Novel potent blockers for TWIK-1/TREK-1 heterodimers as potential antidepressants
- Authors
- Lee, Elliot H.; Park, Jung-eun; Gotina, Lizaveta; Han, Young-Eun; Viswanath, Ambily Nath Indu; Yoo, Seonguk; Moon, Bongjin; Hwang, Jin-Young; Park, Woo Kyu; Cho, Yoonjeong; Song, Chiman; Min, Sun-Joon; Hwang, Eun Mi; Lee, Hyunbeom; Pae, Ae Nim; Roh, Eun Joo; Oh, 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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