TROX-1

TROX-1 is a selective, orally active and brain-penetrant N-type calcium channel (Cav2.2) inhibitor with an IC₅₀ value of 0.11 μM. TROX-1 exerts state-dependent and use-dependent inhibition, preferentially targets open/inactivated channels, blocks depolarization-associated calcium influx, and fully blocks calcium influx in rat dorsal root ganglion neurons. TROX-1 reverses inflammatory-induced hyperalgesia, nerve injury-induced allodynia. TROX-1 can be used for the research of pain^[1][2]. In Vitro:TROX-1 (0.3-3 μM) potently inhibits CaV2.2 channels in stable HEK293 bMHN-4 cells under depolarized (inactivated/open state-biased) conditions with an IC₅₀ of 0.11 μM, and shows drastically reduced potency under hyperpolarized (closed state-biased) conditions^[1].
TROX-1 inhibits CaV2.2 channels in stable HEK293 bMHN-4 cells in a voltage-dependent manner, with potency increasing 11.7-fold as the holding potential shifts from -110 mV (IC₅₀ = 4.2 μM) to -70 mV (IC₅₀ = 0.36 μM)^[1].
TROX-1 inhibits CaV2.2 channels in stable HEK293 CBK cells in a use-dependent manner, with 10-fold higher potency at the 20th pulse (IC₅₀ = 2.4 μM) compared to the first pulse (IC₅₀ = 24 μM) of a depolarizing train^[1].
TROX-1 inhibits CaV2.1, CaV2.2, and CaV2.3 channels in stable HEK293 cells with similar potency (IC₅₀ values = 0.29, 0.19, 0.28 μM, respectively) when tested under depolarized conditions with matched ~30% channel inactivation, and shows apparent selectivity for CaV2.2 and CaV2.3 over CaV2.1 under hyperpolarized conditions^[1].
TROX-1 (1 nM-30 μM; 30 min preincubation) inhibits CaV2.1, CaV2.2, and CaV2.3 channel-mediated calcium influx in stable HEK293 cells in vitro in a state-dependent manner, with similar potency across all three subtypes when normalized to channel inactivation levels, and larger potency shifts for CaV2.2 and CaV2.3 between hyperpolarized and depolarized conditions compared to CaV2.1^[1].
TROX-1 (0.001-30 μM) potently and state-dependently inhibits calcium influx through recombinant Cav2.2 channels in CBK cells, with an IC₅₀ of 0.27 μM under depolarized conditions and >10 μM under hyperpolarized conditions^[2].
TROX-1 (0.3-3 μM) state-dependently inhibits Cav2.2-mediated barium currents in rat DRG neurons, with an IC₅₀ of 0.4 μM under depolarized conditions and 2.6 μM under hyperpolarized conditions^[2].
TROX-1 (1-30 μM; 20 min) dose-dependently and fully inhibits calcium influx mediated by all Cav2 family channels in neonatal rat DRG neurons^[2]. In Vivo:TROX-1 (3-30 mg/kg; p.o.; single dose or daily for 3 days) reverses CFA (HY-153808)-induced mechanical hyperalgesia in rats^[2].
TROX-1 (3-30 mg/kg; p.o.; single dose) dose-dependently reverses SNL-induced tactile allodynia in rats after oral administration, with maximal 72% reversal at 30 mg/kg and an ED₅₀ of 8 mg/kg^[2].
TROX-1 (3-30 mg/kg; p.o.; single dose) dose-dependently reverses Capsaicin (HY-10448)-induced secondary allodynia in rats after oral administration^[2].
TROX-1 (3-30 mg/kg; p.o.; single dose) dose-dependently reverses Iodoacetate-induced allodynia and weight bearing changes in rats after oral administration, with maximal 49% reversal of allodynia and 43% reversal of weight bearing changes at 30 mg/kg^[2].
TROX-1 (10-30 mg/kg; p.o.; single dose) does not alter thermal latency in the rat hot-plate model of acute nociception at oral doses up to 30 mg/kg^[2].
TROX-1 (30 mg/kg; p.o.; single dose) significantly reverses CFA-induced thermal hyperalgesia in wild-type mice after oral administration at 30 mg/kg, but its efficacy is abrogated in Cav2.2-deficient mice^[2].
TROX-1 (30-100 mg/kg; p.o.; single dose) causes mild motor impairment in rats only at an oral dose of 100 mg/kg, providing a CNS therapeutic window of ~12.5 relative to its analgesic efficacy in neuropathic pain^[2].
TROX-1 (0.1-1 mg/kg/min; i.v.; 30 min infusion) does not significantly alter baroreflex function in conscious rats at intravenous infusion doses up to 0.3 mg/kg/min, with mild HR range reduction only at 1 mg/kg/min, providing a cardiovascular therapeutic window of 38-fold relative to analgesic efficacy^[2].
TROX-1 (1-7 mg/kg; i.v.; 30 min infusion, cumulative doses 1-10 mg/kg) dose-dependently decreases MAP and HR in anesthetized, vagotomized dogs at cumulative intravenous doses of 3 mg/kg and higher, with significant effects observed at plasma levels ≥18 μM^[2].