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 Ki 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.