5-(4-Chlorophenyl)-furan-2-carboxylic acid 3,5<br>-dimethoxyphenylamide

Description

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.

Chemical Properties

White Solid

Uses

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

General Description

The small molecule A-803467 is a potent and selective Nav1.8 sodium channel blocker. Nav1.8 is a tetrodotoxin-resistant (TTX-R) sodium channel that contributes to pain sensation by transmitting pain stimuli in peripheral sensory neurons; blockage of this channel by A-803467 reduces pain with varying effectiveness in a number of different models. A-803467 has been used to further understand the role of Nav1.8 in transmitting pain stimuli and also can be used as an analgesic.

Biological Activity

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.

Biochem/physiol Actions

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.

storage

+4°C

References

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