HC-030031是TRPA1选择性拮抗剂，可减轻炎症和神经病引起的机械性超敏反应。,Molecular Pain

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HC-030031是TRPA1选择性拮抗剂，可减轻炎症和神经病引起的机械性超敏反应。
Molecular Pain ( IF 2.8 ) Pub Date : 2008-10-29 , DOI: 10.1186/1744-8069-4-48
Samer R Eid ₁ , Eric D Crown , Eric L Moore , Hongyu A Liang , Kar-Chan Choong , Shelley Dima , Darrell A Henze , Stefanie A Kane , Mark O Urban

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背景技术对慢性炎性和神经性疼痛的安全有效治疗仍然是许多患者未满足的关键医疗需求。包括TRPV1和TRPA1在内的受体的瞬时受体潜在家族的最新发现和描述为治疗慢性疼痛提供了许多潜在的新治疗靶标。最近的报道表明TRPA1可能在急性福尔马林和CFA引起的疼痛中起重要作用。当前的研究旨在进一步探索药理学上的TRPA1拮抗作用治疗炎性和神经性疼痛的治疗潜力。结果HC-030031与肉桂醛或异硫氰酸烯丙酯（AITC或芥子油）诱导的TRPA1活化的体外效价分别为4.9 +/- 0.1和7.5 +/- 0.2 microM（IC50）。这些发现与先前报道的针对AITC激活TRPA1 1的IC50为6.2 microM相似。在大鼠中，口服HC-030031以100 mg / kg的剂量降低了AITC诱导的伤害行为。此外，口服HC-030031（100 mg / kg）在完全慢性弗氏佐剂（CFA）诱发的炎性疼痛和神经性疼痛的脊髓神经结扎模型的更慢性模型中显着逆转了机械性超敏反应。结论通过口服选择性TRPA1拮抗剂HC-030031，我们的研究结果表明TRPA1在炎症性和神经性疼痛模型中观察到的机械超敏反应的机制中起着重要作用。

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HC-030031, a TRPA1 selective antagonist, attenuates inflammatory- and neuropathy-induced mechanical hypersensitivity.

BACKGROUND Safe and effective treatment for chronic inflammatory and neuropathic pain remains a key unmet medical need for many patients. The recent discovery and description of the transient receptor potential family of receptors including TRPV1 and TRPA1 has provided a number of potential new therapeutic targets for treating chronic pain. Recent reports have suggested that TRPA1 may play an important role in acute formalin and CFA induced pain. The current study was designed to further explore the therapeutic potential of pharmacological TRPA1 antagonism to treat inflammatory and neuropathic pain. RESULTS The in vitro potencies of HC-030031 versus cinnamaldehyde or allyl isothiocyanate (AITC or Mustard oil)-induced TRPA1 activation were 4.9 +/- 0.1 and 7.5 +/- 0.2 microM respectively (IC50). These findings were similar to the previously reported IC50 of 6.2 microM against AITC activation of TRPA1 1. In the rat, oral administration of HC-030031 reduced AITC-induced nocifensive behaviors at a dose of 100 mg/kg. Moreover, oral HC-030031 (100 mg/kg) significantly reversed mechanical hypersensitivity in the more chronic models of Complete Freunds Adjuvant (CFA)-induced inflammatory pain and the spinal nerve ligation model of neuropathic pain. CONCLUSION Using oral administration of the selective TRPA1 antagonist HC-030031, our results demonstrated that TRPA1 plays an important role in the mechanisms responsible for mechanical hypersensitivity observed in inflammatory and neuropathic pain models. These findings suggested that TRPA1 antagonism may be a suitable new approach for the development of a potent and selective therapeutic agent to treat both inflammatory and neuropathic pain.

更新日期：2019-11-01

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