Development of the First Two-Pore Domain Potassium Channel TWIK-Related K⁺ Channel 1-Selective Agonist Possessing in Vivo Antinociceptive Activity

Abstract

The TWIK-related K channel, TREK-1, has recently emerged as an attractive therapeutic target for the development of a novel class of analgesic drugs, suggesting that activation of TREK-1 could result in pain inhibition. Here, we report the synthesis of a series of substituted acrylic acids (1-54) based on our previous work with caffeate esters. The analogues were evaluated for their ability to modulate TREK-1 channel by electrophysiology and for their in vivo antinociceptive activity (acetic acid-induced writhing and hot plate assays), leading to the identification of a series of novel molecules able to activate TREK-1 and displaying potent antinociceptive activity in vivo. Furyl analogue 36 is the most promising of the series.

Two‐pore domain potassium channels: emerging targets for novel analgesic drugs: IUPHAR Review 26

“…K2P2 channel activation by the μ‐opioid receptor is a component of morphine‐induced signalling and is integral to its analgesic effects but does not contribute to the adverse effects of morphine (Devilliers et al, ). In keeping with this finding, a series of acrylic acid compounds that selectively activate K2P2 channels has recently been reported to show significant pain mitigation in vivo (Vivier et al, ). Similarly, a selective activator of K2P2 and K2P10, GI‐530139, has been reported to be effective in hyperpolarizing DRG neurons by increasing channel activity (Loucif et al, ).…”

GI‐530159, a novel, selective, mechanosensitive two‐pore‐domain potassium (K2P) channel opener, reduces rat dorsal root ganglion neuron excitability

“…More recently, a range of substituted caffeic acid esters based on a hybrid of CDC and CAPE have been developed, the most promising of which (compound 12U) both enhances the activity of TREK1 channels and displays potent analgesic activity in vivo (Rodrigues et al ., ). Very recently, these authors have extended this work by developing a series of substituted acrylic acids, which activate TREK1 channels and show anti‐nociceptive activity in vivo (Vivier et al ., ). Also recently, Dadi et al .…”

“…Subsequently, this compound was shown to activate TREK1 and TREK2 channels directly (Veale et al ., ; Dong et al ., ); however, this compound lacks the selectivity required for it to be useful, in isolation, as an indicator of TREK channel activity (see ). Other activators of TREK channels have been described including ML67‐33 (Bagriantsev et al ., ) and a number of caffeic acid esters (Danthi et al ., ; Rodrigues et al ., ; Vivier et al ., ) (see ).…”

Molecular determinants of chemical modulation of two‐pore domain potassium channels

“…With a notable exception (Ji, Zhao, Cao, Shi, & Wang, 2011), TREK channels are considerably difficult to be modulated by chemical compounds, as high-throughput screens usually reveal modest-affinity modulators (Bagriantsev et al, 2013;Vivier et al, 2017), with IC 50 values frequently around 20 μM. This can be explained by their large inner pore (Brohawn et al, 2014) which has an unusual high flexibility due to much more numerous glycine hinges than other K2P members (Aryal et al, 2017).…”