tcsc0028325 AM-0902

AM-0902 is a potent, selective transient receptor potential A1 (TRPA1) antagonist with IC₅₀s of 71 and 131 nM for rTRPA1 and hTRPA1, respectively.

IC50 & Target: IC50: 71 nM (rTRPA1), 131 nM (hTRPA1)^[1]

In Vitro: AM-0902 is a potent, selective antagonist of TRPA1 with IC₅₀s 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 ⁴⁵Ca²⁺ flux upon activation of rat TRPA1 with methylglyoxal with an IC₅₀ of 0.019 μM^[1].

In Vivo: 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 ⁴⁵Ca²⁺ IC₅₀ 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 IC₅₀ of 0.35 μM, which is in good agreement with the in vitro rat TRPA1 ⁴⁵Ca²⁺ IC₅₀, and unbound in vivo IC₉₀ 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 IC₉₀, making it a useful tool for exploration of in vivo models of acute pain^[1].