Neuroprotective effects of RPR 104632, a novel antagonist at the glycine site of the NMDA receptor, in vitro
| Autor: | Jean Marie Miquet, Marie-Claude Burgevin, M. Daniel, C. Malgouris, Mireille Meunier, Francoise Bordier, Colette Peny, Gabrielle Durand, Adam Doble, Jean-Charles Blanchard, Alain Boireau, Thierry Chevet, Serge Mignani, Patrick Jimonet |
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| Rok vydání: | 1996 |
| Předmět: |
Stereochemistry
Phencyclidine Guanosine In Vitro Techniques Pharmacology Biology Benzothiadiazines Kynurenic Acid Binding Competitive Hippocampus Receptors N-Methyl-D-Aspartate Neuroprotection Rats Sprague-Dawley chemistry.chemical_compound stomatognathic system medicine Animals Cyclic GMP Cerebral Cortex Antagonist Glycine receptor antagonist Rats Mechanism of action chemistry Benzothiadiazine Nerve Degeneration Glycine Aminoquinolines NMDA receptor medicine.symptom Excitatory Amino Acid Antagonists |
| Zdroj: | European Journal of Pharmacology. 300:237-246 |
| ISSN: | 0014-2999 |
| DOI: | 10.1016/0014-2999(95)00780-6 |
| Popis: | The NMDA antagonist and neuroprotective effects of RPR 104632 (2H-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 Ki 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) (IC50 = 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 (IC50 = 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. |
| Databáze: | OpenAIRE |
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