Novel potent blockers for TWIK-1/TREK-1 heterodimers as potential antidepressants

Authors
Lee, Elliot H.Park, Jung-eunGotina, LizavetaHan, Young-EunViswanath, Ambily Nath InduYoo, SeongukMoon, BongjinHwang, Jin-YoungPark, Woo KyuCho, YoonjeongSong, ChimanMin, Sun-JoonHwang, Eun MiLee, HyunbeomPae, Ae NimRoh, Eun JooOh, Soo-Jin
Issue Date
2023-09
Publisher
Elsevier Masson
Citation
Biomedicine & Pharmacotherapy, v.165
Abstract
TREK-1 (TWIK-related potassium channel-1) is a subunit of the two-pore domain potassium (K2p) channel and is widely expressed in the brain. TREK-1 knockout mice were shown to have antidepressant-like effects, providing evidence for the channel's potential as a therapeutic target. However, currently there is no good pharmacological inhibitor specifically targeting TREK-1 containing K2p channels that also displays similar antidepressant-like effects. Here, we sought to find selective and potent inhibitors for TREK-1 related dimers both in vitro and in vivo. We synthesized and evaluated 2-hydroxy-3-phenoxypropyl piperidine derivatives yielding a library from which many TREK-1 targeting candidates emerged. Among these, hydroxyl-phenyl- (2a), piperidino- (2g), and pyrrolidino- (2h) piperidinyl substituted compounds showed high potencies to TREK-1 homodimers with significant antidepressant-like effects in forced swim test and tail suspension test. Interestingly, these compounds were found to have high potencies to TWIK-1/TREK-1 heterodimers. Contrastingly, difluoropiperidinyl-4fluorophenoxy (3e) and 4-hydroxyphenyl-piperidinyl-4-fluorophenoxy (3j) compounds had high potencies to TREK-1 homodimer but lower potency to TWIK-1/TREK-1 heterodimers without significant antidepressant-like effects. We observed positive correlation between inhibition potency to TWIK-1/TREK-1 and immobility time, and no correlation between inhibition potency to TREK-1 homodimer and immobility time. This was consistent with molecular docking simulations of selected compounds to TREK-1 homodimeric and TWIK-1/TREK-1 heterodimeric models. Existing antidepressant fluoxetine was also found to potently inhibit TWIK-1/TREK-1 heterodimers. Our study reveals novel potent TWIK-1/TREK-1 inhibitors 2a, 2g, and 2h as potential antidepressants and suggest that the TWIK-1/TREK-1 heterodimer could be a potential novel molecular therapeutic target for antidepressants.
Keywords
DOMAIN POTASSIUM CHANNEL; ACCURATE DOCKING; TREK-1; DEPRESSION; FLUOXETINE; ASTROCYTES; EXPRESSION; GLIDE; MOOD; TWIK-1; Depressive -like behavior; Fluoxetine; Astrocytes; Antidepressant
ISSN
0753-3322
URI
https://pubs.kist.re.kr/handle/201004/113344
DOI
10.1016/j.biopha.2023.115139
Appears in Collections:
KIST Article > 2023
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