Synthesis and structure–activity relationship study of substituted caffeate esters as antinociceptive agents modulating the TREK-1 channel

Rodrigues, Nélson; Bennis, Khalil; Vivier, Delphine; Pereira, Vanessa; Chatelain, Franck C.; Chapuy, Eric; Deokar, Hemantkumar; Busserolles, Jérôme; Lesage, Florian; Eschalier, Alain; Ducki, Sylvie

doi:10.1016/j.ejmech.2014.01.049

Cited by 35 publications

(34 citation statements)

References 29 publications

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“…However, riluzole subsequently induced a sustained inhibition of TREK1 current due to activation of protein kinase A [30]. As such, the overall effect of this compound in vivo is difficult to predict, although riluzole has been shown to hyperpolarise DRG neurons [30] and have strong antinociceptive activity [84].…”

Section: Riluzolementioning

confidence: 99%

“…It has been suggested that caffeic acid derivatives bind to an external site to produce their effects on TREK1 channels, since activity was retained when the compounds were applied externally in outside-out patch recordings [24]. 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 [84].…”

Section: Caffeic Acid Estersmentioning

confidence: 99%

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Two-pore domain potassium channels: potential therapeutic targets for the treatment of pain

Mathie

Veale

2014

Pflugers Arch - Eur J Physiol

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Recent evidence points to a pivotal contribution of a variety of different potassium channels, including two-pore domain potassium (K2P) channels, in chronic pain processing. Expression of several different K2P channel subunits has been detected in nociceptive dorsal root ganglion neurons and trigeminal ganglion neurons, in particular, TREK1, TREK2, TRESK, TRAAK, TASK3 and TWIK1 channels. Of these, the strongest body of evidence from functional studies highlights the importance of TREK1, TRESK and, recently, TREK2 channels. For example, TREK1 knockout mice are more sensitive than wild-type mice to a number of painful stimuli but less sensitive to morphine-induced analgesia. TRESK knockdown mice show behavioural evidence of increased pain and increased sensitivity to painful pressure. Importantly, familial migraine with aura is associated with a dominant-negative mutation in human TRESK channels. Thus, the functional up-regulation of K2P channel activity may be a useful strategy in the development of new therapies for the treatment of pain. Whilst there are few currently available compounds that selectively and directly enhance the activity of TRESK and TREK2 channels, recent advances have been made in terms of identifying compounds that activate TREK1 channels and in understanding how they might act on the channel. Large-scale bio-informatic approaches and the further development of databases of putative ligands, channel structures and putative ligand binding sites on these structures may form the basis for future experimental strategies to detect novel molecules acting to enhance K2P channel activity that would be useful in the treatment of pain.

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Section: Riluzolementioning

confidence: 99%

Section: Caffeic Acid Estersmentioning

confidence: 99%

Two-pore domain potassium channels: potential therapeutic targets for the treatment of pain

Mathie

Veale

2014

Pflugers Arch - Eur J Physiol

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“…Caffeic acid and some of its esters and amides derivatives exhibit a broad spectrum of biological activities including anti-inflammatory [7], antimicrobial [8,9], antioxidant [10], anti-Alzheimer [11], analgesic [12] and anticancer effects [13][14][15]. In addition, some studies have shown that caffeic acid esters have high anti-leishmanial activity [16][17][18][19].…”

Section: Subgenus) As Well As L Mexicana and L Amazonensis (Membermentioning

confidence: 99%

Triclosan-caffeic acid hybrids: Synthesis, leishmanicidal, trypanocidal and cytotoxic activities

Otero

García

Palacios

et al. 2017

European Journal of Medicinal Chemistry

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The synthesis, cytotoxicity, anti-leishmanial and anti-trypanosomal activities of twelve triclosan-caffeic acid hybrids are described herein. The structure of the synthesized products was elucidated by a combination of spectrometric analyses. The synthesized compounds were evaluated against amastigotes forms of L. (V) panamensis, which is the most prevalent Leishmania species in Colombia, and against Trypanosoma cruzi, which is the pathogenic species to humans. Cytotoxicity was evaluated against human U-937 macrophages. Eight compounds were active against L. 26 and 28, the remaining compounds were toxic for mammalian cells, yet they have potential to be considered as candidates for anti-trypanosomal and anti-leishmanial drug development. The activity is dependent on the length of the alkyl linker with compound 19, bearing a four-carbon alkyl chain, the most performing hybrid. In general, hydroxyl groups increase both activity and cytotoxicity and the presence of the double bond in the side chain is not decisive for cytotoxicity and anti-protozoal activity.

