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

• Published in: British Journal of Pharmacology
• Main Authors: Potschka, H, Löscher, W, Wlaź, P, Behl, B, Hofmann, H P, Treiber, H‐J, Szabo, L
• Format: Article in Journal/Newspaper
• Language: English
• Published: Wiley 1998
• Subjects: Carbonic acid
• Online Access: http://dx.doi.org/10.1038/sj.bjp.0702172; https://api.wiley.com/onlinelibrary/tdm/v1/articles/10.1038%2Fsj.bjp.0702172; https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1038/sj.bjp.0702172

The aim of this study was to assess whether a drug which combines an antagonistic action at both NMDA and non‐NMDA receptors offers advantages for treatment of epileptic seizures compared to drugs which antagonize only one of these ionotropic glutamate receptors. The novel glutamate receptor antagonist LU 73068 (4,5‐dihydro‐1‐methyl‐4‐oxo‐7‐trifluoromethyl‐imidazo[1,2a]quinoxaline‐2‐carbonic acid) binds with high affinity to both the glycine site of the NMDA receptor ( K i 185 n m ) and to the AMPA receptor ( K i 158 n m ). Furthermore, binding experiments with recombinant kainate receptor subunits showed that LU 73068 binds to several of these subunits, particularly to rGluR7 ( K i 104 n m ) and rGluR5 ( K i 271 n m ). In comparison, the prototype non‐NMDA receptor antagonist NBQX (2,3‐dihydroxy‐6‐nitro‐7‐sulphamoyl‐benzo[f]quinoxaline) binds with high affinity to AMPA receptors only. Both NBQX and LU 73068 were about equieffective after i.p. injection in mice to block lethal convulsions induced by AMPA or NMDA. In the rat amygdala kindling model of temporal lobe epilepsy, LU 73068 dose‐dependently increased the focal seizure threshold (afterdischarge threshold, ADT). When rats were stimulated with a current 20% above the individual control ADT, LU 73068 completely blocked seizures with an ED 50 of 4.9 mg kg −1 . Up to 20 mg kg −1 , only moderate adverse effects, e.g. slight ataxia, were observed. NBQX, 10 mg kg −1 , and the glycine/NMDA site antagonist L‐701,324 (7‐chloro‐4‐hydroxy‐3‐(3‐phenoxy)phenyl‐quinoline‐2(1H)one), 2.5 or 5 mg kg −1 , exerted no anticonvulsant effects in kindled rats when administered alone, but combined treatment with both drugs resulted in a significant ADT increase. The data indicate that combination of glycine/NMDA and non‐NMDA receptor antagonism in a single drug is an effective means of developing a potent and effective anticonvulsant agent. British Journal of Pharmacology (1998) 125 , 1258–1266; doi: 10.1038/sj.bjp.0702172