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Deschloroclozapine, a potent and selective chemogenetic actuator enables rapid neuronal and behavioral modulations in mice and monkeys.
Nature Neuroscience ( IF 25.0 ) Pub Date : 2020-07-06 , DOI: 10.1038/s41593-020-0661-3
Yuji Nagai 1 , Naohisa Miyakawa 1 , Hiroyuki Takuwa 1 , Yukiko Hori 1 , Kei Oyama 1 , Bin Ji 1 , Manami Takahashi 1 , Xi-Ping Huang 2, 3 , Samuel T Slocum 2 , Jeffrey F DiBerto 2 , Yan Xiong 4 , Takuya Urushihata 1 , Toshiyuki Hirabayashi 1 , Atsushi Fujimoto 1 , Koki Mimura 1 , Justin G English 2 , Jing Liu 4 , Ken-Ichi Inoue 5, 6 , Katsushi Kumata 7 , Chie Seki 1 , Maiko Ono 1 , Masafumi Shimojo 1 , Ming-Rong Zhang 7 , Yutaka Tomita 8 , Jin Nakahara 8 , Tetsuya Suhara 1 , Masahiko Takada 5 , Makoto Higuchi 1 , Jian Jin 4 , Bryan L Roth 2, 3, 9 , Takafumi Minamimoto 1
Affiliation  

The chemogenetic technology designer receptors exclusively activated by designer drugs (DREADDs) afford remotely reversible control of cellular signaling, neuronal activity and behavior. Although the combination of muscarinic-based DREADDs with clozapine-N-oxide (CNO) has been widely used, sluggish kinetics, metabolic liabilities and potential off-target effects of CNO represent areas for improvement. Here, we provide a new high-affinity and selective agonist deschloroclozapine (DCZ) for muscarinic-based DREADDs. Positron emission tomography revealed that DCZ selectively bound to and occupied DREADDs in both mice and monkeys. Systemic delivery of low doses of DCZ (1 or 3 μg per kg) enhanced neuronal activity via hM3Dq within minutes in mice and monkeys. Intramuscular injections of DCZ (100 μg per kg) reversibly induced spatial working memory deficits in monkeys expressing hM4Di in the prefrontal cortex. DCZ represents a potent, selective, metabolically stable and fast-acting DREADD agonist with utility in both mice and nonhuman primates for a variety of applications.



中文翻译:

去氯氯氮平是一种有效的、选择性的化学遗传学促动器,能够快速调节小鼠和猴子的神经元和行为。

专门由设计药物(DREADD)激活的化学遗传学技术设计受体可以对细胞信号、神经元活动和行为进行远程可逆控制。尽管基于毒蕈碱的 DREADD 与氯氮平-N-氧化物 (CNO)的组合已被广泛使用,但 CNO 的缓慢动力学、代谢能力和潜在的脱靶效应代表了需要改进的领域。在这里,我们为基于毒蕈碱的 DREADD 提供了一种新的高亲和力和选择性激动剂去氯氯氮平 (DCZ)。正电子发射断层扫描显示,DCZ 选择性地结合并占据小鼠和猴子的 DREADD。低剂量 DCZ(1 或 3 μg/kg)的全身给药可在几分钟内通过 hM3Dq 增强小鼠和猴子的神经元活动。肌内注射 DCZ(100 μg/kg)可逆地诱导前额皮质表达 hM4Di 的猴子空间工作记忆缺陷。DCZ 是一种有效、选择性、代谢稳定且起效快的 DREADD 激动剂,在小鼠和非人类灵长类动物中具有多种用途。

更新日期:2020-07-06
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