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Papers of the Week

Papers: 7 Mar 2020 - 13 Mar 2020

Animal Studies, Pharmacology/Drug Development

2020 Mar 12

J Med Chem

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


Qiu Y, Huang L, Fu J, Han C, Fang J, Liao P, Chen Z, Mo Y, Sun P, Liao D, Yang L, Wang J, Zhang Q, Liu J, Liu F, Liu T, Huang W, Yang H, Jiang R
J Med Chem. 2020 Mar 12.
PMID: 32162512.


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 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. Further, we identify the carboxyl group of C3001a as a structural determinant for the binding to TREK-1/2, and the key residue that defines the subtype-selectivity of C3001a. C3001a targets TREK channels in 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.