Animal experiment: | The antagonistic effect of naloxone, a non-specific opioid antagonist, on the anti-nociceptive effect of JTC-801 and morphine is examined by formalin stimulation test. Limb licking response is induced by subcutaneous injection of 50 μL of 5% formalin to the left hind limb of each rat. The first 5 min (from immediately after the injection of formalin) and the subsequent 15 min (15-30 min post-injection) are designated as the first and second phases, respectively. The limb licking time during each of the phases is measured and used as an indicator of pain. Fifteen min before the injection of formalin, naloxone (10 mg/kg, dissolved in physiological saline) is given subcutaneously. Five min before the injection of formalin, JTC-801 and morphine are dissolved in 5% sorbitol and given into the tail vein at doses of 0.03 and 1.0 mg/kg, respectively. JTC-801 (3.0 mg/kg) and morphine (30 mg/kg) are administered orally 60 min before the formalin injection. |
| 产品描述 | JTC-801 is a selective opioid receptor-like1 (ORL1) receptor antagonist, binding to ORL1 receptor with a Ki value of 8.2 nM.
JTC-801 inhibits [3H]-nociceptin binding to ORL1 receptor expressed in HeLa cells with an IC50 value of 94±8.6 nm at a [3H]-nociceptin concentration of 50 pM. JTC-801 weakly inhibits the binding of the ligands to human δ receptor (IC50>10 μM), κ receptor (IC50>10 μM), and μ receptor (IC50=325 nM). In rat cerebrocortical membrane, JTC-801 inhibits ORL1 receptor (IC50=472 nM) and μ receptor (IC50=1831 nM). JTC-801 at a concentration of 10 μM reverses the inhibitory action of nociceptin against forskolin-induced increase in cyclic AMP level (IC50: 2.58 μM, 1 nM of nociceptin used). JTC-801 alone does not affect the the production of cyclic AMP[1]. The affinity of JTC-801 for ORL1 receptor, human opioid μ-, κ-, and δ-receptors is 8.2 nM, 102.9 nM, 1057.5 nM and 8647.2 nM[2].
JTC-801 (≥0.01 mg/kg, i.v. or 1 mg/kg, p.o.) antagonizes the nociceptin-induced allodynia in mice. In mouse hot-plate test, JTC-801 prolongs escape response latency (ERL) to exposed heat stimulus with minimum effective doses (MED) of 0.01 mg/kg by i.v. or 1 mg/kg by p.o. In the rat formalin test, JTC-801 reduces both the first and second phases of the nociceptive response with MED of 0.01 mg/kg by i.v. administration or 1 mg/kg by p.o. administration. This anti-nociceptive action of JTC-801 is not inhibited by naloxone (10 mg/kg, s.c.). JTC-801 antagonizes the ORL1 receptor response, and has efficacious and potent anti-nociceptive effects in acute pain animal models not only by intravenous injection but also oral administration[1]. JTC-801 (0.3 mg/kg) decreases allodynia induced by the intrathecal injection of nociceptin in mice[2]. JTC-801 (6 mg/kg i.p., once daily) reverses SPS-induced mechanical allodynia, thermal hyperalgesia, anxiety-like behaviour and hypocortisolism. JTC-801 treatment also reverses NOP receptor protein and mRNA up-regulation in amygdala and PAG. JTC-801 blocks elevated N/OFQ levels in serum, CSF, PAG and hippocampus at day 21 of SPS[3]. JTC-801 (0.05-5 mg/kg, i.p.) supresses the the analgesic effect of N2O in 129Sv mice by the writhing test and tail flick test[4].
Reference：
[1]. Yamada H, et al. Pharmacological profiles of a novel opioid receptor-like1 (ORL(1)) receptor antagonist, JTC-801. Br J Pharmacol, 2002, 135(2), 323-332.
[2]. Koyama T, et al. Nociceptin receptor antagonist JTC-801 inhibits nitrous oxide-induced analgesia in mice. J Anesth. 2009;23(2):301-3.
[3]. Shinkai H, et al. 4-Aminoquinolines: novel nociceptin antagonists with analgesic activity. J Med Chem, 2000, 43(24), 4667-4677.
[4]. Zhang Y, et al. Nociceptin/orphanin FQ peptide receptor antagonist JTC-801 reverses pain and anxiety symptoms in a rat model of post-traumatic stress disorder. Br J Pharmacol. 2015 Jan;172(2):571-82. |
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