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

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.