Sub-anesthetic concentrations of (R,S)-ketamine metabolites inhibit acetylcholine-evoked currents in α7 nicotinic acetylcholine receptors
Sub-anesthetic concentrations of (R,S)-ketamine metabolites inhibit acetylcholine-evoked currents in α7 nicotinic acetylcholine receptors
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DOI：
10.1016/j.ejphar.2012.11.023
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发表时间：
2013-01-05
影响因子：
5
通讯作者：
Wainer, Irving W.
中科院分区：
文献类型：
--
作者：
Moaddel, Ruin;Abdrakhmanova, Galia;Wainer, Irving W.
采用膜片钳技术研究了（R，S）-氯胺酮代谢物（R，S）-诺氯胺酮、（R，S）-脱氢诺氯胺酮、(2S,6S)-羟诺氯胺酮和(2R,6R)-羟诺氯胺酮对α 7和α 3 β 4神经元烟碱受体活性的影响。结果表明，（R，S）-脱氢诺氯胺酮抑制α - 7-烟碱受体乙酰胆碱诱发电流，IC50=55 +/- 6 nM; (2S,6S)-羟诺氯胺酮、(2R,6R)-羟诺氯胺酮和（R，S）-诺氯胺酮在100 μ m浓度下也抑制α - 7-烟碱受体功能。用大鼠脑膜和选择性NMDA受体拮抗剂[H-3]-MK-801测定(2S,6S)-羟诺氯胺酮和(2R,6R)-羟诺氯胺酮对NMDA受体的影响。(S)-脱氢诺氯胺酮的K-i值为38.95 μ M, (2S,6S)-羟诺氯胺酮的K-i值为21.19 μ M, (2R,6R)-羟诺氯胺酮的K-i值为100 μ M。结果提示，氯胺酮代谢物对α - 7-烟碱乙酰胆碱受体的抑制作用可能与该药的临床疗效有关。Elsevier B.V.出版
The effect of the (R,S)-ketamine metabolites (R,S)-norketamine, (R,S)-dehydronorketamine, (2S,6S)-hydroxynorketamine and (2R,6R)-hydroxynorketamine on the activity of alpha 7 and alpha 3 beta 4 neuronal nicotinic acetylcholine receptors was investigated using patch-clamp techniques. The data indicated that (R,S)-dehydronorketamine inhibited acetylcholine-evoked currents in alpha 7-nicotinic acetylcholine receptor, IC50=55 +/- 6 nM, and that (2S,6S)-hydroxynorketamine, (2R,6R)-hydroxynorketamine and (R,S)-norketamine also inhibited alpha 7-nicotinic acetylcholine receptor function at concentrations 100 mu M. The binding affinities of (R,S)-dehydronorketamine, (2S,6S)-hydroxynorketamine and (2R,6R)-hydroxynorketamine at the NMDA receptor were also determined using rat brain membranes and the selective NMDA receptor antagonist [H-3]-MK-801. The calculated K-i values were 38.95 mu M for (S)-dehydronorketamine, 21.19 mu M for (2S,6S)-hydroxynorketamine and > 100 mu M for (2R,6R)-hydroxynorketamine. The results suggest that the inhibitory activity of ketamine metabolites at the alpha 7-nicotinic acetylcholine receptor may contribute to the clinical effect of the drug. Published by Elsevier B.V.