Design and Characterization of a Noncompetitive Antagonist of the Transient Receptor Potential Vanilloid Subunit 1 Channel With In Vivo Analgesic and Anti-inflammatory Activity
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- 作者：Carolina Garcí ; a-Martí ; nez ; Asia Ferná ; ndez-Carvajal ; Belen Valenzuela ; Ana Gomis ; Wim Van Den Nest ; Stefano Ferroni ; Cristina Carreñ ; o ; Carlos Belmonte ; Antonio Ferrer-Montiel
- 关键词：Vanilloid receptor subunit 1 ; inflammatory pain ; capsaicin ; formalin ; analgesic
- 刊名：The Journal of Pain
- 出版年：2006
- 出版时间：October 2006
- 年：2006
- 卷：7
- 期：10
- 页码：735-746
- 全文大小：604 K
文摘
Vanilloid receptor subunit 1 (TRPV1) is an integrator of physical and chemical stimuli in the peripheral nervous system. This receptor plays a key role in the pathophysiology of inflammatory pain. Thus, the identification of receptor antagonists with analgesic and anti-inflammatory activity in vivo is an important goal of current neuropharmacology. Here, we report that [L-arginyl]-[N-[2,4-dichlorophenethyl]glycyl]-N-(2,4-dichlorophenethyl) glycinamide (H-Arg-15-15C) is a channel blocker that abrogates capsaicin and pH-evoked TRPV1 channel activity with submicromolar activity. Compound H-Arg-15-15C preferentially inhibits TRPV1, showing marginal block of other neuronal receptors. Compound H-Arg-15-15C acts as a noncompetitive capsaicin antagonist with modest voltage-dependent blockade activity. The compound inhibited capsaicin-evoked nerve activity in afferent fibers without affecting mechanically activated activity. Notably, administration of compound H-Arg-15-15C prevented the irritant activity of a local administration of capsaicin and formalin and reversed the thermal hyperalgesia evoked by injection of complete Freund’s adjuvant. Furthermore, it attenuated carrageenan-induced paw inflammation. Compound H-Arg-15-15C specifically decreased inflammatory conditions without affecting normal nociception. Taken together, these findings demonstrate that compound H-Arg-15-15C is a channel blocker of TRPV1 with analgesic and anti-inflammatory activity in vivo at clinically useful doses and substantiate the tenet that TRPV1 plays an important role in the etiology of chronic inflammatory pain.
Perspective
This study reports the design of a potent TRPV1 noncompetitive antagonist that exhibits anti-inflammatory and analgesic activity in preclinical models of acute and chronic pain. This compound is a lead for analgesic drug development.