Comparison of the pharmacological properties of GK11 and MK801, two NMDA receptor antagonists: towards an explanation for the lack of intrinsic neurotoxicity of GK11.
J Neurochem
; 103(4): 1682-96, 2007 Nov.
Article
en En
| MEDLINE
| ID: mdl-17908242
Over-stimulation of NMDA receptors (NMDARs) is involved in many neurodegenerative disorders. Thus, developing safe NMDAR antagonists is of high therapeutic interest. GK11 is a high affinity uncompetitive NMDAR antagonist with low intrinsic neurotoxicity, shown to be promising for treating CNS trauma. In the present study, we investigated the molecular basis of its interaction with NMDARs and compared this with the reference molecule MK801. We show, on primary cultures of hippocampal neurons, that GK11 exhibits neuroprotection properties similar to those of MK801, but in contrast with MK801, GK11 is not toxic to neurons. Using patch-clamp techniques, we also show that on NR1a/NR2B receptors, GK11 totally blocks the NMDA-mediated currents but has a six-fold lower IC(50) than MK801. On NR1a/NR2A receptors, it displays similar affinity but fails to totally prevent the currents. As NR2A is preferentially localized at synapses and NR2B at extrasynaptic sites, we investigated, using calcium imaging and patch-clamp approaches, the effects of GK11 on either synaptic or extrasynaptic NMDA-mediated responses. Here we demonstrate that in contrast with MK801, GK11 better preserve the synaptic NMDA-mediated currents. Our study supports that the selectivity of GK11 for NR2B containing receptors accounts contributes, at least partially, for its safer pharmacological profile.
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Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Piperidinas
/
Maleato de Dizocilpina
/
Receptores de N-Metil-D-Aspartato
/
Antagonistas de Aminoácidos Excitadores
/
Ciclohexenos
Límite:
Animals
Idioma:
En
Revista:
J Neurochem
Año:
2007
Tipo del documento:
Article
País de afiliación:
Francia
Pais de publicación:
Reino Unido