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“…TREK1 is activated by opioid receptors and contributes to morphine-induced analgesia, but is not involved in morphine-induced constipation, respiratory depression, and dependence (5). TREK1 openers, acting downstream from opioid receptors, might have strong analgesic effects without adverse effects (6). TRAAK may also be a good target for analgesia: Its activation by angiotensin II receptors is responsible for the painless nature of the early lesions of the necrotizing tropical disease Buruli ulcer (7).…”

mentioning

confidence: 99%

Mixing and matching TREK/TRAAK subunits generate heterodimeric K _2P channels with unique properties

Blin

Soussia

Kim

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The tandem of pore domain in a weak inwardly rectifying K + channel (Twik)-related acid-arachidonic activated K + channel (TRAAK) and Twikrelated K + channels (TREK) 1 and TREK2 are active as homodimers gated by stretch, fatty acids, pH, and G protein-coupled receptors. These two-pore domain potassium (K 2P ) channels are broadly expressed in the nervous system where they control excitability. TREK/TRAAK KO mice display altered phenotypes related to nociception, neuroprotection afforded by polyunsaturated fatty acids, learning and memory, mood control, and sensitivity to general anesthetics. These channels have emerged as promising targets for the development of new classes of anesthetics, analgesics, antidepressants, neuroprotective agents, and drugs against addiction. Here, we show that the TREK1, TREK2, and TRAAK subunits assemble and form active heterodimeric channels with electrophysiological, regulatory, and pharmacological properties different from those of homodimeric channels. Heteromerization occurs between all TREK variants produced by alternative splicing and alternative translation initiation. These results unveil a previously unexpected diversity of K 2P channels that will be challenging to analyze in vivo, but which opens new perspectives for the development of clinically relevant drugs. + channels (TREK) 1, TREK2, and Twik-related acid-arachidonic activated K + channel (TRAAK) channels produce inhibitory background K + currents (1-3). These channels respond to neuroprotective fatty acids, mechanical stretch, temperature, pH, and neurotransmitters through G proteincoupled receptors (GPCRs) (for a recent review, see ref. 4). TREK1 is activated by volatile anesthetics and plays a role in general anesthesia. These channels have emerged as promising targets for the development of other classes of clinical compounds. TREK1 is activated by opioid receptors and contributes to morphine-induced analgesia, but is not involved in morphine-induced constipation, respiratory depression, and dependence (5). TREK1 openers, acting downstream from opioid receptors, might have strong analgesic effects without adverse effects (6). TRAAK may also be a good target for analgesia: Its activation by angiotensin II receptors is responsible for the painless nature of the early lesions of the necrotizing tropical disease Buruli ulcer (7). Also, activation of TREK1 by GABA B receptors in the hippocampus (8), and inhibition of TREK2 by neurotensin receptors in the entorhinal cortex (9), suggests that specific modulators of these channels might also have beneficial actions against drug abuse, and against learning slow down and memory deficits in Alzheimer's disease. Finally, inhibition of TREK1 by spadin (10), an endogenous peptide, or by the antidepressant fluoxetine (Prozac) (11), pinpoints it as a valuable target for the treatment of depression. TREK/TRAAK channels are broadly expressed in the nervous system (12-15). TREK1 is more specifically expressed in the striatum, TREK2 in the cerebellum, and TRAAK in the thalamus. All...

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Synthesis and structure–activity relationship study of substituted caffeate esters as antinociceptive agents modulating the TREK-1 channel

Cited by 35 publications

References 29 publications

Two-pore domain potassium channels: potential therapeutic targets for the treatment of pain

Two-pore domain potassium channels: potential therapeutic targets for the treatment of pain

Triclosan-caffeic acid hybrids: Synthesis, leishmanicidal, trypanocidal and cytotoxic activities

Mixing and matching TREK/TRAAK subunits generate heterodimeric K _2P channels with unique properties

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Synthesis and structure–activity relationship study of substituted caffeate esters as antinociceptive agents modulating the TREK-1 channel

Cited by 35 publications

References 29 publications

Two-pore domain potassium channels: potential therapeutic targets for the treatment of pain

Two-pore domain potassium channels: potential therapeutic targets for the treatment of pain

Triclosan-caffeic acid hybrids: Synthesis, leishmanicidal, trypanocidal and cytotoxic activities

Mixing and matching TREK/TRAAK subunits generate heterodimeric K 2P channels with unique properties

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Mixing and matching TREK/TRAAK subunits generate heterodimeric K _2P channels with unique properties