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 2024-01-19T09:00:25Z 2024-01-19T09:00:25Z 2023-08-17 2023-09 0753-3322 https://pubs.kist.re.kr/handle/201004/113344 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. English Elsevier Masson Novel potent blockers for TWIK-1/TREK-1 heterodimers as potential antidepressants Article 10.1016/j.biopha.2023.115139 1 Biomedicine & Pharmacotherapy, v.165 Biomedicine & Pharmacotherapy 165 Y scie scopus 001037199300001 2-s2.0-85165236401 Medicine, Research & Experimental Pharmacology & Pharmacy Research & Experimental Medicine Pharmacology & Pharmacy Article DOMAIN POTASSIUM CHANNEL ACCURATE DOCKING TREK-1 DEPRESSION FLUOXETINE ASTROCYTES EXPRESSION GLIDE MOOD TWIK-1 Depressive -like behavior Fluoxetine Astrocytes Antidepressant