A-803467 is a potent and selective tetrodotoxin-resistant Nav1.8 sodium channel blocker (IC50=8 nM). A-803467 (20 mg/kg, i.v.) blocked mechanically evoked firing of wide dynamic range neurons in the rat spinal dorsal horn. A-803467 also dose-dependently reduced mechanical allodynia in a variety of rat pain models including: spinal nerve ligation (ED(50) = 47 mg/kg, i.p.), sciatic nerve injury (ED(50) = 85 mg/kg, i.p.), capsaicin-induced secondary mechanical allodynia (ED(50) approximately 100 mg/kg, i.p.), and thermal hyperalgesia after intraplantar complete Freund's adjuvant injection (ED(50) = 41 mg/kg, i.p.)[3]. A-803467 selectively and significantly reverses the ABCG2-mediated multidrug resistance. A-803467 (7.5 μM) significantly increased the intracellular accumulation of [(3)H]-mitoxantrone by inhibiting the transport activity of ABCG2, without altering its expression levels. In addition, A-803467 stimulated 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 inhibited the tumor growth in mice xenografted with ABCG2-overexpressing cancer cells[4]. A-803467 significantly shortened ventricular effective refractory period, APD90, and ventricular fibrillation threshold compared to control. In the A-803467 group, the incidence of ventricular arrhythmias was significantly higher compared to control. A-803467 suppressed the slowing of heart rate response to high-frequency electrical stimulation of the anterior right GP(ganglionated plexi), suggesting that A-803467 could inhibit GP activity[5].
A-803467 细胞实验
Cell Line
Concentration
Treated Time
Description
References
HEK cells
8 nM
A-803467 inhibited inward currents in HEK cells
Arthritis Res Ther. 2012 Jan 7;14(1):R5.
ND7/23 cells
30 nM
Evaluate the selective inhibition of Nav1.8 current by A-803467
Circ Res. 2012 Jul 20;111(3):322-32.
HEK-293 cells
8 nM
Block human Nav1.8 channels
Proc Natl Acad Sci U S A. 2007 May 15;104(20):8520-5.
GH3 cells
3 µM
Suppressed the peak density of voltage-gated Na+ current (INa)
Int J Mol Sci. 2020 Mar 31;21(7):2416.
Human hypertrophic cardiomyocytes
30 nM
10 min
Significantly reduced the persistent Na+ current (INaL), shortened action potential duration, and decreased sarcoplasmic reticulum Ca2+ leak
ESC Heart Fail. 2019 Feb;6(1):154-163.
Human atrial cardiomyocytes
30 nM
15 minutes
To investigate the effect of NaV1.8 inhibition on late sodium current, results showed A-803467 significantly reduced late sodium current.
Basic Res Cardiol. 2020 Feb 20;115(2):20.
Small-sized DRG neurons
5 µM
Used to block Nav1.8 currents and confirm the modulation effect of BmK I on Nav1.8
Protein Cell. 2015 Jun;6(6):443-52.
Rat dorsal root ganglion neurons
140 nM
Block TTX-R currents and inhibit action potential generation
Proc Natl Acad Sci U S A. 2007 May 15;104(20):8520-5.
ND-7/23 cells
0.73±0.08 µM (IC50)
Determination of the half-maximal inhibitory concentration (IC50) of A-803467 on Na v1.8
Proc Natl Acad Sci U S A. 2022 Jul 26;119(30):e2208211119.
TSA201 cells
100 nM
To investigate the electrophysiological effects of A-803467 on SCN10A-SCN5A-SCN3B co-transfected TSA201 cells. Results showed that A-803467 significantly reduced INa,P and INa,L and altered channel kinetics.
J Am Heart Assoc. 2016 Nov 2;5(11):e004050.
Mouse dorsal root ganglion neurons
500 nM
A-803467 blocked repetitive action potential firing in DRG neurons of both HDC−/− and wild-type mice.
CNS Neurosci Ther. 2013 Sep;19(9):649-58.
Mouse dorsal root ganglion neurons
300 nM
A-803467 selectively blocked Nav1.8 channels, reduced the excitability of DRG neurons in HDC−/− mice, and blocked repetitive action potential firing.
CNS Neurosci Ther. 2013 Sep;19(9):649-58.
Ventricular myocytes
100 nM
To evaluate the effect of Nav1.8 inhibitor A-803467 on INa,Late, results showed no significant effect of A-803467 on INa,Late
Int J Mol Sci. 2022 May 20;23(10):5735.
A-803467 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Dogs
Acute atrial fibrillation model
Injection into ganglionated plexi
1 μmol/0.5 mL per GP
Single injection followed by 6-hour rapid atrial pacing
To evaluate the effect of A-803467 on an acute atrial fibrillation model. Results showed that A-803467 significantly reduced the incidence of AF, shortened AF duration, and prolonged AF cycle length.
J Am Heart Assoc. 2016 Nov 2;5(11):e004050.
Canine
Acute ischemia-induced ventricular arrhythmia model
Left stellate ganglion injection
10 mM, 15 mM, 20 mM
Single injection
Blocking the Nav1.8 channel could significantly attenuate ischemia-induced VA, primarily by suppressing LSG activity
Sci Rep. 2017 Apr 3;7(1):534
Sprague-Dawley rats
Sciatic nerve transection-repair model
Infusion around the injured site
10 μM
For 3 days
A-803467 significantly attenuated Nav1.8 upregulation after sciatic nerve transection and promoted axon regeneration.
Anesthesiology. 2023 Dec 1;139(6):782-800
Mice
Wild-type mice
Intraperitoneal injection
25 mg/kg
Single dose, recorded for 45 minutes
To validate the role of NaV1.8 in the cardiac response to atropine. Results showed that the heart rate response to atropine was significantly lower in wild-type mice after A-803467 treatment.
Front Pharmacol. 2020 Jul 31;11:1163
Rats
Neuropathic pain model (L5/L6 spinal nerve injury)
Intraperitoneal injection
47 mg/kg
Single dose
Reduce mechanical allodynia
Proc Natl Acad Sci U S A. 2007 May 15;104(20):8520-5.
Wistar rats
Osteoarthritis model
Intra-arterial injection
500 μg
Single injection
A-803467 significantly reduced the firing rate of joint afferents during noxious rotation of the joint but had no effect during non-noxious rotation. In the pain studies, peripheral injection of A-803467 into OA knees attenuated hindlimb incapacitance and secondary allodynia.
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