AMG 9810 is a highly selective and competitive TRPV1 antagonist (human: IC50 = 24.5nM; mouse: IC50 = 85.6nM) [1]. AMG 9810 blocks TRPV1 channels activated by capsaicin, acidic conditions, heat, and endogenous ligands such as anandamide, inhibiting ion influx into cells and thereby attenuating the transmission of pain and heat-sensitive signals [2-3]. AMG 9810 exhibits anti-hyperalgesia, anti-inflammatory, and analgesic effects [4].
In HEKn cells, AMG 9810 (0–5μM; 24-72h) was cytotoxic to these cells at the higher concentrations tested and when exposed for longer in culture [5]. In T84 cells, AMG 9810 (100nM; 30min) can block the increase in [Ca2+]i induced by capsaicin and resiniferatoxin [6]. In chinese hamster ovary (CHO) cell, AMG 9810 (3-1000nM; 10min) penetrates faster than capsaicin and is more potent than capsaicin [7].
In Male Wister rats, AMG 9810 (30mg/kg; ip; single injection) injection can induce mild hyperthermia in rats immediately [8]. In C57BL6 mice, AMG 9810 (1nmol; intrathecal injections; single injection) completely blocked NADA-induced allergy 15 and 60 minutes after injection [9].
References:
[1]. Gavva N R, Tamir R, Qu Y, et al. 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[J]. The journal of pharmacology and experimental therapeutics, 2005, 313(1): 474-484.
[2]. Gomtsyan A. Aryl‐Urea Class and Related TRPV1 Antagonists[J]. Vanilloid Receptor TRPV1 in Drug Discovery: Targeting Pain and Other Pathological Disorders, 2010: 293-310.
[3]. Hakimizadeh E, Oryan S, Shamsizadeh A, et al. Endocannabinoid system and TRPV1 receptors in the dorsal hippocampus of the rats modulate anxiety-like behaviors[J]. Iranian Journal of Basic Medical Sciences, 2012, 15(3): 795.
[4]. Gomtsyan A. Aryl‐Urea Class and Related TRPV1 Antagonists[J]. Vanilloid Receptor TRPV1 in Drug Discovery: Targeting Pain and Other Pathological Disorders, 2010: 293-310.
[5]. Park M, Naidoo A A, Burns A, et al. Do TRPV1 antagonists increase the risk for skin tumourigenesis? A collaborative in vitro and in vivo assessment[J]. Cell Biology and Toxicology, 2018, 34(2): 143-162.
[6]. Bouyer P G, Tang X, Weber C R, et al. Capsaicin induces NKCC1 internalization and inhibits chloride secretion in colonic epithelial cells independently of TRPV1[J]. American Journal of Physiology-Gastrointestinal and Liver Physiology, 2013, 304(2): G142-G156.
[7]. Pearce L V, Ann J, Blumberg P M, et al. Combination of a Rapidly Penetrating Agonist and a Slowly Penetrating Antagonist Affords Agonist Action of Limited Duration at the Cellular Level[J]. Biomolecules & Therapeutics, 2019, 27(5): 435.
[8]. Tejada de Rink M M, Naumann U, Kollmar R, et al. A Single Injection of N-Oleoyldopamine, an Endogenous Agonist for Transient Receptor Potential Vanilloid-1, Induced Brain Hypothermia, but No Neuroprotective Effects in Experimentally Induced Cerebral Ischemia in Rats[J]. Therapeutic Hypothermia and Temperature Management, 2020, 10(2): 91-101.
[9]. Pitcher M H, Price T J, Entrena J M, et al. Spinal NKCC1 blockade inhibits TRPV1-dependent referred allodynia[J]. Molecular pain, 2007, 3: 1744-8069-3-17.
AMG 9810是一种高选择性和竞争性TRPV1拮抗剂（人：IC50 = 24.5nM；小鼠：IC50 = 85.6nM） [1]。AMG 9810可阻断由辣椒素、酸性环境、高温以及内源性配体（如花生四烯乙醇胺）激活的TRPV1通道，抑制离子内流进入细胞，从而减弱痛觉和热敏信号的传递 [2-3]。AMG 9810具有抗痛觉过敏、抗炎和镇痛作用 [4]。
在HEKn细胞中，AMG 9810（0-5μM；24-72h）在较高测试浓度下以及在培养条件下暴露时间较长时均对这些细胞表现出细胞毒性 [5]。在T84细胞中，AMG 9810（100nM；30min）可以阻断辣椒素和树脂毒素引起的[Ca2+]i升高 [6]。在中国仓鼠卵巢（CHO）细胞中，AMG 9810（3-1000nM；10min）的渗透速度比辣椒素更快，作用也比辣椒素更强 [7]。
在雄性Wister大鼠中，AMG 9810（30mg/kg；ip；单次注射）注射后可立即引起大鼠轻度高热 [8]。在C57BL6小鼠中，AMG 9810（1nmol；鞘内注射；单次注射）在注射后15和60分钟完全阻断了NADA诱发的过敏反应 [9]。