Pranlukast is a novel small molecule activator of the two-pore domain potassium channel TREK2

Wright, Paul D.; McCoull, David; Walsh, Yvonne; Large, Jonathan M.; Hadrys, Barbara W.; Gaurilcikaite, Egle; Byrom, Lewis; Veale, Emma L.; Jerman, Jeffrey C.; Mathie, Alistair

doi:10.1016/j.bbrc.2019.09.093

Cited by 18 publications

(20 citation statements)

References 30 publications

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“…Involvement in activation by RNE28 of the N‐terminal of the channel, a region of poor homology with TREK2, could account for the selectivity of RNE28 for TREK1, whether the gating mechanism is direct or indirect. Of note, a TREK2 activator with good selectivity for TREK2 versus TREK1, pranlukast, was also found to bind a different site to that of BL‐1249 and ML335/ML402 (Wright et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

TREK1 channel activation as a new analgesic strategy devoid of opioid adverse effects

Busserolles

Soussia

Pouchol

et al. 2020

British J Pharmacology

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Background and Purpose Opioids are effective painkillers. However, their risk–benefit ratio is dampened by numerous adverse effects and opioid misuse has led to a public health crisis. Safer alternatives are required, but isolating the antinociceptive effect of opioids from their adverse effects is a pharmacological challenge because activation of the μ opioid receptor triggers both the antinociceptive and adverse effects of opioids. Experimental Approach The TREK1 potassium channel is activated downstream of μ receptor and involved in the antinociceptive activity of morphine but not in its adverse effects. Bypassing the μ opioid receptor to directly activate TREK1 could therefore be a safer analgesic strategy. Key Results We developed a selective TREK1 activator, RNE28, with antinociceptive activity in naive rodents and in models of inflammatory and neuropathic pain. This activity was lost in TREK1 knockout mice or wild‐type mice treated with the TREK1 blocker spadin, showing that TREK1 is required for the antinociceptive activity of RNE28. RNE28 did not induce respiratory depression, constipation, rewarding effects, or sedation at the analgesic doses tested. Conclusion and Implications This proof‐of‐concept study shows that TREK1 activators could constitute a novel class of painkillers, inspired by the mechanism of action of opioids but devoid of their adverse effects.

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Section: Discussionmentioning

confidence: 99%

TREK1 channel activation as a new analgesic strategy devoid of opioid adverse effects

Busserolles

Soussia

Pouchol

et al. 2020

British J Pharmacology

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“…Our work has allowed the publication of multiple novel K2P activators. [28][29][30] These have subsequently been used to build upon the role of targets within pain and contribute to the validation of K2Ps as targets for analgesia.…”

Section: Discussionmentioning

confidence: 99%

“…We believe that identification of channel activators is highly dependent on the use of appropriately designed assay reagents specifically optimized for this purpose. As described previously, [28][29][30] we developed cellular systems in which a level of channel expression is chosen, based on function, to allow activation to be observed. To achieve this, baculovirus (BacMam) is used to deliver the channel of interest into cells.…”

Section: Designing Specifically Engineered Systems For the Identificamentioning

confidence: 99%

“…N- (2-((4-nitro-2-(trifluoromethyl)phenyl)-ami no)ethyl)benzamide (NPBA) was identified as a selective activator of TASK-3 in a thallium flux screen of 300,000 compounds. 27 We have previously reported using thallium flux to screen a library of 1000 Food and Drug Administration (FDA)-approved compounds and identified cloxyquin, 28 terbinafine, 29 and pranlukast 30 as selective activators of TRESK, TASK-3, and TREK-2, respectively. Recent work 21 has since demonstrated that terbinafine has antinociceptive effects in models of neuropathic and inflammatory pain.…”

Section: Introductionmentioning

confidence: 99%

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A “Target Class” Screen to Identify Activators of Two-Pore Domain Potassium (K2P) Channels

et al. 2021

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Two-pore domain potassium (K2P) channels carry background (or leak) potassium current and play a key role in regulating resting membrane potential and cellular excitability. Accumulating evidence points to a role for K2Ps in human pathophysiologies, most notably in pain and migraine, making them attractive targets for therapeutic intervention. However, there remains a lack of selective pharmacological tools. The aim of this work was to apply a “target class” approach to investigate the K2P superfamily and identify novel activators across all the described subclasses of K2P channels. Target class drug discovery allows for the leveraging of accumulated knowledge and maximizing synergies across a family of targets and serves as an additional approach to standard target-based screening. A common assay platform using baculovirus (BacMam) to transiently express K2P channels in mammalian cells and a thallium flux assay to determine channel activity was developed, allowing the simultaneous screening of multiple targets. Importantly, this system, by allowing precise titration of channel function, allows optimization to facilitate the identification of activators. A representative set of channels (THIK-1, TWIK-1, TREK-2, TASK-3, and TASK-2) were screened against a library of Food and Drug Administration (FDA)-approved compounds and the LifeArc Index Set. Activators were then analyzed in concentration–response format across all channels to assess selectivity. Using the target class approach to investigate the K2P channels has enabled us to determine which of the K2Ps are amenable to small-molecule activation, de-risk multiple channels from a technical point of view, and identify a diverse range of previously undescribed pharmacology.

