A-803467 is a selective NaV1.8 channel blocker.

Nav1.8 channel:8 nM

A-803467 effectively reduced pain sensitivity in a dose-dependent manner in models including spinal nerve ligation (ED50 = 47 mg/kg, ip), sciatic nerve injury (ED50 = 85 mg/kg, ip), capsaicin-induced secondary mechanical allodynia (ED50 ≈ 100 mg/kg, intraperitoneally), and hyperalgesia following complete Freund's adjuvant injection into the plantar foot (ED50 = 41 mg/kg, intraperitoneally). Consistent with its effects on neuronal action potentials in vitro, systemic administration of A-803467 (20 mg/kg, iv) to rats with spinal nerve ligation significantly reduced both spontaneous and von Frey hair-induced responses in wide dynamic range neurons of the spinal cord dorsal horn by 66% and 53%, respectively. However, A-803467 was ineffective in models of harm induced by formalin, as well as acute thermal, postoperative pain, and pain caused by chemotherapy (vincristine).

A-803467 selectively blocks tetrodotoxin-resistant (TTX-R) currents in rat dorsal root ganglion neurons in a concentration-dependent manner, with an IC50 of 140 nM, proving more effective than mexiletine and lamotrigine (IC50> 30 μM). It exhibits 300 to 1,000 times higher selectivity for hNaV1.8 over hNaV1.2, hNaV1.3, hNaV1.5, and hNaV1.7 channels, with respective IC50 values of 7.38 μM, 2.45 μM, 7.34 μM, and 6.74 μM. A-803467 shows no significant activity against other channels and receptors expressed in peripheral sensory neurons (including TRPV1, P2X2/3, CaV2.2, and KCNQ2/3 channels), with an IC50 > 10 μM. It effectively blocks recombinant human or rat Nav1.8 channels at IC50s of 8 nM and 45 nM, maintained at a -40 mV potential. A-803467 also blocks human NaV1.8 channels in a resting state, with an IC50 of 79 nM.

Maize HD2, HD1-B, and HD1-A Enzyme Inhibition.: The enzyme liberats tritiated acetic acid from the substrate, which is quantified by scintillation counting. IC50 values are results of triple determinations. A 50 μL sample of maize enzyme (at 30 °C) is incubated (30 min) with 10 μL of total [3H]acetate-prelabeled chicken reticulocyte histones (2 mg/mL). Reaction is stopped by addition of 50 μL of 1 M HCl/0.4 M acetate and 800 μL of ethyl acetate. After centrifugation (1×104 g, 5 min), an aliquot of 600 μL of the upper phase is counted for radioactivity in 3 mL of liquid scintillation cocktail. MC1568 is tested at a starting concentration of 40 μM, and active substances are diluted further. NaB, VPA, TSA, SAHA, 85 TPX, HC-toxin, and tubacin are used as the reference compounds, and blank solvents are used as negative controls.