AMG 9810 [(E)-3-(4-t-butylphenyl)-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)acrylamide], a novel vanilloid receptor 1 (TRPV1) antagonist with antihyperalgesic properties
AMG 9810 [(E)-3-(4-t-butylphenyl)-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)acrylamide], a novel vanilloid receptor 1 (TRPV1) antagonist with antihyperalgesic properties
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DOI：
10.1124/jpet.104.079855
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发表时间：
2005-04-01
影响因子：
3.5
通讯作者：
Treanor, JJS
中科院分区：
文献类型：
--
作者：
Gavva, NR;Tamir, R;Treanor, JJS
香草酸受体1（VR 1或TRPV 1）是由外周感觉神经元表达的膜结合的非选择性阳离子通道。TRPV 1拮抗剂在炎性和神经性疼痛的动物模型中产生抗痛觉过敏作用。在此，我们描述了一种新型TRPV 1拮抗剂AMG 9810（E）-3-（4-叔丁基苯基）-N-（2，3-二氢苯并[B][1，4]二恶英-6-基）丙烯酰胺的体外和体内药理学。AMG 9810是辣椒素激活的竞争性拮抗剂（人TRPV 1的IC 50值，24.5 +/- 15.7 nM;大鼠TRPV 1，85.6 +/- 39.4 nM）并阻断所有已知的TRPV 1激活模式，包括质子（大鼠TRPV 1的IC 50值，294 +/- 192 nM;人TRPV 1，92.7 +/- 72.8 nM），热（大鼠TRPV 1的IC 50值为21 +/- 17 nM;人TRPV 1为15.8 +/- 10.8 nM）和内源性配体，如花生四烯酸、N-花生四烯酸多巴胺和油酰多巴胺。AMG 9810阻断大鼠背根神经节原代神经元培养物中辣椒素诱发的去极化和降钙素基因相关肽释放。针对一组G蛋白偶联受体和离子通道筛选AMG 9810表明对TRPV 1具有选择性。在体内，AMG 9810以剂量依赖性方式有效预防辣椒素诱导的擦眼，并逆转足底注射完全弗氏佐剂诱导的炎性疼痛模型中的热和机械性痛觉过敏。在有效剂量下，AMG 9810对运动功能未显示任何显著影响，如通过旷场运动活动和运动协调试验测量的。AMG 9810是第一个在炎性疼痛动物模型中报告可阻断辣椒素诱导的擦眼行为并逆转痛觉过敏的肉桂酰胺TRPV 1拮抗剂。
The vanilloid receptor 1 (VR1 or TRPV1) is a membrane-bound, nonselective cation channel expressed by peripheral sensory neurons. TRPV1 antagonists produce antihyperalgesic effects in animal models of inflammatory and neuropathic pain. Here, we describe the in vitro and in vivo pharmacology of a novel TRPV1 antagonist, AMG 9810, (E)-3-(4-t- butylphenyl)-N-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)acrylamide. AMG 9810 is a competitive antagonist of capsaicin activation (IC50 value for human TRPV1, 24.5 +/- 15.7 nM; rat TRPV1, 85.6 +/- 39.4 nM) and blocks all known modes of TRPV1 activation, including protons (IC50 value for rat TRPV1, 294 +/- 192 nM; human TRPV1, 92.7 +/- 72.8 nM), heat (IC50 value for rat TRPV1, 21 +/- 17 nM; human TRPV1, 15.8 +/- 10.8 nM), and endogenous ligands, such as anandamide, N-arachidonyl dopamine, and oleoyldopamine. AMG 9810 blocks capsaicin-evoked depolarization and calcitonin gene-related peptide release in cultures of rat dorsal root ganglion primary neurons. Screening of AMG 9810 against a panel of G protein-coupled receptors and ion channels indicated selectivity toward TRPV1. In vivo, AMG 9810 is effective at preventing capsaicin-induced eye wiping in a dose-dependent manner, and it reverses thermal and mechanical hyperalgesia in a model of inflammatory pain induced by intraplantar injection of complete Freund's adjuvant. At effective doses, AMG 9810 did not show any significant effects on motor function, as measured by open field locomotor activity and motor coordination tests. AMG 9810 is the first cinnamide TRPV1 antagonist reported to block capsaicin-induced eye wiping behavior and reverse hyperalgesia in an animal model of inflammatory pain.