Neuroprotective effects of RPR 104632, a novel antagonist at the glycine site of the NMDA receptor, in vitro

The NMDA antagonist and neuroprotective effects of RPR 104632 (2 H-1,2,4-benzothiadiazine-1-dioxide-3-carboxylic acid), a new benzothiadiazine derivative, with affinity for the glycine site of the NMDA receptor-channel complex are described. RPR 104632 antagonized the binding of [ 3H]5,7-dichlorokyn...

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Bibliographic Details
Published in:European journal of pharmacology 1996-04, Vol.300 (3), p.237-246
Main Authors: Boireau, Alain, Malgouris, Christiane, Burgevin, Marie-Claude, Pény, Colette, Durand, Gabrielle, Bordier, Françoise, Meunier, Mireille, Miquet, Jean Marie, Daniel, Marc, Chevet, Thierry, Jimonet, Patrick, Mignani, Serge, Blanchard, Jean-Charles, Doble, Adam
Format: Article
Language:English
Subjects:
Aminoquinolines
Animals
Benzothiadiazines - pharmacology
Binding, Competitive
Biological and medical sciences
Cerebral Cortex - drug effects
Cyclic GMP - biosynthesis
Excitatory Amino Acid Antagonists - metabolism
Glutamate
Glycine receptor antagonist
Hippocampus - drug effects
Hippocampus - physiology
In Vitro Techniques
Kynurenic Acid - analogs & derivatives
Kynurenic Acid - metabolism
Medical sciences
Nerve Degeneration
Neuropharmacology
Neuroprotective agent
Neurotoxicity
NMDA receptor-channel complex
Pharmacology. Drug treatments
Phencyclidine - analogs & derivatives
Phencyclidine - metabolism
Rats
Rats, Sprague-Dawley
Receptors, N-Methyl-D-Aspartate - metabolism
RPR 104632
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Summary:The NMDA antagonist and neuroprotective effects of RPR 104632 (2 H-1,2,4-benzothiadiazine-1-dioxide-3-carboxylic acid), a new benzothiadiazine derivative, with affinity for the glycine site of the NMDA receptor-channel complex are described. RPR 104632 antagonized the binding of [ 3H]5,7-dichlorokynurenic acid to the rat cerebral cortex, with a K i of 4.9 nM. This effect was stereospecific, since the (-)-isomer was 500-fold more potent than the (+)-isomer. The potent affinity of RPR 104632 for the glycine site was confirmed by the observation that RPR 104632 inhibited [ 3H] N-(1-(2-thienyl)cyclohexyl]-3,4-piperidine ([ 3H]TCP) binding in the presence of N-methyl- d-aspartate (NMDA) (IC 50 = 55 nM), whereas it had no effect on the competitive NMDA site or on the dissociative anaesthetic site. RPR 104632 inhibited the NMDA-evoked increase in guanosine 3′,5′-cyclic monophosphate (cGMP) levels of neonatal rat cerebellar slices (IC 50 = 890 nM) in a non-competitive manner and markedly reduced NMDA-induced neurotoxicity in rat hippocampal slices and in cortical primary cell cultures. These results suggest that RPR 104632 is a high-affinity specific antagonist of the glycine site coupled to the NMDA receptor channel with potent neuroprotective properties in vitro.
ISSN:0014-2999
1879-0712
DOI:10.1016/0014-2999(95)00780-6