GSK1016790A

GSK1016790A is a potent and selective transient receptor potential vanilloid 4 (TRPV4) channel agonist^[1]. TRPV4 is a Ca²⁺-permeable, non-selective cation channel involved in a variety of physiological functions, such as regulation of systemic osmotic pressure, vascular function, skin barrier function, airway and lung function, and pain^[2]. GSK1016790A is a cell-permeable piperazinamide derivative that is approximately 300 times more potent than 4-α-PDD in activating TRPV4 channels^[3].

In vitro, GSK1016790A (10 nM) treatment of HeLa cells transfected with TRPV4-mCerulean and TRPV4-mVenus for 30 min resulted in rapid early activation of TRPV4 and a significant and sustained increase in cytoplasmic Ca²⁺ levels, which then rapidly decayed to a pseudo-steady state within approximately 3 minutes^[4]. GSK1016790A (0.1-1000 nM) treatment of HEK cells induced Ca²⁺ influx, with EC₅₀ values ​​of 18 and 2.1 nM for human and mouse HEK cells, respectively^[5].

In vivo, oral treatment of atherosclerotic mice with GSK1016790A (10 mg/kg) for 3 days significantly reduced the development of atherosclerotic plaques and the content of macrophages in the aortic sinus^[6]. GSK1016790A (0.5 nM/5 mL) treated mice with intracerebral hemorrhage (ICH) by intraventricular injection alleviated neurological and motor deficits and upregulated the expression level of c-fos, a marker of neuronal activity^[7].

References:
[1] Kittaka H, Yamanoi Y, Tominaga M. Transient receptor potential vanilloid 4 (TRPV4) channel as a target of crotamiton and its bimodal effects[J]. Pflügers Archiv-European Journal of Physiology, 2017, 469: 1313-1323.
[2] Nilius B, Voets T. The puzzle of TRPV4 channelopathies[J]. EMBO reports, 2013, 14(2): 152-163.
[3] Thorneloe K S, Sulpizio A C, Lin Z, et al. N-((1S)-1-{[4-((2S)-2-{[(2, 4-dichlorophenyl) sulfonyl] amino}-3-hydroxypropanoyl)-1-piperazinyl] carbonyl}-3-methylbutyl)-1-benzothiophene-2-carboxamide (GSK1016790A), a novel and potent transient receptor potential vanilloid 4 channel agonist induces urinary bladder contraction and hyperactivity: Part I[J]. Journal of Pharmacology and Experimental Therapeutics, 2008, 326(2): 432-442.
[4] Jin M, Wu Z, Chen L, et al. Determinants of TRPV4 activity following selective activation by small molecule agonist GSK1016790A[J]. PloS one, 2011, 6(2): e16713.
[5] Fichna J, Poole D P, Veldhuis N, et al. Transient receptor potential vanilloid 4 inhibits mouse colonic motility by activating NO-dependent enteric neurotransmission[J]. Journal of Molecular Medicine, 2015, 93: 1297-1309.
[6] Xu S, Liu B, Yin M, et al. A novel TRPV4-specific agonist inhibits monocyte adhesion and atherosclerosis[J]. Oncotarget, 2016, 7(25): 37622.
[7] Asao Y, Tobori S, Kakae M, et al. Transient receptor potential vanilloid 4 agonist GSK1016790A improves neurological outcomes after intracerebral hemorrhage in mice[J]. Biochemical and Biophysical Research Communications, 2020, 529(3): 590-595.

GSK1016790A是一种有效的选择性瞬时受体电位香草酸4（TRPV4）通道激动剂^[1]。TRPV4是一种Ca²⁺渗透性、非选择性阳离子通道，参与多种生理功能，例如全身渗透压的调节、血管功能、皮肤屏障功能、气道和肺功能以及疼痛^[2]。GSK1016790A是一种细胞渗透性哌嗪酰胺衍生物，激活TRPV4通道的效力比4-α-PDD强约300倍^[3]。

在体外，GSK1016790A（10 nM）分别处理 TRPV4-mCerulean和TRPV4-mVenus转染的HeLa细胞30min，导致TRPV4早期快速激活，胞质Ca²⁺水平明显持续升高，随后在大约3分钟内迅速衰减至伪稳态^[4]。GSK1016790A（0.1-1000 nM）处理HEK细胞，引起 Ca²⁺ 流入，对人和小鼠HEK细胞的EC₅₀ 值分别为18和2.1 nM^[5]。

在体内，GSK1016790A（10mg/kg）通过口服治疗动脉粥样硬化小鼠3天，动脉粥样硬化斑块的发展和主动脉窦中的巨噬细胞含量显著减少^[6]。GSK1016790A（0.5nM/5mL）通过脑室内注射治疗脑出血（ICH）小鼠，可减轻神经和运动缺陷，上调了神经元活动标志物c-fos的表达水平^[7]。