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

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.

PKC‐ and PKA‐dependent phosphorylation modulates TREK‐1 function in naïve and neuropathic rats

“…This discrepancy may be due to different sensory modalities and species used in each study. In support of our data, C3001a, a specific activator of TREK-1, reduces nociceptive responses in neuropathic mice (Qiu et al, 2020). Thus, our results imply that spinal TREK-1 maintains an inhibitory tone in normal condition and it reduces allodynic responses in neuropathic rodents.…”

“…Taken together, our data support the idea that phosphorylation state of spinal TREK‐1 modulates excitability of DRG and/or spinal cord neurons to reduce neuropathic pain. In support of this, the activation of TREK‐1 in reduces excitability in isolated DRG neurons (Qiu et al., 2020).…”

The Prostacyclin Analogue, Treprostinil, Used in the Treatment of Pulmonary Arterial Hypertension, is a Potent Antagonist of TREK-1 and TREK-2 Potassium Channels

“…A recent paper by Qiu et al (2020) , identified Y270 on TREK-1 (Y285 in their human TREK-1 construct, NM_001017425.3), as an important amino acid regulating the effectiveness of the anti-nociceptive activator, C3001a. In our hands, TREK-1 channels with the mutated amino acid Y270A carried negligible current, 3.3 pA pF −1 (95% CI: 2.1 to 4.5, n = 6) in the absence of any activator ( Supplementary Figure S1 ), so it was not possible to determine the effect of this mutation on inhibition by treprostinil.…”

“…A tyrosine in the TM4 region (Y270 in the TREK-1 isoform used here) was recently shown to be important in regulating the effectiveness of an anti-nociceptor activator, C3001a ( Qiu et al, 2020 ). We found, however, that this mutation carried negligible current at −40 mV in the absence of a high concentration of a TREK-1 channel activator and thus were unable to test whether it interfered with treprostinil inhibition.…”

“…Moreover, TREK-1 and TREK-2 knockout (KO) mice show increased sensitivity to a range of noxious stimuli, including heat, mechanical and inflammatory agents ( Alloui et al, 2006 ; Noel et al, 2009 ; Pereira et al, 2014 ). Conversely, TREK channel activation by riluzole, BL-1249, GI-530159, RNE28 and C3001a was found, respectively, to eliminate oxaliplatin-induced pain ( Poupon et al, 2018 ), decrease tactile allodynia in neuropathic rats ( Garcia et al, 2020 ), reduce excitability of small DRG neurons ( Loucif et al, 2018 ), increase antinociceptive activity in mouse models of pain ( Busserolles et al, 2020 ) and alleviate stimuli-induced hyperalgesia, allodynia and inflammation in mice ( Qiu et al, 2020 ).…”