NORKETAMINE, THE MAIN METABOLITE OF KETAMINE, IS A NONCOMPETITIVE NMDA RECEPTOR ANTAGONIST IN THE RAT CORTEX AND SPINAL-CORD

The enantiomers of the potent non-competitive NMDA receptor antagonist ketamine and its major metabolite, norketamine were evaluated as NMDA receptor antagonists using the rat cortical wedge preparation and the neonatal rat spinal cord preparation, respectively, for electrophysio logical studies and 0,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine ([H-3]MK-801) in homogenate binding experiments. In agreement with ea rlier studies (S)-ketamine (K-i 0.3 mu M) was found to possess a 5 tim es higher affinity for the NMDA receptor complex than (R)-ketamine (K- i 1.4 mu M). (S)-Norketamine (K-i 1.7 mu M) had approximately an 8 tim es higher affinity than (R)-norketamine (K-i 13 mu M) in the inhibitio n of [H-3]MK-801 binding. All compounds inhibited responses to NMDA in the rat cortical wedge preparation and the hemisected neonatal rat sp inal cord, being approximately four times more potent in the cortex th an in the spinal cord except for (R)-norketamine being only twice as p otent. In light of the clinically obtained concentrations of norketami ne after oral administration of ketamine, these data strongly suggest that (S)-norketamine may contribute significantly to the clinical acti vity of (S)-ketamine, especially when given orally. (C) 1997 Elsevier Science B.V.