AMG 9810 is a vanilloid receptor 1 (VR1 or TRPV1) antagonist, with IC50 values for human TRPV1 of 24.5±15.7 nM, for rat TRPV1 of 85.6 ±39.4 nM as a competitive antagonist of capsaicin activation. To block protons, its IC50 values for rat TRPV1 is 294±192 nM, for human TRPV1 is 92.7±72.8 nM. To block heat, its IC50 value for rat TRPV1 is 21±17 nM, for human TRPV1 is 15.8±10.8 nM. It can also block endogenous ligands, such as N-arachidonyl dopamine, anandamide and oleoyldopamine [1].
TRPV1 is expressed by peripheral sensory neurons. It is a membrane-bound, nonselective cation channel [1].
In rat dorsal root ganglia neurons with the presence of endogenous TRPV1, 45Ca2+ uptake was induced by capsaicin in a dose-dependent manner, the EC90 value is 300 nM. In a Ca2+-dependent manner, capsaicin induces CGRP release through the activation of TRPV1. Capsaicin at 300 nM induced a greater level of CGRP release from cultured neurons into the media, compared with the basal level. Capsaicin-induced 45Ca2+ uptake and CGRP release was potently blocked by AMG 9810 with IC50 values of 9±6 nM and 6±3 nM, respectively. AMG 9810 alone up to 10 ?M had no effect on the basal 45Ca2+ uptake or CGRP release of exposed neurons [1].
In animals capsaicin induced eye wipes. Intraperitoneally, AMG 9810 at 3, 10, and 30 mg/kg, dose-dependently decrease this effect at 15 min. Treatment with AMG 9810 at 10 and 30 mg/kg, 30 min before capsaicin treatment, statistically significantly reduced the number of eye wipes. Only treatment with AMG 9810 at 30 mg/kg 60 min before capsaicin administration significantly reduced eye wipes. Vehicle did not affect capsaicin-evoked eye wipes [1].
Reference:
[1].? Gavva NR, 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 Pharmacol Exp Ther, 2005, 313(1):474-84.
