TREK Channel Family Activator with a Well-Defined Structure-Activation Relationship for Pain and Neurogenic Inflammation

doi:10.1021/acs.jmedchem.9b02163

	TREK Channel Family Activator with a Well-Defined Structure-Activation Relationship for Pain and Neurogenic Inflammation
	Qiu, Yunguang 1,4,5,6; Huang, Lu 2,3; Fu, Jie 1; Han, Chenxia 7,8; Fang, Jing 9,10; Liao, Ping 2,3; Chen, Zhuo 2,3; Mo, Yiqing 1; Sun, Peihua 9,10; Liao, Daqing 2,3
刊名	JOURNAL OF MEDICINAL CHEMISTRY
	2020-04-09
卷号	63 期号:7 页码:3665-3677
ISSN号	0022-2623
DOI	10.1021/acs.jmedchem.9b02163
通讯作者	Yang, Huaiyu(hyyang@bio.ecnu.edu.cn) ; Jiang, Ruotian(ruotianjiang@scu.edu.cn)
英文摘要	TWIK-related K+ (TREK) channels are potential analgesic targets. However, selective activators for TREK with both defined action mechanism and analgesic ability for chronic pain have been lacking. Here, we report (1S,3R)-3-((4-(6-methylbenzo[d]thiazol-2-yl)phenyl) carbamoyl)cyclopentane-1-carboxylic acid (C3001a), a selective activator for TREK, against other two-pore domain K+ (K2P) channels. C3001a binds to the cryptic binding site formed by P1 and TM4 in TREK-1, as suggested by computational modeling and experimental analysis. Furthermore, we identify the carboxyl group of C3001a as a structural determinant for binding to TREK-1/2 and the key residue that defines the subtype selectivity of C3001a. C3001a targets TREK channels in the peripheral nervous system to reduce the excitability of nociceptive neurons. In neuropathic pain, C3001a alleviated spontaneous pain and cold hyperalgesia. In a mouse model of acute pancreatitis, C3001a alleviated mechanical allodynia and inflammation. Together, C3001a represents a lead compound which could advance the rational design of peripherally acting analgesics targeting K2P channels without opioid-like adverse effects.
资助项目	National-Local Joint Engineering Research Center of Translational Medicine of Anesthesiology of West China Hospital of Sichuan University[2019-180] ; Personalized Medicines-Molecular Signature-based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12040220] ; National Science and Technology Major Project Key New Drug Creation and Manufacturing Program of China[2018ZX09711002] ; XingFuZhiHua of ECNU[44300-19311542500/006] ; Fundamental Research Funds for the Central Universities[2018SCUH0086] ; National Natural Science Foundation of China[31600832] ; National Natural Science Foundation of China[21422208] ; Thousand Talents Plan in Sichuan Province ; 1.3.5 Project for Disciplines of Excellence of West China Hospital of Sichuan University[ZY2016101] ; ECNU Multifunctional Platform for Innovation[001] ; ECNU Multifunctional Platform for Innovation[011] ; Natural Science Foundation of the Jiangsu Higher Education Institutions of China[18KJA350001] ; Priority Academic Program Development of the Jiangsu Higher Education Institutes (PAPD)
WOS关键词	ACUTE-PANCREATITIS ; POTASSIUM CHANNELS ; K+ ; MECHANO ; TRAAK ; COLD ; CRYSTAL ; NEURONS ; WARM
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER CHEMICAL SOC
WOS记录号	WOS:000526405300017
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/281096]
专题	中国科学院上海药物研究所
通讯作者	Yang, Huaiyu; Jiang, Ruotian
作者单位	1.East China Normal Univ, Sch Life Sci, Inst Biomed Sci, Shanghai Key Lab Regulatory Biol, Shanghai 200241, Peoples R China 2.Sichuan Univ, West China Hosp, Natl Local Joint Engn Res Ctr Translat Med Anesth, Lab Anesthesia & Crit Care Med, Chengdu 610000, Peoples R China 3.Chinese Acad Med Sci, Res Units West China 2018RU012, Chengdu 610000, Peoples R China 4.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 5.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, Shanghai 201203, Peoples R China 6.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 7.Sichuan Univ, West China Hosp, Sichuan Prov Pancreatitis Ctr, Dept Integrated Tradit Chinese & Western Med, Chengdu 610000, Peoples R China 8.Sichuan Univ, West China Hosp, West China Liverpool Biomed Res Ctr, Chengdu 610000, Peoples R China 9.Soochow Univ, Jiangsu Key Lab Neuropsychiat Dis, Suzhou 215123, Peoples R China 10.Soochow Univ, Coll Pharmaceut Sci, Suzhou 215123, Peoples R China
推荐引用方式 GB/T 7714	Qiu, Yunguang,Huang, Lu,Fu, Jie,et al. TREK Channel Family Activator with a Well-Defined Structure-Activation Relationship for Pain and Neurogenic Inflammation[J]. JOURNAL OF MEDICINAL CHEMISTRY,2020,63(7):3665-3677.
APA	Qiu, Yunguang.,Huang, Lu.,Fu, Jie.,Han, Chenxia.,Fang, Jing.,...&Jiang, Ruotian.(2020).TREK Channel Family Activator with a Well-Defined Structure-Activation Relationship for Pain and Neurogenic Inflammation.JOURNAL OF MEDICINAL CHEMISTRY,63(7),3665-3677.
MLA	Qiu, Yunguang,et al."TREK Channel Family Activator with a Well-Defined Structure-Activation Relationship for Pain and Neurogenic Inflammation".JOURNAL OF MEDICINAL CHEMISTRY 63.7(2020):3665-3677.