Excitatory amino acid neurotoxicity at the N-methyl-D-aspartate receptor in cultured neurons: protection by SKF 10,047.
SKF 10,047 (N-allylnormetazocine) was found to be neuroprotective against glutamate-induced excitotoxicity in our model system of energy-stressed neurons which rapidly succumb to glutamate via N-methyl-D-aspartate (NMDA) receptor-mediated events. The 50% protective concentration (PC50) of the (+) and (-) enantiomers was 3.3 microM and 9 microM, respectively, against the toxic action of 100 microM glutamate. Protection by SKF 10,047 seemed to be mediated by the lower-affinity phencyclidine (PCP) binding site rather than the higher-affinity sigma-site since the potent sigma-ligand (+)-3-(3-hydroxyphenyl-N-1-propyl)piperidine [+)-3-PPP) did not protect at concentrations up to 2 mM. A reversed stereoselectivity was apparent for neuroprotection since (-)-3-PPP was weakly protective with a PC50 of 1.5 mM. These data suggest that energy-stressed rat cerebellar granule cells are a useful model for identifying neuroprotective agents, as shown by SKF 10,047.
Lysko
P G
PG
Department of Pharmacology, SmithKline Beecham, King of Prussia, PA 19406-0939.
Feuerstein
G
G
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000502:physiology; D015259:Dopamine Agents / Q000494:pharmacology; D005971:Glutamates / Q000494:pharmacology*; D018698:Glutamic Acid; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000502:physiology; D009498:Neurotoxins; D010620:Phenazocine / Q000031:analogs & derivatives* / Q000494:pharmacology; D010622:Phencyclidine / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000502:physiology*; D017981:Receptors, Neurotransmitter / Q000378:metabolism; D017478:Receptors, Phencyclidine
D015259:Dopamine Agents; D005971:Glutamates; D009498:Neurotoxins; D010880:Piperidines; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter; D017478:Receptors, Phencyclidine; D018698:Glutamic Acid; C012134:SK&F 10047; C026539:preclamol; D010620:Phenazocine; D010622:Phencyclidine