AM-0902是一种有效的、选择性的瞬时受体电位 A1 (TRPA1) 拮抗剂，作用于 rTRPA1 和 hTRPA1 的 IC50 值分别为 71 和 131 nM，已被证明在与疼痛相关的生物学途径中发挥重要作用。
AM-0902 is a potent, selective antagonist of TRPA1 with IC
50
s of 71 and 131 nM for rTRPA1 and hTRPA1, respectively. AM-0902 is highly permeable (average P
app
=44.5 μcm/s in MDCK cells), an unlikely substrate for P-gp (efflux ratio=1.3 in P-gp overexpressing MDCK cells), and demonstrates good solubility (PBS pH 7.4: 226 μM, SIF: 248 μM). AM-0902 shows good selectivity over other TRP channels, as no activity is observed against human TRPV1 or TRPV4, or rat TRPV1, TRPV3, or TRPM8, at concentrations up to 10 μM. AM-0902 inhibits
45
Ca
2+
flux upon activation of rat TRPA1 with methylglyoxal with an IC
50
of 0.019 μM.
AM-0902 is a potent, selective antagonist of TRPA1 in vivo. AM-0902 has moderate terminal elimination half-life (t
1/2
=0.6 h and 2.8 h for rat (0.5 mg/kg, iv), rat (30 mg/kg, oral)). A dose-dependent reduction of allyl isothiocyanate (AITC)-induced flinching is observed for AM-0902, with a significant reduction in flinching observed postdosing of 10 and 30 mg/kg. The unbound plasma concentrations (C
u
) at 1 h for the 1, 3, 10, and 30 mg/kg doses are 0.051±0.024 (n=8), 0.19±0.11 (n=8), 0.58±0.35 (n=8), and 2.2±0.40 (n=8) μM, covering the in vitro rat TRPA1
45
Ca
2+
IC
50
at 0.72, 2.7, 8.2, and 30.3 fold, respectively. A good exposure-response relationship is observed in this target coverage model. An unbound in vivo IC
50
of 0.35 μM, which is in good agreement with the in vitro rat TRPA1
45
Ca
2+
IC
50
, and unbound in vivo IC
90
of 1.7 μM are determined. It is noteworthy that at a dose of 30 mg/kg, AM-0902 engages TRPA1 at concentrations that exceed the in vivo IC
90
, making it a useful tool for exploration of in vivo models of acute pain.