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.

中文翻译：

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TREK通道家族激活剂具有明确定义的针对疼痛和神经源性炎症的结构激活关系。

TWIK相关的K ⁺（TREK）通道是潜在的止痛目标。然而，一直缺乏既具有确定的作用机制又具有针对慢性疼痛的镇痛能力的TREK选择性激活剂。在这里，我们报告（1 S，3 R）-3-（（4-（6-甲基苯并[ d ]噻唑-2-基）苯基）氨基甲酰基）环戊烷-1-羧酸（C3001a），TREK的选择性活化剂，针对其他两孔域K ⁺（K2P）频道。正如计算模型和实验分析所表明的，C3001a与TREK-1中P1和TM4形成的密码结合位点结合。此外，我们确定C3001a的羧基是结合TREK-1 / 2的结构决定因素和定义C3001a亚型选择性的关键残基。C3001a靶向外周神经系统中的TREK通道，以降低伤害性神经元的兴奋性。在神经性疼痛中，C3001a减轻了自发性疼痛和感冒痛觉过敏。在急性胰腺炎的小鼠模型中，C3001a减轻了机械性异常性疼痛和炎症。C3001a共同代表了一种铅化合物，该化合物可以促进针对K2P通道的外周镇痛药的合理设计，而不会产生类似阿片类药物的副作用。