A-317491 exhibits high efficacy and selectivity as a non-nucleotide P2X3 and P2X2/3 receptor blocker, presenting Kis of 22, 22, 9, and 92 nM against hP2X3, rP2X3, hP2X2/3, and rP2X2/3, respectively. Its selective action (IC50>10 μM) spans beyond other P2 receptors and a range of neurotransmitter receptors, ion channels, and enzymes, mitigating inflammatory and neuropathic pain by obstructing P2X3 and P2X2/3 receptor-mediated calcium movement .
体内研究
Given as a single subcutaneous injection ranging from 0.1 to 30 mg/kg, it systematically alleviates inflammatory mechanical sensitivity in rats .
Administered intravenously at doses between 3 and 30 mg/kg, A-317491 displays a half-life of 7.38 hours, a clearance rate of 1.83 L/h/kg, and a distribution volume of 0.17 L/kg .
体外研究
A-317491 effectively inhibits calcium movement through recombinant human and rat P2X3 and P2X2/3 receptors with a Ki range of 22-92 nM .
Administered at concentrations between 1 nM and 10 μM, it progressively obstructs DRG currents, evidenced by an IC50 of 15 nM .
作用机制
A-317491 is a competitive antagonist which can stabilize the apo/resting state of P2X3.[2][3]
A-317491 细胞实验
Cell Line
Concentration
Treated Time
Description
References
Rat dorsal root ganglion neurons
15 nM
3 minutes
To evaluate the antagonistic effects of A-317491 on native P2X3 receptors, results showed that A-317491 effectively blocked currents in these receptors
Proc Natl Acad Sci U S A. 2002 Dec 24;99(26):17179-84.
1321N1 human astrocytoma cells
22–92 nM
3 minutes
To evaluate the antagonistic effects of A-317491 on P2X3 and P2X2/3 receptors, results showed that A-317491 effectively blocked calcium flux in these receptors
Proc Natl Acad Sci U S A. 2002 Dec 24;99(26):17179-84.
1321N1 human astrocytoma cells expressing hP2X2/3
1.3–660 nM
2–5 hours
To determine the affinity of AF-353 for P2X2/3 receptors
Br J Pharmacol. 2010 Jul;160(6):1387-98.
CHO-K1 cells expressing recombinant human P2X3
1.7–140 nM
2–5 hours
To determine the affinity of AF-353 for P2X3 receptors
Br J Pharmacol. 2010 Jul;160(6):1387-98.
1321N1 cells
3 nM
30 minutes
To assess whether naloxone could compete for binding to human P2X3 receptors. Results showed that naloxone, at concentrations up to 1 μM, did not compete for [3H] A-317491 binding.
Br J Pharmacol. 2005 Sep;146(2):180-8.
NG108-15 cells
3–100 μM
To evaluate the agonist activity of A-317491 at δ opioid receptors endogenously expressed in NG108-15 cells. Results showed that A-317491 did not produce any agonist response at the tested concentrations.
Br J Pharmacol. 2005 Sep;146(2):180-8.
1321N1 astrocytoma cells
12.5–500 nM
To investigate the competitive antagonism of A-317491 on the P2X2/C03 chimeric receptor, results showed that A-317491 is a potent competitive antagonist with a pA2 value of 52.1 nM.
Br J Pharmacol. 2003 Sep;140(1):202-10.
A-317491 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Hanover Wistar rats
Not specified
Intravenous and oral
2 mg/kg
Single dose
To evaluate the pharmacokinetic parameters of AF-353
Br J Pharmacol. 2010 Jul;160(6):1387-98.
Sprague-Dawley rats
Chronic morphine-induced analgesic tolerance model
Intrathecal injection
1.5 μg/μL
Once daily for 7 days
To evaluate the effect of A-317491 on chronic morphine-induced analgesic tolerance. Results showed that A-317491 significantly attenuated the loss of morphine’s analgesic potency.
Br J Pharmacol. 2018 May;175(10):1760-1769
Rats
CFA-induced inflammatory pain model
Subcutaneous injection
3, 10, 30 mg/kg
Single dose, observed for 1 hour
Evaluate the analgesic effect of A-317491 analogs in an inflammatory pain model, results showed compound B significantly reversed CFA-induced weight bearing deficit at 3 and 10 mg·kg-1 doses
Br J Pharmacol. 2011 Jul;163(6):1315-25
Xenopus oocytes
Not used
Injection
2 µM
Single injection, lasting 1-2 days
To evaluate the inhibitory effect of A-317491 on ATP-induced currents
Nature. 2016 Oct 6;538(7623):66-71
Rat
Chronic constriction injury model
Subcutaneous injection
10–15 μmol/kg
Single or multiple dosing
To evaluate the analgesic effects of A-317491 in chronic pain models, results showed that A-317491 significantly reduced thermal hyperalgesia and mechanical allodynia
Proc Natl Acad Sci U S A. 2002 Dec 24;99(26):17179-84.
Single administration, testing started 30 min after administration
To evaluate the antinociceptive effects of A-317491 in inflammatory and chemogenic pain models. Results showed that naloxone (1–10 mg/kg, i.p.) dose-dependently reduced the antinociceptive effects of A-317491 in the CFA thermal hyperalgesia model and formalin model but not in the L5–L6 nerve ligation model.
Br J Pharmacol. 2005 Sep;146(2):180-8.
Rats
Chronic constriction injury (CCI) model
Intravenous injection
1, 3, 10 mg/kg
Cumulative dosing, each dose observed for 45 minutes
To investigate the effects of A-317491 on neuronal responses in a neuropathic pain model. Results showed that in CCI-operated rats, 3 mg/kg A-317491 significantly inhibited C fibre-evoked responses, and 10 mg/kg significantly inhibited Aδ and C fibre-evoked responses.
Br J Pharmacol. 2006 Jul;148(6):845-52
Suncus murinus (house musk shrews)
Emesis model
Intraperitoneal injection
100 mg/kg
Single administration, observed for 60 minutes
To investigate the inhibitory effect of A-317491 on α,β-meATP-induced emetic responses, results showed complete inhibition at 100 mg/kg dose.
Intrathecal injections 5 min before testing, intraplantar injections 30 min before testing
To evaluate the antinociceptive effects of A-317491 in various acute and chronic pain models. Results showed that intrathecal and intraplantar injections of A-317491 significantly reduced thermal hyperalgesia in the CFA model, intrathecal administration significantly attenuated mechanical allodynia in neuropathic pain models, and both routes significantly reduced nocifensive behaviors in the formalin model.
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