactions between the NMDA and glycine recognition sites in brain

The interaction between glycine and competitive N-methyl-D-aspartate (NMDA) antagonists was investigated. Glycine (IC 50 = 170 nM) partially (≈ 60%) inhibited [ 3H]CGS-19755 ((±)-4-phosphonomethyl-2-piperdine carboxylic acid), but not [ 3H]CPP (3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid) binding. The action of glycine was mimicked by D-serine and antagonized by 7-chlorokynurenate. CGS-19755 (IC 50 = 230 nM) partially inhibited [ 3H]glycine binding from strychnine-insensitive sites: this effect was antagonized by NMDA. CPP and NPC 12626 (2-amino-4,5-(1,2-cyclohexyl)-7-phosphonoheptanoic acid) inhibited [ 3H]glycine binding, but only at concentrations 100- to 1000-fold greater than required to displace [ 3H]CGS-19755 or [ 3H]CPP. These data provide the first evidence for bidirectional interactions between glycine and NMDA recognition sites and suggest pharmacological differences among competitive NMDA antagonists.