Comparison of binding at strychnine-sensitive (inhibitory glycine receptor) and strychnine-insensitive ( [formula omitted] receptor) glycine binding sites

Abstract

We compared, for a number of ligands to the two receptors, the displacement of [ 3H]strychnine binding to the glycine-gated chloride channel of spinal cord and brainstem synaptic membranes to the displacement of [ 3H]glycine binding to the NMDA receptor complex of hippocampal and cortex synaptic membranes. Glycine and β-alanine are recognized by both receptors. In the NMDA receptor glycine antagonists, the kynurenic acids, most of the quinoxalinediones, and the ( R)-enantiomer of HA-966 had little affinity at the strychnine-sensitive site. Surprisingly, the quinoxalinedione widely used as an AMPA (α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) receptor antagonist, NBQX (2,3-dihydro-6-nitro-sulfamoylbenzo[f]quinoxaline-2,3-dione) displaced [ 3H]strychnine binding (IC 50 = 11 μM) and to a lesser extent [ 3H]glycine binding (IC 50 = 119 μM). Of the compounds tested, only strychnine, brucine, taurine and ( S)-HA-966 were more potent displacers of [ 3H]strychnine than of glycine binding. Generally, the two glycine recognition sites appear to have remarkably different structural requirements.