Towards a TREK-1/2 (TWIK-Related K+ Channel 1 and 2) dual activator tool compound: Multi-dimensional optimization of BL-1249

Iwaki, Yuzo; Yashiro, Kentaro; Kokubo, Mitsunori; Mori, Takeo; Wieting, Joshua M.; McGowan, Kevin M.; Bridges, Thomas M.; Engers, Darren W.; Denton, Jerod S.; Kurata, Haruto; Lindsley, Craig W.

doi:10.1016/j.bmcl.2019.04.048

Cited by 5 publications

(3 citation statements)

References 20 publications

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“…A few compounds have been previously identified that selectively activate TREK channels including ML67-33, BL-1249, ML335, ML402, and GI-530159. − However, to the best of our knowledge, except for a derivative of BL-1249, the pharmacokinetic profiles and the in vivo ability of these compounds remain largely unreported. So far, the selective TREK-1 activators with reported in vivo analgesic properties are cinnamyl 3,4-dihydroxyl-α-cyanocinnamate analogues derived from caffeate esters .…”

Section: Introductionmentioning

confidence: 99%

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

Qiu

Huang

et al. 2020

J. Med. Chem.

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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.

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Section: Introductionmentioning

confidence: 99%

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

Qiu

Huang

et al. 2020

J. Med. Chem.

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“…Our study shows, for the first time, that BL-1249 enhances the Kv10.1 activity and that it can hyperpolarize the resting membrane potential of cells expressing this channel; these effects were absent when BL-1249 (at the highest concentration tested) was applied to wild-type HEK293 cells, indicating a direct consequence of BL-1249 on Kv10.1 channels. BL-1249 is a non-steroidal anti-inflammatory, which has been described as an activator of K + channels of the K2P, TREK-1, and TREK-2 type, showed an EC50 of ∼5 µM and ∼8 μM, respectively ( Iwaki et al, 2019 ). Here, the EC50 for BL on the Kv10.1 channel was five times higher.…”

Section: Discussionmentioning

confidence: 99%

Fluorescent membrane potential assay for drug screening on Kv10.1 channel: identification of BL-1249 as a channel activator

Gómez-Herrera,

Patlán,

Estrada-Garrido

et al. 2023

Front. Pharmacol.

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Resting membrane potential is a bioelectric property of all cells. Multiple players govern this property, the ion channels being the most important. Ion channel dysfunction can affect cells’ resting membrane potential and could be associated with numerous diseases. Therefore, the drug discovery focus on ion channels has increased yearly. In addition to patch-clamp, cell-based fluorescent assays have shown a rapid and reliable method for searching new ion channel modulators. Here, we used a cell-based membrane potential assay to search for new blockers of the Kv10.1, a potassium channel strongly associated with cancer progression and a promising target in anticancer therapy. We found that fluoxetine and miconazole can inhibit the Kv10.1 channel in the micromolar range. In contrast, BL-1249 potentiates Kv10.1 currents in a dose-dependent manner, becoming the first molecule described as an activator of the channel. These results demonstrate that cell-based membrane potential assay can accelerate the discovery of new Kv10.1 modulators.

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“…For example, negatively charged activators like 5,6,7,8-tetrahydro-naphthalen-1-yl)-[ 2 -(1H-tetrazol-5-yl)-phenyl]-amine (BL-1249), 2,7-dichloro-9,9-dimethyl-10-[ 2 -(1H-tetrazol-5-yl)-ethyl]-9,10-dihydro-acridine (ML67-33) and 4-(2-butyl-6,7-dichlor-2-cyclopentylindan-1-on-5-yl) oxobutyric acid (DCPIB) bind below the selectivity filter, where their negative charge promotes K + binding to the pore cavity, and thereby alter ion occupancy in the selectivity filter [ 72 ]. However, the biological consequences of these compounds activating K2P channels remain unknown, which is likely due to poor in vivo pharmacological profile or low selectivity [ 73 , 74 ].…”

Section: Introductionmentioning

confidence: 99%

Development of Non-opioid Analgesics Targeting Two-pore Domain Potassium Channels

Huang

Jiang

et al. 2022

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: Two-pore domain potassium (K2P) channels are a diverse family of potassium channels. K2P channels generate background leak potassium currents to regulate cellular excitability and are thereby involved in a wide range of neurological disorders. K2P channels are modulated by a variety of physicochemical factors such as mechanical stretch, temperature, and pH. In the the peripheral nervous system (PNS), K2P channels are widely expressed in nociceptive neurons and play a critical roles in pain perception. In this review, we summarize the recent advances in the pharmacological properties of K2P channels, with a focus on the exogenous small-molecule activators targeting K2P channels. We emphasize the subtype-selectivity, cellular and in vivo pharmacological properties of all the reported small-molecule activators. The key underlying analgesic mechanisms mediated by K2P are also summarized based on the data in the literature from studies using small-molecule activators and genetic knock-out animals. We discuss advantages and limitations of the translational perspectives of K2P in pain medicine and provide outstanding questions for future studies in the end.

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Towards a TREK-1/2 (TWIK-Related K+ Channel 1 and 2) dual activator tool compound: Multi-dimensional optimization of BL-1249

Cited by 5 publications

References 20 publications

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

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

Fluorescent membrane potential assay for drug screening on Kv10.1 channel: identification of BL-1249 as a channel activator

Development of Non-opioid Analgesics Targeting Two-pore Domain Potassium Channels

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