Treatment with HC-070, a potent inhibitor of TRPC4 and TRPC5, leads to anxiolytic and antidepressant effects in mice.
Treatment with HC-070, a potent inhibitor of TRPC4 and TRPC5, leads to anxiolytic and antidepressant effects in mice.
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DOI：
10.1371/journal.pone.0191225
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发表时间：
2018
期刊：
影响因子：
3.7
通讯作者：
Moran MM
中科院分区：
文献类型：
--
作者：
Just S;Chenard BL;Ceci A;Strassmaier T;Chong JA;Blair NT;Gallaschun RJ;Del Camino D;Cantin S;D'Amours M;Eickmeier C;Fanger CM;Hecker C;Hessler DP;Hengerer B;Kroker KS;Malekiani S;Mihalek R;McLaughlin J;Rast G;Witek J;Sauer A;Pryce CR;Moran MM
美国有4000万成年人患有焦虑症，这使焦虑症成为最常见的精神疾病。瞬时受体电位通道典型亚家族(TRPC)成员4和5是非选择性阳离子通道，在大脑皮层和杏仁核高表达，这两个区域被认为是调节焦虑的重要区域。先前对空小鼠的研究表明，抑制TRPC4和TRPC5可能具有缓解焦虑的作用。为了评估TRPC4/5抑制剂作为治疗途径的潜力，我们发明了一种高度有效的TRPC4和TRPC5的小分子拮抗剂，我们称之为HC-070。HC-070抑制异源表达系统中重组的TRPC4和TRPC5同源多聚体，具有纳摩尔效力。它还抑制效力相似的TRPC1/5和TRPC1/4异源多聚体，并减少杏仁核中CCK-4引起的反应。该化合物对包括离子通道、受体和激动酶在内的广泛分子靶标具有400倍的选择性。在小鼠口服剂量后，HC-070在大脑和血浆中的暴露水平被认为足以测试行为活动。HC-070可减弱CCK-4在高架+迷宫(EPM)中的焦虑效应。该化合物概括了在标准EPM中观察到的TRPC4和TRPC5缺失型小鼠的表型。HC-070的抗焦虑和抗抑郁作用也在体内药理试验中观察到，包括大理石埋藏、尾部悬吊和强迫游泳。此外，HC-070还可改善慢性社会应激引起的恐惧记忆增强。对药代动力学-药效学关系的仔细评估显示，在与体外记录的50%抑制浓度(IC50)相似甚至更低的非结合脑水平上观察到实质性疗效，从而增强了人们对所观察到的效果确实是由TRPC4和/或TRPC5抑制介导的信心。总之，本实验数据集介绍了一种新型的、高质量的含有TRPC4和TRPC5通道的小分子拮抗剂，并支持靶向TRPC4和TRPC5通道作为治疗精神症状的新作用机制。
Forty million adults in the US suffer from anxiety disorders, making these the most common forms of mental illness. Transient receptor potential channel canonical subfamily (TRPC) members 4 and 5 are non-selective cation channels highly expressed in regions of the cortex and amygdala, areas thought to be important in regulating anxiety. Previous work with null mice suggests that inhibition of TRPC4 and TRPC5 may have anxiolytic effects. To assess the potential of TRPC4/5 inhibitors as an avenue for treatment, we invented a highly potent, small molecule antagonist of TRPC4 and TRPC5 which we call HC-070. HC-070 inhibits recombinant TRPC4 and TRPC5 homomultimers in heterologous expression systems with nanomolar potency. It also inhibits TRPC1/5 and TRPC1/4 heteromultimers with similar potency and reduces responses evoked by cholecystokinin tetrapeptide (CCK-4) in the amygdala. The compound is >400-fold selective over a wide range of molecular targets including ion channels, receptors, and kinases. Upon oral dosing in mice, HC-070 achieves exposure levels in the brain and plasma deemed sufficient to test behavioral activity. Treatment with HC-070 attenuates the anxiogenic effect of CCK-4 in the elevated plus maze (EPM). The compound recapitulates the phenotype observed in both null TRPC4 and TRPC5 mice in a standard EPM. Anxiolytic and anti-depressant effects of HC-070 are also observed in pharmacological in vivo tests including marble burying, tail suspension and forced swim. Furthermore, HC-070 ameliorates the increased fear memory induced by chronic social stress. A careful evaluation of the pharmacokinetic-pharmacodynamic relationship reveals that substantial efficacy is observed at unbound brain levels similar to, or even lower than, the 50% inhibitory concentration (IC50) recorded in vitro, increasing confidence that the observed effects are indeed mediated by TRPC4 and/or TRPC5 inhibition. Together, this experimental data set introduces a novel, high quality, small molecule antagonist of TRPC4 and TRPC5 containing channels and supports the targeting of TRPC4 and TRPC5 channels as a new mechanism of action for the treatment of psychiatric symptoms.
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影响因子：
3.4
作者：
Lucki, I;Dalvi, A;Mayorga, AJ
通讯作者：
Mayorga, AJ
影响因子：
4.8
作者：
Miller, Melissa;Shi, Jie;Zhu, Michael X.
通讯作者：
Zhu, Michael X.
影响因子：
64.5
作者：
Riccio A;Li Y;Moon J;Kim KS;Smith KS;Rudolph U;Gapon S;Yao GL;Tsvetkov E;Rodig SJ;Van't Veer A;Meloni EG;Carlezon WA Jr;Bolshakov VY;Clapham DE
通讯作者：
Clapham DE
影响因子：
3.6
作者：
NJUNGE, K;HANDLEY, SL
通讯作者：
HANDLEY, SL
DOI：
10.1085/jgp.200810153
发表时间：
2009-05
期刊：
The Journal of general physiology
影响因子：
--
作者：
Blair NT;Kaczmarek JS;Clapham DE
通讯作者：
Clapham DE