2020年7月6日出版的《自然—神经科学》发表了日本国立放射线医学综合研究所Takafumi Minamimoto课题组的最新研究成果。该研究发现脱氯氯氮平（DCZ）是一种有效且高选择性的化学遗传学致动器，可在小鼠和猴子中快速调节神经元和行为。

基于毒蕈碱的只能由设计药物激活的设计受体（DREADDs）提供了新的高亲和力和高选择性激动剂DCZ。阳离子发射断层扫描显示DCZ在小鼠和猴子中选择性结合并占据DREADD。在小鼠和猴子中，通过hM3Dq系统几分钟内递送低剂量的DCZ（1或3μg/ 每 kg）可增强神经元活性。肌肉注射DCZ（100μg/ 每kg）可逆地诱导前额叶皮层中表达hM4Di猴子的空间工作记忆缺陷。DCZ代表一种有效、高选择性、代谢稳定和快速作用的DREADD激动剂，可在小鼠和非人类灵长类动物中发挥多种用途。

研究人员表示，只能由设计药物激活的设计受体（DREADDs）可提供对细胞信号传导、神经元活动和行为的远程可逆调控。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，但其缓慢的动力学、代谢障碍和CNO的脱靶效应仍亟待改进。

附：英文原文

Title: Deschloroclozapine, a potent and selective chemogenetic actuator enables rapid neuronal and behavioral modulations in mice and monkeys

Author: Yuji Nagai, Naohisa Miyakawa, Hiroyuki Takuwa, Yukiko Hori, Kei Oyama, Bin Ji, Manami Takahashi, Xi-Ping Huang, Samuel T. Slocum, Jeffrey F. DiBerto, Yan Xiong, Takuya Urushihata, Toshiyuki Hirabayashi, Atsushi Fujimoto, Koki Mimura, Justin G. English, Jing Liu, Ken-ichi Inoue, Katsushi Kumata, Chie Seki, Maiko Ono, Masafumi Shimojo, Ming-Rong Zhang, Yutaka Tomita, Jin Nakahara, Tetsuya Suhara, Masahiko Takada, Makoto Higuchi, Jian Jin, Bryan L. Roth, Takafumi Minamimoto

Issue&Volume: 2020-07-06

Abstract: 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 3μgperkg) enhanced neuronal activity via hM3Dq within minutes in mice and monkeys. Intramuscular injections of DCZ (100μgperkg) 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.

DOI: 10.1038/s41593-020-0661-3

Source: https://www.nature.com/articles/s41593-020-0661-3