944261-79-4

Na_v1.8 is a tetrodotoxin-resistant (TTX-R) sodium channel with high activation threshold and slow inactivating kinetics that is highly expressed in small-diameter sensory neurons and has been implicated in signaling various types of pain. A-803467 is a sodium channel blocker with high-affinity and selectivity for inhibiting human Na_v1.8 sodium channels (IC₅₀ = 8 nM when stimulated at half-maximal inactivation and IC₅₀ = 79 nM at a resting state). This compound is unusual in that it blocks hNav1.8 at negative resting membrane potentials (many small molecule sodium channel blockers show a reduced affinity for the resting state) and does not demonstrate significant frequency-dependent block during a 10 Hz pulse train. A-803467 dose-dependently reduces behavioral responses in a variety of neuropathic and inflammatory pain models.

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A selective NaV1.8 sodium channel blocker, reduces behavioral measures of chronic pain.

Selective blocker of Na V 1.8 channels (IC 50 values are 8, 2450, 6740, 7340 and 7380 nM for hNa V 1.8, hNa V 1.3, hNa V 1.7, hNa V 1.5 and hNa V 1.2 channels respectively). Shows no significant activity against TRPV1, P2X 2/3 , Ca V 2.2 and KCNQ2/3 channels. Antinociceptive; potently attenuates mechanical allodynia in two models of neuropathic pain following i.p. administration.

A-803467 blocks Nav1.8 in both half-maximal inactive and resting states with an IC50 of 8 nM and IC50 of 79 nM, respectively. A-803467 is over 100-fold more selective vs. human Nav1.2, 1.3, 1.5 and 1.7.

This potent sodium channel blocker (FW = 357.79 g/mol; CAS 944261-79- 4; Solubility: 72 mg/mL DMSO; <1 mg/mL H2O), also named 5- (4- chlorophenyl) -N- (3,5-dimethoxyphenyl) furan-2-carboxamide, selectively targets NaV1.8 channels (IC50 = 8 nM), blocking tetrodotoxin-resistant currents and exhibiting >100x selectivity against human NaV1.2, NaV1.3, NaV1.5, and NaV1.7. A-803467 potently blocks tetrodotoxin-resistant currents (IC50 = 140 nM), generating spontaneous and electrically evoked action potentials in vitro in rat dorsal root ganglion neurons. Later studies reported the additive antinociceptive effects of the selective Nav1.8 blocker A-803467 and selective TRPV1 antagonists in rat inflammatory and neuropathic pain models. Inhibition of Drug Efflux: ATP-binding cassette (ABC) multidrug transporters (such as ABCB1, or MDR1/P- glycoprotein); ABCC1 (MRP1) and ABCG2 (BCRP/MXR) ) mediate drug efflux in human cancers. ABCG2 is a 72-kDa half transporter that is specifically localized at the apical surface of enterocytes, the luminal surface of liver canaliculi, the luminal surface of the proximal convoluted tubule of the kidneys, the blood–brain barrier (BBB), blood–testis barrier (BTB), blood–placental and blood–retinal barriers. Because of its localization on the secretory surface of the major organs involved in drug transport, ABCG2 alters absorption, distribution, metabolism and elimination of its substrate drugs. A-803467 significantly increases the cellular sensitivity to ABCG2 substrates in drug-resistant cells overexpressing either wild-type or mutant ABCG2. At 7.5 μM, A-803467 3 significantly increases the intracellular accumulation of [H]-mitoxantrone by inhibiting the transport activity of ABCG2, without altering its expression levels. In addition, A-803467 stimulates the ATPase activity in membranes overexpressed with ABCG2. In a murine model system, combination treatment of A-803467 (35 mg/kg) and topotecan (3 mg/kg) significantly inhibits the tumor growth in mice xenografted with ABCG2- overexpressing cancer cells. Such findings indicate that a combination of A-803467 and ABCG2 substrates may potentially be a novel therapeutic treatment in ABCG2-positive drug resistant cancers.

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1) Jarvis et al. (2007), A-803467, a potent and selective Nav1.8 sodium channel blocker, attenuates neuropathic and inflammatory pain in the rat; Proc. Natl. Acad. Sci. USA, 104 8520 2) McGaraughty et al. (2008), A selective Nav1.8 sodium channel blocker, A-803467 [5-(4-chlorophenyl-N-(3,5-dimethoxyphenyl)furan-2-carboxamide], attenuates spinal neuronal activity in neuropathic rats; J. Pharmacol. Exp. Ther., 324 1204