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
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 antagoni...
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ftpubmed:oai:pubmedcentral.nih.gov:1565685 2023-05-15T15:52:59+02:00 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 Potschka, H Löscher, W Wlaź, P Behl, B Hofmann, H P Treiber, H-J Szabo, L 1998-11 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1565685 http://www.ncbi.nlm.nih.gov/pubmed/9863655 https://doi.org/10.1038/sj.bjp.0702172 en eng http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1565685 http://www.ncbi.nlm.nih.gov/pubmed/9863655 http://dx.doi.org/10.1038/sj.bjp.0702172 Copyright 1998, Nature Publishing Group Papers Text 1998 ftpubmed https://doi.org/10.1038/sj.bjp.0702172 2013-08-31T06:36:55Z 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 (Ki 185 nM) and to the AMPA receptor (Ki 158 nM). Furthermore, binding experiments with recombinant kainate receptor subunits showed that LU 73068 binds to several of these subunits, particularly to rGluR7 (Ki 104 nM) and rGluR5 (Ki 271 nM). 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 ED50 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. Text Carbonic acid PubMed Central (PMC) British Journal of Pharmacology 125 6 1258 1266 |
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Papers Potschka, H Löscher, W Wlaź, P Behl, B Hofmann, H P Treiber, H-J Szabo, L 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 |
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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 (Ki 185 nM) and to the AMPA receptor (Ki 158 nM). Furthermore, binding experiments with recombinant kainate receptor subunits showed that LU 73068 binds to several of these subunits, particularly to rGluR7 (Ki 104 nM) and rGluR5 (Ki 271 nM). 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 ED50 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. |
format |
Text |
author |
Potschka, H Löscher, W Wlaź, P Behl, B Hofmann, H P Treiber, H-J Szabo, L |
author_facet |
Potschka, H Löscher, W Wlaź, P Behl, B Hofmann, H P Treiber, H-J Szabo, L |
author_sort |
Potschka, H |
title |
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 |
title_short |
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 |
title_full |
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 |
title_fullStr |
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 |
title_full_unstemmed |
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 |
title_sort |
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 |
publishDate |
1998 |
url |
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1565685 http://www.ncbi.nlm.nih.gov/pubmed/9863655 https://doi.org/10.1038/sj.bjp.0702172 |
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Carbonic acid |
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Carbonic acid |
op_relation |
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1565685 http://www.ncbi.nlm.nih.gov/pubmed/9863655 http://dx.doi.org/10.1038/sj.bjp.0702172 |
op_rights |
Copyright 1998, Nature Publishing Group |
op_doi |
https://doi.org/10.1038/sj.bjp.0702172 |
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British Journal of Pharmacology |
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125 |
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6 |
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1258 |
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1266 |
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1766388063757402112 |