(-)-beta-cyclazocine is an antagonist of NMDA receptor-mediated responses and a potent neuroprotectant in rat cortical neurons.
Microspectrofluorimetry and excitotoxicity experiments were performed to study the NMDA receptor-blocking and neuroprotective actions of (-)- and (+)-beta-cyclazocine in cultured rat cortical neurons. (-)-beta-Cyclazocine potently antagonized NMDA-induced[Ca2+]i increases (IC50 = 220 nM) in neurons loaded with the Ca2+ fluorophore, fura-2. (-)-beta-Cyclazocine was specific for NMDA receptor-mediated responses versus those mediated through non-NMDA receptors or voltage-activated Ca2+ channels. The agent was active against NMDA-induced neurotoxicity, even at 1 microM. In all experiments, the (+)-enantiomer was found to be considerably less potent than the (-)-enantiomer. These results indicate that (-)-beta-cyclazocine is a specific NMDA receptor antagonist with potent neuroprotective properties in rat cortical neurons.
Sawyer
D C
DC
Department of Pharmacology and Therapeutics, University of British Columbia, Vancouver, Canada.
McLarnon
J G
JG
Church
J
J
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects*; D003496:Cyclazocine / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism
D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate; D003496:Cyclazocine; D002118:Calcium