The N-methyl-D-aspartate (NMDA)-subtype of glutamate receptors has been well described as a result of the early appearance of NMDA antagonists, but no potent antagonist for the "non-NMDA" glutamate receptors has been available. Quinoxaline- diones have now been found to be potent and competitive antagonists at non-NMDA glutamate receptors. These compounds will be useful in the determination of the structure-activity relations of quisqualate and kainate receptors and the role of such receptors in synaptic transmission in the mammalian brain.
E XCITATORY AMINO ACIDS SUCH AS glutamate are major neurotransmitters in the mammalian central ner- vous system (1, 2). From electrophysiological (3, 4) and binding (5) studies there appear to be at least three major subtypes of receptors mediating the postsynaptic action of glutamate. Several classes of antagonists are available for the NMDA subtype (6), but there have been no potent and selective antagonists that both displace the binding of quisqualate or kainate, or both, and reduce their excitatory actions on central neurons. We report here two novel and potent non-NMDA receptor antagonists, 6,7-dinitro- quinoxaline-2,3-dione (DNQX, FG 9041) and 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, FG 9065) (Fig. 1). These non- NMDA receptor antagonists, DNQX and CNQX, inhibit [3H]AMPA ([3H]a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) binding to quisqualate receptors at submicromolar concentrations. They are one-fifth as effective at kainate receptors, and are considerably weaker at other bind- ing sites that include a range of neurotrans- mitter receptors. The compounds also selec- tively block the excitatory action of quisqualate and kainate on spinal neurons with little or no effect on that of NMDA.
Binding experiments were performed at 4ยฐC with extensively washed rat cortical membranes (7). We used [3H]kainate (5 nM) binding in 50 mM tris-citrate buffer to examine kainate receptors ' (8), and [3H]AMPA (5 nM) binding in 30 mM tris- HCI buffer with 2.5 mM CaCl2 and 100 mM potassium thiocyanide for quisqualate receptors (7). We studied NMDA receptors by using [3H]3-(2-carboxypiperazine-4yl)propyl-l-phosphonic acid (CPP) binding