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

• Published in: Biomedicine & pharmacotherapy 2023-09, Vol.165, p.115139-115139, Article 115139
• Main 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
• Format: Article
• Language: English
• Subjects: Antidepressant; Astrocytes; Depressive-like behavior; Fluoxetine; TREK-1; TWIK-1
• ISSN: 0753-3322; 1950-6007
• DOI: 10.1016/j.biopha.2023.115139

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-4-fluorophenoxy (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. [Display omitted] •Novel compounds were discovered that potently inhibit TWIK-1/TREK-1 heterodimers.•Potency against astrocytic TWIK-1/TREK-1 heterodimers was necessary to have antidepressant-like effects.•Assessment of TWIK-1/TREK-1 inhibition may be a novel therapeutic strategy for development of antidepressants.