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“…A range of physical and chemical signals control K2P function (Enyedi and Czirjak, 2010;Feliciangeli et al, 2014;Renigunta et al, 2015) and various K2P subtypes have emerging roles in a multitude of physiological responses and pathological conditions such as action potential propagation in myelinated axons (Brohawn et al, 2019;Kanda et al, 2019), anesthetic responses (Heurteaux et al, 2004;Lazarenko et al, 2010), microglial surveillance (Madry et al, 2018), sleep duration (Yoshida et al, 2018), pain (Alloui et al, 2006;Devilliers et al, 2013;Vivier et al, 2017), arrythmia (Decher et al, 2017), ischemia (Heurteaux et al, 2004;Laigle et al, 2012;Wu et al, 2013), cardiac fibrosis (Abraham et al, 2018), depression (Heurteaux et al, 2006), migraine (Royal et al, 2019), intraocular pressure regulation (Yarishkin et al, 2018), and pulmonary hypertension (Lambert et al, 2018). Although there have been recent advances in identifying new K2P modulators (Bagriantsev et al, 2013;Lolicato et al, 2017;Pope et al, 2018;Su et al, 2016;Tian et al, 2019;Vivier et al, 2017;Wright et al, 2019) and in defining key structural aspects of K2P channel pharmacology (Dong et al, 2015;Lolicato et al, 2017;Schewe et al, 2019), as is the case with many ion channel classes, pharmacological agents targeting K2Ps remain poorly developed and limit the ability to probe K2P mechanism and biological functions (Sterbuleac, 2019).…”

Section: Introductionmentioning

confidence: 99%

Polynuclear ruthenium amines inhibit K_2P channels via a ‘finger in the dam’ mechanism

Pope¹,

Lolicato²,

Minor³

2019

Preprint

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The trinuclear ruthenium amine Ruthenium Red (RuR) inhibits diverse ion channels including K2P potassium channels, TRPs, the mitochondrial calcium uniporter, CALHMs, ryanodine receptors, and Piezos. Despite this extraordinary array, there is very limited information for how RuR engages its targets. Here, using X-ray crystallographic and electrophysiological studies of an RuR-sensitive K2P, K2P2.1 (TREK-1) I110D, we show that RuR acts by binding an acidic residue pair comprising the 'Keystone inhibitor site' under the K2P CAP domain archway above the channel pore. We further establish that Ru360, a dinuclear ruthenium amine not known to affect K2Ps, inhibits RuR-sensitive K2Ps using the same mechanism. Structural knowledge enabled a generalizable RuR 'super-responder' design strategy for creating K2Ps having nanomolar sensitivity. Together, the data define a 'finger in the dam' inhibition mechanism acting at a novel K2P inhibitor binding site.These findings highlight the polysite nature of K2P pharmacology and provide a new framework for K2P inhibitor development.

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Pranlukast is a novel small molecule activator of the two-pore domain potassium channel TREK2

Cited by 18 publications

References 30 publications

TREK1 channel activation as a new analgesic strategy devoid of opioid adverse effects

TREK1 channel activation as a new analgesic strategy devoid of opioid adverse effects

A “Target Class” Screen to Identify Activators of Two-Pore Domain Potassium (K2P) Channels

Polynuclear ruthenium amines inhibit K_2P channels via a ‘finger in the dam’ mechanism

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Pranlukast is a novel small molecule activator of the two-pore domain potassium channel TREK2

Cited by 18 publications

References 30 publications

TREK1 channel activation as a new analgesic strategy devoid of opioid adverse effects

TREK1 channel activation as a new analgesic strategy devoid of opioid adverse effects

A “Target Class” Screen to Identify Activators of Two-Pore Domain Potassium (K2P) Channels

Polynuclear ruthenium amines inhibit K2P channels via a ‘finger in the dam’ mechanism

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Polynuclear ruthenium amines inhibit K_2P channels via a ‘finger in the dam’ mechanism