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化学遗传学发现:通过转换的克洛扎DREADD占用和激活

Juan L Gomez¹, Jordi Bonaventura¹, Wojciech Lesniak²

¹Biobehavioral Imaging and Molecular Neuropsychopharmacology Unit, National Institute on Drug Abuse (NIDA) Intramural Research Program, Baltimore, MD 21224, USA.

Science (New York, N.Y.)

|August 5, 2017

概括

仅由设计药物 (DREADD) 激活的设计受体对于神经科学研究至关重要. 克洛扎N氧化物 (CNO) 间接激活DREADDs,而克洛扎是大脑中的活性化合物.

科学领域:

神经科学
药理学
分子生物学

背景情况:

化学遗传工具如DREADD (专用药物激活的设计受体) 能够远程控制神经元活动.
DREADDs是由特定的配体激活的工程受体,通常是clozapine N-oxide (CNO).
在DREADD中CNO作用的精确体内机制仍未得到证实.

研究的目的:

在DREADD中介化学遗传学中阐明克洛扎N氧化物 (CNO) 的体内作用机制.
在DREADD激活中研究clozapine的代谢物.
为了确认CNO和克洛扎的脑透和DREADD亲和力.

主要方法:

在动物模型中对 CNO 和 clozapine 进行全身注射.
测量DREADD激活和神经元活动.
在大脑中CNO和克洛扎的药理动力学分析.

主要成果:

CNO不容易穿过血脑屏障,对DREADDs的亲和力很低.
在体内,CNO迅速转化为克洛扎,它很容易进入大脑.
克洛扎对DREADDs具有很高的亲和力,调解DREADD特异性行为.

结论:

归因于CNO的化学遗传效应主要由其活性代谢物克洛扎介导.
克洛扎,而不是CNO,是激活中枢神经系统DREADD的关键配体.
这一发现澄清了DREADD技术的机制,并为未来的化学遗传实验设计提供了信息.

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