AMPA Receptor Antagonists

The most commonly used AMPA receptor antagonists are the quinoxiline derivatives CNQX and NBQX, which show a 20-150 fold selectivity for AMPA over kainate receptor subunits. A further useful antagonist is (R)-3,4-DCPG. This compound has no detectable antagonist activity at kainate receptors, although it is active at NMDA receptors. However, this cross-reactivity is easily overcome by the use of AP-5, a selective NMDA receptor antagonist. A compound that has been synthesised recently, LY293558, shows good selectivity for AMPA receptors over GluR6 homomeric channels and GluR7/KA-2 heteromeric channels. However, this compound, based on the decxahydroisoquinoline structural motif is active at GluR5 homomeric receptor channels with a similar Ki to AMPA receptor channels. This may reveal a template for the synthesis of kainate selective compounds (see LY382884 below).

Another useful antagonist is GYKI53655, a non-competitive antagonist that shows good selectivity for AMPA receptors over kainate receptors. This compound can thus be used to distinguish these two receptor subtypes. Cyclothiazide, another commonly used modulator of AMPA/kainate receptors, blocks receptor desensitisation and thus potentiates the current passed by these receptor channels.