Novel potent blockers for TWIK-1/TREK-1 heterodimers as potential antidepressants,Biomedicine & Pharmacotherapy

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Novel potent blockers for TWIK-1/TREK-1 heterodimers as potential antidepressants
Biomedicine & Pharmacotherapy ( IF 6.9 ) Pub Date : 2023-07-15 , 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 ₃ , Eun Joo Roh ₁₂ , Soo-Jin Oh ₄

Affiliation

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.
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.
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.
Brain Science Institute, Korea Institute of Science and Technology, Seoul 02792, Republic of Korea.
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.
Department of Chemistry, Sogang University, Baekbeomno 35, Mapo-gu, Seoul, Republic of Korea.
Department of Anesthesiology and Pain Medicine, SMG-SNU Boramae Medical Center, College of Medicine, Seoul National University, Seoul, Republic of Korea.
Rare Disease Therapeutic Technology Center, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea.
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.
Department of Chemical & Molecular Engineering/Applied Chemistry, Center for Bionano Intelligence Education and Research, Hanyang University, Ansan, Gyeonggi-do 15588, Republic of Korea.
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.
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.

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- (), piperidino- (), and pyrrolidino- ( 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 ( and 4-hydroxyphenyl-piperidinyl-4-fluorophenoxy ( 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 , , and as potential antidepressants and suggest that the TWIK-1/TREK-1 heterodimer could be a potential novel molecular therapeutic target for antidepressants.

中文翻译：

TWIK-1/TREK-1 异二聚体的新型有效阻断剂作为潜在的抗抑郁药

TREK-1（TWIK 相关钾通道-1）是双孔域钾 (K2p) 通道的一个亚基，在大脑中广泛表达。 TREK-1 基因敲除小鼠被证明具有抗抑郁样作用，为该通道作为治疗靶点的潜力提供了证据。然而，目前还没有专门针对含有 K2p 通道的 TREK-1 且具有类似抗抑郁样作用的良好药理学抑制剂。在这里，我们寻求在体外和体内寻找 TREK-1 相关二聚体的选择性和有效抑制剂。我们合成并评估了 2-羟基-3-苯氧基丙基哌啶衍生物，产生了一个库，从中出现了许多 TREK-1 靶向候选物。其中，羟基-苯基-()、哌啶基-()和吡咯烷-(哌啶基取代的化合物对TREK-1同二聚体表现出高效能，在强迫游泳试验和悬尾试验中具有显着的抗抑郁样作用。有趣的是，这些化合物是发现对 TWIK-1/TREK-1 异二聚体具有高效能，相比之下，二氟哌啶基-4-氟苯氧基 ( 和 4-羟基苯基-哌啶基-4-氟苯氧基 () 化合物对 TREK-1 同二聚体具有高效能，但对 TWIK-1 的效力较低。 /TREK-1 异二聚体没有显着的抗抑郁样作用，我们观察到 TWIK-1/TREK-1 的抑制效力与不动时间之间呈正相关，而 TREK-1 同二聚体的抑制效力与不动时间之间没有相关性，这与此一致。所选化合物与 TREK-1 同二聚体和 TWIK-1/TREK-1 异二聚体模型的分子对接模拟还发现，现有抗抑郁药氟西汀可有效抑制 TWIK-1/TREK-1 异二聚体。我们的研究揭示了新型有效的 TWIK-1/TREK-1 抑制剂，作为潜在的抗抑郁药，并表明 TWIK-1/TREK-1 异二聚体可能是抗抑郁药的潜在新型分子治疗靶点。

更新日期：2023-07-15

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