Norketamine, the main metabolite of ketamine, is a non-competitive NMDA receptor antagonist in the rat cortex and spinal cord
Norketamine, the main metabolite of ketamine, is a non-competitive NMDA receptor antagonist in the rat cortex and spinal cord
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DOI：
10.1016/s0014-2999(97)01116-3
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发表时间：
1997-08-20
影响因子：
5
通讯作者：
Borgbjerg, FM
中科院分区：
文献类型：
--
作者：
Ebert, B;Mikkelsen, S;Borgbjerg, FM
分别用大鼠皮质楔形物和新生大鼠脊髓标本进行电生理实验和[H-3](RS)-5-methyl-10，11-dihydro-5H-dibenzo[a，d]环庚烯-5，10-亚胺([H-3]MK-80 1)的匀浆结合实验，评价非竞争性受体拮抗剂氯胺酮及其主要代谢产物去甲氯胺酮的对映体。与前人的研究结果一致，氯胺酮(K-I，0.3mM)对N-甲基-D-天冬氨酸受体复合体的亲和力是(R)-氯胺酮(K-I，1.4mM)的5倍。(S)-去甲氯胺酮抑制[H-3]MK-801结合的亲和力约为(R)-去甲氯胺酮(K-I)的8倍。除(R)-去甲氯胺酮的效力仅为脊髓的两倍外，所有化合物均可抑制大鼠皮质楔形制剂和新生大鼠脊髓对NMDA的反应，其在皮质中的效力约为脊髓中的四倍。根据口服氯胺酮后临床获得的去甲氯胺酮浓度，这些数据强烈表明(S)-去甲氯胺酮可能对(S)-氯胺酮的临床活性有显著贡献，尤其是口服时。(C)1997年爱思唯尔科学公司。
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 electrophysiological studies and [H-3](RS)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine ([H-3]MK-801) in homogenate binding experiments. In agreement with earlier studies (S)-ketamine (K-i 0.3 mu M) was found to possess a 5 times 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 times higher affinity than (R)-norketamine (K-i 13 mu M) in the inhibition of [H-3]MK-801 binding. All compounds inhibited responses to NMDA in the rat cortical wedge preparation and the hemisected neonatal rat spinal cord, being approximately four times more potent in the cortex than in the spinal cord except for (R)-norketamine being only twice as potent. In light of the clinically obtained concentrations of norketamine after oral administration of ketamine, these data strongly suggest that (S)-norketamine may contribute significantly to the clinical activity of (S)-ketamine, especially when given orally. (C) 1997 Elsevier Science B.V.