Pharmacology of 5-chloro-7-trifluoromethyl-1,4-dihydro-2,3-quinoxalinedione: a novel systemically active ionotropic glutamate receptor antagonist.

5-Chloro-7-trifluoromethyl-1,4-dihydro-2,3-quinoxalinedione (ACEA-1011) has analgesic properties in animal models of tonic pain. To investigate the mechanisms underlying this effect we used electrical recording techniques to characterize the in vitro pharmacology of ACEA-1011 at mammalian glutamate receptors. Two preparations were used: Xenopus oocytes expressing rat brain receptors and cultured rat cortical neurons. Results showed that ACEA-1011 is a competitive antagonist at NMDA receptor glycine sites. Apparent antagonist affinities (Kb values) were 0.4 to 0.8 microM in oocytes and approximately 0.6 microM in neurons. IC50 values for ACEA-1011 against four binary subunit combinations of cloned rat NMDA receptors (NR1A/NR2A, 2B, 2C or 2D) ranged from 0.4 to 8 microM (1 microM glycine). The 20-fold variation in sensitivity was due to a combination of subunit-dependent differences in glycine and antagonist affinities; EC50 values for glycine ranged between 0.08 to 0.8 microM and Kb values for ACEA-1011 between 0.2 to 0.8 microM. In addition, ACEA-1011 inhibited AMPA-preferring non-NMDA receptors by competitive antagonism at glutamate binding sites. Kb values were 4 to 9 microM in oocytes and 9 to 10 microM in neurons. The ED50 for ACEA-1011 in a mouse maximum electroshock-induced seizure model was approximately 12 mg/kg i.v.. Our results indicate that ACEA-1011 is a systemically active broad selectivity ionotropic glutamate receptor antagonist.