LTGO-33 is a potent and selective voltage-gated sodium channel NaV1.8 inhibitor. LTGO-33 inhibits NaV1.8 in the nM potency range and exhibits over 600-fold selectivity against human NaV1.1-NaV1.7 and NaV1.9. LTGO-33 exhibits state-independent inhibition with similar potencies on channels in the closed and inactivated conformations. LTGO-33 inhibits native TTX-R NaV1.8 currents in non-human primate and human DRG neurons, where it reduces action potential firing. LTGO-33 can be used for pain disorders research.
LTGO-33 exhibits an IC50 of 33 nM from the closed state and 24 nM from an inactivated state[1].LTGO-33 displays species specificity for primate NaV1.8 over dog and rodent NaV1.8 and inhibits action potential firing in human dorsal root ganglia neurons[1].LTGO-33 inhibits TTX-R currents in primary DRG neurons from human (male donors: IC50 of 110 nM, 95% CI: 92 to 120 nM, n = 3-15 neurons per concentration; female donors: IC50 of 120 nM, 95% CI: 100 to 140 nM, 4- 6 neurons per concentration) and cynomolgus monkey (IC50 of 100 nM, 95% CI: 71 to 150 nM, n = 6 cells) but is markedly less effective on DRG neurons from dog (IC50 >10 µM, n = 6 cells), rat (IC50 >30 µM, n = 7 cells), and mouse (IC50 >30 µM, n = 8 cells)[1].LTGO-33 stabilizs the deactivated state of VSDII, effectively keeping the channel closed by preventing movement of VSDII[1].
References:
[1]. Gilchrist JM, et al. Pharmacologic Characterization of LTGO-33, a Selective Small Molecule Inhibitor of the Voltage-Gated Sodium Channel NaV1.8 with a Unique Mechanism of Action. Mol Pharmacol. 2024 Feb 15;105(3):233-249.