2. Academic Validation
  3. Novel potent blockers for TWIK-1/TREK-1 heterodimers as potential antidepressants

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

  • Biomed Pharmacother. 2023 Sep:165:115139. doi: 10.1016/j.biopha.2023.115139.
Elliot H Lee 1,  Jung-Eun Park 2,  Lizaveta Gotina 3,  Young-Eun Han 4,  Ambily Nath Indu Viswanath 3,  Seonguk Yoo 5,  Bongjin Moon 6,  Jin-Young Hwang 7,  Woo Kyu Park 8,  Yoonjeong Cho 4,  Chiman Song 9,  Sun-Joon Min 10,  Eun Mi Hwang 3,  Hyunbeom Lee 11,  Ae Nim Pae 12,  Eun Joo Roh 13,  Soo-Jin Oh 14
Affiliations

Affiliations

  • 1 Brain Science Institute, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea; Department of Anesthesiology and Pain Medicine, SMG-SNU Boramae Medical Center, College of Medicine, Seoul National University, Seoul, Republic of Korea.
  • 2 Chemical Kinomics Research Center, Korea Institute of Science and Technology, Seoul, Republic of Korea; Department of Chemistry, Sogang University, Baekbeomno 35, Mapo-gu, Seoul, Republic of Korea.
  • 3 Brain Science Institute, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea; Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology, Seoul 02792, Republic of Korea.
  • 4 Brain Science Institute, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea.
  • 5 Center for Advanced Biomolecular Recognition, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea; Department of Life and Nanopharmaceutical Sciences, Kyung Hee University, Seoul 02447, Republic of Korea.
  • 6 Department of Chemistry, Sogang University, Baekbeomno 35, Mapo-gu, Seoul, Republic of Korea.
  • 7 Department of Anesthesiology and Pain Medicine, SMG-SNU Boramae Medical Center, College of Medicine, Seoul National University, Seoul, Republic of Korea.
  • 8 Rare Disease Therapeutic Technology Center, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea.
  • 9 Chemical Kinomics Research Center, Korea Institute of Science and Technology, Seoul, Republic of Korea; Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology, Seoul 02792, Republic of Korea; Biomedical Research Division, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea.
  • 10 Department of Chemical & Molecular Engineering/Applied Chemistry, Center for Bionano Intelligence Education and Research, Hanyang University, Ansan, Gyeonggi-do 15588, Republic of Korea.
  • 11 Center for Advanced Biomolecular Recognition, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea; Department of HY-KIST Bio-convergence, Hanyang University, Seoul 04763, Republic of Korea.
  • 12 Brain Science Institute, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea; Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology, Seoul 02792, Republic of Korea. Electronic address: anpae@kist.re.kr.
  • 13 Chemical Kinomics Research Center, Korea Institute of Science and Technology, Seoul, Republic of Korea; Division of Bio-Medical Science & Technology, KIST School, Korea University of Science and Technology, Seoul 02792, Republic of Korea. Electronic address: r8636@kist.re.kr.
  • 14 Brain Science Institute, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea. Electronic address: osj@kist.re.kr.
PMID: 37454597 DOI: 10.1016/j.biopha.2023.115139
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-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.

Keywords

Antidepressant; Astrocytes; Depressive-like behavior; Fluoxetine; TREK-1; TWIK-1.

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