Species-specific pharmacology of trichloro(sulfanyl)ethyl benzamides as transient receptor potential ankyrin 1 (TRPA1) antagonists
Species-specific pharmacology of trichloro(sulfanyl)ethyl benzamides as transient receptor potential ankyrin 1 (TRPA1) antagonists
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DOI：
10.1186/1744-8069-3-39
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发表时间：
2007-12-17
期刊：
影响因子：
3.3
通讯作者：
Gavva, Narender R.
中科院分区：
文献类型：
--
作者：
Klionsky, Lana;Tamir, Rami;Gavva, Narender R.
TRPA1的激动剂如芥末油及其关键成分AITC可引起人类疼痛和神经源性炎症以及啮齿动物的疼痛行为。TRPA1被许多活性化合物激活，使其成为体内活性化合物的传感器。在TRPA1基因敲除小鼠中，AITC、福尔马林等反应性化合物无法触发疼痛行为，以及TRPA1反义减轻脊神经结扎后冷痛过敏的能力，提示TRPA1是新型镇痛药物的潜在靶点。在这里，我们表征了CHO细胞在诱导启动子驱动下表达人和大鼠TRPA1。如前所述，人和大鼠TRPA1均被AITC激活，并被钌红抑制。我们还描述了这些细胞系的有害寒冷反应，并表明有害寒冷激活了人和大鼠的TRPA1。此外，我们利用表达人TRPA1的CHO细胞筛选了一个小分子化合物文库，发现“三氯（磺胺基）乙基苯酰胺”（AMG2504、AMG5445、AMG7160和AMG9090）是AITC和毒寒激活的人TRPA1的有效拮抗剂。然而，三氯（磺胺基）乙基苯酰胺（TCEB）化合物对大鼠TRPA1表现出不同的药理作用。AMG2504和AMG7160通过AITC略微抑制大鼠TRPA1的激活，而AMG5445和AMG9090作为部分激动剂。总之，我们得出结论，人和大鼠的TRPA1通道都表现出相似的AITC和毒冷激活谱，但TCEB化合物在TRPA1上表现出物种特异性的差异药理学。
Agonists of TRPA1 such as mustard oil and its key component AITC cause pain and neurogenic inflammation in humans and pain behavior in rodents. TRPA1 is activated by numerous reactive compounds making it a sensor for reactive compounds in the body. Failure of AITC, formalin and other reactive compounds to trigger pain behavior in TRPA1 knockout mice, as well as the ability of TRPA1 antisense to alleviate cold hyperalgesia after spinal nerve ligation, suggest that TRPA1 is a potential target for novel analgesic agents. Here, we have characterized CHO cells expressing human and rat TRPA1 driven by an inducible promoter. As reported previously, both human and rat TRPA1 are activated by AITC and inhibited by ruthenium red. We have also characterized noxious cold response of these cell lines and show that noxious cold activates both human and rat TRPA1. Further, we have used CHO cells expressing human TRPA1 to screen a small molecule compound library and discovered that 'trichloro(sulfanyl)ethyl benzamides' (AMG2504, AMG5445, AMG7160 and AMG9090) act as potent antagonists of human TRPA1 activated by AITC and noxious cold. However, trichloro(sulfanyl) ethyl benzamides' (TCEB compounds) displayed differential pharmacology at rat TRPA1. AMG2504 and AMG7160 marginally inhibited rat TRPA1 activation by AITC, whereas AMG5445 and AMG9090 acted as partial agonists. In summary, we conclude that both human and rat TRPA1 channels show similar AITC and noxious cold activation profiles, but TCEB compounds display species-specific differential pharmacology at TRPA1.