Drofenine：对人 TRPV3 具有更高选择性的 2-APB 类似物。,Pharmacology Research & Perspectives

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Drofenine：对人 TRPV3 具有更高选择性的 2-APB 类似物。
Pharmacology Research & Perspectives ( IF 2.9 ) Pub Date : 2014-10-01 , DOI: 10.1002/prp2.62
Cassandra E Deering-Rice ₁ , Virginia K Mitchell ₁ , Erin G Romero ₁ , May H Abdel Aziz ₁ , Daniel A Ryskamp ₂ , David Križaj ₂ , V Raj Gopal ₃ , Christopher A Reilly ₁

Affiliation

瞬时受体电位 vanilloid-3 (TRPV3) 是 TRP 离子通道的 TRPV 亚家族的成员。TRPV3 的生理功能尚不完全清楚，部分原因是缺乏选择性激动剂和拮抗剂，它们既可以促进 TRPV3 在哺乳动物生理学中的作用，也可能作为治疗剂来调节 TRPV3 改变的条件功能受到牵连。在这项研究中，利用 TRPV3 过表达 HEK-293 细胞中钙通量的改变，筛选了微源光谱集合中的 TRPV3 激动剂和拮抗剂。解痉剂 drofenine 被确定为一种新的 TRPV3 激动剂。Drofenine 在 HEK-293 细胞中表现出与已知的 TRPV3 激动剂 2-氨基乙氧基二苯基硼酸酯 (2-APB) 和香芹酚相似的效力，但基于缺乏 TRPA1、V1、V2、V4 或 M8 的激活，对 TRPV3 的选择性更高。还鉴定了多种抑制剂，但所有化合物要么无活性，要么不具有特异性。Drofenine 通过与残基 H426 的相互作用激活 TRPV3，这是 2-APB 激活 TRPV3 所必需的。Drofenine 是一种更有效的 TRPV3 激动剂，并且在人角质形成细胞中比香芹酚或 2-APB 更具细胞毒性，使用拮抗剂 icilin 进一步证明了它对 HaCaT 细胞中 TRPV3 的影响。由于现有 TRPV3 调节剂缺乏特异性，并且在细胞/组织中表达多个 TRP 通道，因此 drofenine 可能是阐明复杂生物系统中 TRPV3 功能的有价值的探针。

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Drofenine: A 2-APB Analogue with Greater Selectivity for Human TRPV3.

Transient receptor potential vanilloid-3 (TRPV3) is a member of the TRPV subfamily of TRP ion channels. The physiological functions of TRPV3 are not fully understood, in part due to a lack of selective agonists and antagonists that could both facilitate the elucidation of roles for TRPV3 in mammalian physiology, as well as potentially serve as therapeutic agents to modulate conditions for which altered TRPV3 function has been implicated. In this study, the Microsource Spectrum Collection was screened for TRPV3 agonists and antagonists using alterations in calcium flux in TRPV3 over-expressing HEK-293 cells. The antispasmodic agent drofenine was identified as a new TRPV3 agonist. Drofenine exhibited similar potency to the known TRPV3 agonists 2-aminoethoxydiphenylboronate (2-APB) and carvacrol in HEK-293 cells, but greater selectivity for TRPV3 based on a lack of activation of TRPA1, V1, V2, V4, or M8. Multiple inhibitors were also identified, but all of the compounds were either inactive or not specific. Drofenine activated TRPV3 via interactions with the residue, H426, which is required for TRPV3 activation by 2-APB. Drofenine was a more potent agonist of TRPV3 and more cytotoxic than either carvacrol or 2-APB in human keratinocytes and its effect on TRPV3 in HaCaT cells was further demonstrated using the antagonist icilin. Due to the lack of specificity of existing TRPV3 modulators and the expression of multiple TRP channels in cells/tissue, drofenine may be a valuable probe for elucidating TRPV3 functions in complex biological systems. Identification of TRPV3 as a target for drofenine may also suggest a mechanism by which drofenine acts as a therapeutic agent.

更新日期：2019-11-01

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