LU-73068, A NEW NON-NMDA AND GLYCINE NMDA RECEPTOR ANTAGONIST - PHARMACOLOGICAL CHARACTERIZATION AND COMPARISON WITH NBQX AND L-701,324 IN THE KINDLING MODEL OF EPILEPSY/

1 The aim of this study was to assess whether a drug which combines an antagonistic action at both NMDA and non-NMDA receptors offers advant ages for treatment of epileptic seizures compared to drugs which antag onize only one of these ionotropic glutamate receptors. 2 The novel gl utamate receptor antagonist LU 73068 rifluoromethyl-imidazo[1,2a]quino xaline-2-carbonic acid) binds with high affinity to both the glycine s ite of the NMDA receptor (K-i 185 nM) and to the AMPA receptor (K-i 15 8 nM). Furthermore, binding experiments with recombinant kainate recep tor subunits showed that LU 73068 binds to several of these subunits, particularly to rGluR7 (K-i 104 nM) and rGluR5 (K-i 271 nM). In compar ison, the prototype non-NMDA receptor antagonist NBQX ihydroxy-6-nitro -7-sulphamoyl-benzo[f]quinoxaline) binds with high affinity to AMPA re ceptors only.3 Both NBQX and LU 73068 were about equieffective after i .p. injection in mice to block lethal convulsions induced by AMPA or N MDA. 4 In the rat amygdala kindling model of temporal lobe epilepsy, L U 73068 dose-dependently increased the focal seizure threshold (afterd ischarge threshold, ADT). When rats were stimulated with a current 20% above the individual control ADT, LU 73068 completely blocked seizure s with an ED50 of 4.9 mg kg(-1). 5 Up to 20 mg kg(-1), only moderate a dverse effects, e.g. slight ataxia, were observed. 6 NBQX, 10 mg kg(-1 ), and the glycine/NMDA site antagonist L-701,324 4-hydroxy-3-(3-pheno xy)phenyl-quinoline-2(1H)one), 2.5 or 5 mg kg(-1), exerted no anticonv ulsant effects in kindled rats when administered alone, but combined t reatment with both drugs resulted in a significant ADT increase. 7 The data indicate that combination of glycine/NMDA and non-NMDA receptor antagonism in a single drug is an effective means of developing a pote nt and effective anticonvulsant agent.