2. Academic Validation
  3. TREK Channel Family Activator with a Well-Defined Structure-Activation Relationship for Pain and Neurogenic Inflammation

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

  • J Med Chem. 2020 Apr 9;63(7):3665-3677. doi: 10.1021/acs.jmedchem.9b02163.
Yunguang Qiu 1 2 3,  Lu Huang 4,  Jie Fu 1,  Chenxia Han 5,  Jing Fang 6,  Ping Liao 4,  Zhuo Chen 4,  Yiqing Mo 1,  Peihua Sun 6,  Daqing Liao 4,  Linghui Yang 4,  Jing Wang 4,  Qiansen Zhang 1,  Jin Liu 4,  Feng Liu 6,  Tingting Liu 5,  Wei Huang 5,  Huaiyu Yang 1,  Ruotian Jiang 4
Affiliations

Affiliations

  • 1 Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai 200241, China.
  • 2 State Key Laboratory of Drug Research and CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 3 University of Chinese Academy of Sciences, Beijing 100049, China.
  • 4 Laboratory of Anesthesia and Critical Care Medicine, National-Local Joint Engineering Research Center of Translational Medicine of Anesthesiology, West China Hospital, Sichuan University & The Research Units of West China (2018RU012), Chinese Academy of Medical Sciences, Chengdu 610000, China.
  • 5 Department of Integrated Traditional Chinese and Western Medicine, Sichuan Provincial Pancreatitis Centre and West China-Liverpool Biomedical Research Centre, West China Hospital, Sichuan University, Chengdu 610000, China.
  • 6 Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China.
PMID: 32162512 DOI: 10.1021/acs.jmedchem.9b02163
Abstract

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.

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