The DREADD agonist clozapine N-oxide (CNO) is reverse-metabolized to clozapine and produces clozapine-like interoceptive stimulus effects in rats and mice.
The DREADD agonist clozapine N-oxide (CNO) is reverse-metabolized to clozapine and produces clozapine-like interoceptive stimulus effects in rats and mice.
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DOI：
10.1038/s41598-018-22116-z
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发表时间：
2018-03-01
影响因子：
4.6
通讯作者：
Weinshenker D
中科院分区：
文献类型：
--
作者：
Manvich DF;Webster KA;Foster SL;Farrell MS;Ritchie JC;Porter JH;Weinshenker D
氯氮平-N-氧化物（CNO）长期以来一直是选择性激活设计师受体的配体，该受体仅由设计师药物激活（DREADD）。然而，最近的研究对长期以来认为CNO在其他方面具有药理学惰性的说法提出了挑战。本研究旨在1）确定CNO是否在小鼠中被逆代谢为其母体化合物氯氮平（如最近在大鼠中报道的那样），以及2）确定CNO是否在大鼠和/或小鼠中发挥氯氮平样内感受性刺激作用。在给予10.0 mg/kg CNO后，药代动力学分析复制了最近关于大鼠回复为氯氮平的报告，并显示这种现象也发生在小鼠中。在接受过区分1.25 mg/kg氯氮平和溶剂的训练的大鼠和小鼠中，CNO（1.0-20.0 mg/kg）平均对氯氮平刺激产生了部分替代，在两个物种的一些个体动物中检测到了经常用于激活DREADD的剂量的完全替代。目前的证明，CNO转化为氯氮平，并发挥氯氮平样的行为效应，在小鼠和大鼠进一步强调需要适当的对照组在研究中采用DREADD，并强调实用的药物歧视程序作为一种工具，以筛选脱靶效应的新型DREADD激动剂。
Clozapine-N-oxide (CNO) has long been the ligand of choice for selectively activating Designer Receptors Exclusively Activated by Designer Drugs (DREADDs). However, recent studies have challenged the long-held assertion that CNO is otherwise pharmacologically inert. The present study aimed to 1) determine whether CNO is reverse-metabolized to its parent compound clozapine in mice (as has recently been reported in rats), and 2) determine whether CNO exerts clozapine-like interoceptive stimulus effects in rats and/or mice. Following administration of 10.0 mg/kg CNO, pharmacokinetic analyses replicated recent reports of back-conversion to clozapine in rats and revealed that this phenomenon also occurs in mice. In rats and mice trained to discriminate 1.25 mg/kg clozapine from vehicle, CNO (1.0–20.0 mg/kg) produced partial substitution for the clozapine stimulus on average, with full substitution being detected in some individual animals of both species at doses frequently used to activate DREADDs. The present demonstration that CNO is converted to clozapine and exerts clozapine-like behavioral effects in both mice and rats further emphasizes the need for appropriate control groups in studies employing DREADDs, and highlights the utility of the drug discrimination procedure as a tool with which to screen the off-target effects of novel DREADD agonists.
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DOI：
10.1073/pnas.0700293104
发表时间：
2007-03-20
影响因子：
11.1
作者：
Armbruster, Blaine N.;Li, Xiang;Roth, Bryan L.
通讯作者：
Roth, Bryan L.
DOI：
10.1038/npp.2010.127
发表时间：
2010-11
期刊：
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
影响因子：
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通讯作者：
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DOI：
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发表时间：
1996-08-01
影响因子：
3.4
作者：
Lin, G;McKay, G;Midha, KK
通讯作者：
Midha, KK
影响因子：
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DOI：
10.1073/pnas.0906593106
发表时间：
2009-11-10
影响因子：
11.1
作者：
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Wess, Juergen