Sub-anesthetic concentrations of (R,S)-ketamine metabolites inhibit acetylcholine-evoked currents in ¦Á7 nicotinic acetylcholine receptors

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• 作者：Ruin Moaddel^a ; Galia Abdrakhmanova^b ; Joanna Kozak^c ; ^d ; Krzysztof Jozwiak^c ; Lawrence Toll^e ; Lucita Jimenez^f ; Avraham Rosenberg^a ; Thao Tran^g ; Yingxian Xiao^g ; Carlos A. Zarate^h ; Irving W. Wainer^a ; ^{wainerir@grc.nia.nih.gov}
• 关键词：Dehydronorketamine ; Hydroxynorketamine ; Norketamine ; Depression ; Pain ; Negative allosteric modifiers ; Neuronal nicotinic acetylcholine receptors
• 刊名：European Journal of Pharmacology
• 出版年：2013
• 出版时间：5 January, 2013
• 年：2013
• 卷：698
• 期：1-3
• 页码：228-234
• 全文大小：462 K

文摘

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 ¦Á7 and ¦Á3¦Â4 neuronal nicotinic acetylcholine receptors was investigated using patch-clamp techniques. The data indicated that (R,S)-dehydronorketamine inhibited acetylcholine-evoked currents in ¦Á7-nicotinic acetylcholine receptor, IC₅₀=55¡À6 nM, and that (2S,6S)-hydroxynorketamine, (2R,6R)-hydroxynorketamine and (R,S)-norketamine also inhibited ¦Á7-nicotinic acetylcholine receptor function at concentrations ¡Ü1 ¦ÌM, while (R,S)-ketamine was inactive at these concentrations. The inhibitory effect of (R,S)-dehydronorketamine was voltage-independent and the compound did not competitively displace selective ¦Á7-nicotinic acetylcholine receptor ligands [¹²⁵I]-¦Á-bungarotoxin and [³H]-epibatidine indicating that (R,S)-dehydronorketamine is a negative allosteric modulator of the ¦Á7-nicotinic acetylcholine receptor. (R,S)-Ketamine and (R,S)-norketamine inhibited (S)-nicotine-induced whole-cell currents in cells expressing ¦Á3¦Â4-nicotinic acetylcholine receptor, IC₅₀ 3.1 and 9.1 ¦ÌM, respectively, while (R,S)-dehydronorketamine, (2S,6S)-hydroxynorketamine and (2R,6R)-hydroxynorketamine were weak inhibitors, IC₅₀ >100 ¦ÌM. 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 [³H]-MK-801. The calculated K_i values were 38.95 ¦ÌM for (S)-dehydronorketamine, 21.19 ¦ÌM for (2S,6S)-hydroxynorketamine and>100 ¦ÌM for (2R,6R)-hydroxynorketamine. The results suggest that the inhibitory activity of ketamine metabolites at the ¦Á7-nicotinic acetylcholine receptor may contribute to the clinical effect of the drug.