Ralfinamide
(Synonyms: (S)-2-[[4-[(2-氟苄基)氧基]苄基]氨基]丙酰胺,FCE-26742A) 目录号 : GC37069
Ralfinamide (FCE-26742A) 是一种口服可利用，来源于 α-aminoamide 的钠离子通道阻滞剂, 具有镇痛作用。
Cas No.:133865-88-0
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.00%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
Ralfinamide (FCE-26742A) is an orally available Na(+) channel blocker derived from α-aminoamide, with function of suppressing pain[1]. Sodium Channel[1]
[1]. Zhang SH, et al. Ralfinamide administered orally before hindpaw neurectomy or postoperatively provided long-lasting suppression of spontaneous neuropathic pain-related behavior in the rat. Pain. 2008 Oct 15;139(2):293-305. [2]. Liang X, et al. Effects of ralfinamide in models of nerve injury and chemotherapy-induced neuropathic pain. Eur J Pharmacol. 2018 Mar 15;823:27-34.
| Cas No. | 133865-88-0 | SDF | |
| 别名 | (S)-2-[[4-[(2-氟苄基)氧基]苄基]氨基]丙酰胺,FCE-26742A | ||
| Canonical SMILES | C[C@H](NCC1=CC=C(OCC2=CC=CC=C2F)C=C1)C(N)=O | ||
| 分子式 | C17H19FN2O2 | 分子量 | 302.34 |
| 溶解度 | DMSO: ≥ 125 mg/mL (413.44 mM) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 3.3075 mL | 16.5377 mL | 33.0753 mL |
| 5 mM | 0.6615 mL | 3.3075 mL | 6.6151 mL |
| 10 mM | 0.3308 mL | 1.6538 mL | 3.3075 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
3. 以上所有助溶剂都可在 GlpBio 网站选购。
Effects of Ralfinamide in models of nerve injury and chemotherapy-induced neuropathic pain
Eur J Pharmacol 2018 Mar 15;823:27-34.PMID:29408090DOI:10.1016/j.ejphar.2018.01.041.
Neuropathic pain is among the most common and difficult-to-treat types of chronic pain and is associated with sodium channel malfunction. The sodium channel blocker Ralfinamide has exhibited potent analgesic effects in several preclinical pain models and in patients with mixed neuropathic pain syndromes (Phase II trials), but it failed to ameliorate neuropathic low back pain in Phase III trials. It is unclear whether Ralfinamide is effective against neuropathic pain induced by specified etiologies. In the present study, the antinociceptive effects of Ralfinamide in neuropathic pain models induced by spared nerve injury and chemotherapy were compared in a gabapentin-controlled manner. The effects of Ralfinamide on physiological pain were evaluated in mechanical withdrawal, hot plate, and acetic acid writhing tests. We also investigated the effects of Ralfinamide on cardiovascular function and locomotor activity. Oral Ralfinamide dose-dependently alleviated spared nerve injury-induced allodynia in rats and mice. Ralfinamide increased mechanical withdrawal thresholds in oxaliplatin-induced and paclitaxel-induced neuropathic pain. Ralfinamide did not affect physiological pain, locomotion, or cardiovascular function. Together, Ralfinamide attenuated mechanical allodynia in all the neuropathic pain models tested, with subtle differences in efficacy. The effect of Ralfinamide is comparable to that of gabapentin, but with no interference in basal mechanical sensitivity. The present study supports the effectiveness of selective sodium channel blockade as an analgesic strategy, as well as the development of compounds similar to Ralfinamide.
Ralfinamide administered orally before hindpaw neurectomy or postoperatively provided long-lasting suppression of spontaneous neuropathic pain-related behavior in the rat
Pain 2008 Oct 15;139(2):293-305.PMID:18583049DOI:10.1016/j.pain.2008.04.020.
Ralfinamide is analgesic when applied as a single dose in rodent models of stimulus-evoked chronic pain. However, it is unknown whether its chronic application after nerve injury can suppress spontaneous chronic pain, the main symptom driving patients to seek treatment. In this study Ralfinamide was administered to rats at doses producing plasma levels similar to those causing analgesia in pain patients. The analgesic effect was tested on autotomy, a behavior of self-mutilation of a denervated paw that models spontaneous neuropathic pain. Sprague-Dawley male rats (N=10-20/group) underwent transection of the sciatic and saphenous nerves unilaterally. Ralfinamide or its vehicle were administered per os for 7 days preoperatively (80 mg/kg; bid), followed by the vehicle or Ralfinamide, until postoperative d42. Autotomy was scored daily until d63. Lasting 'preemptive analgesia' was found in rats treated with Ralfinamide preoperatively, expressed by delayed autotomy onset (P=0.009) and reduced scores on d63 (P=0.01). Rats treated with Ralfinamide (30 or 60 mg/kg; bid) from the operation till d42, but not preoperatively, also showed delayed autotomy (P=0.05, P=0.006), and reduced autotomy scores lasting till d63 (P=0.02, P=0.01), for the two doses, respectively. Combining Ralfinamide treatments for 7 days preoperatively and 42 days postoperatively also resulted in significantly suppressed scores on d42 and d63 (P=0.005, P=0.001, respectively). Suppression of neuropathic pain-related behavior was likely caused by a combination of mechanisms reported for Ralfinamide, including inhibition of Na+ and Ca++ currents in Nav1.3, Nav1.7, Nav1.8, and Cav2.2 channels in rat DRG neurons, inhibition of substance P release from spinal cord synaptosomes, NMDA receptor antagonism and neuroprotection.
Effects of Ralfinamide, a Na+ channel blocker, on firing properties of nociceptive dorsal root ganglion neurons of adult rats
Exp Neurol 2007 Nov;208(1):63-72.PMID:17707373DOI:10.1016/j.expneurol.2007.07.010.
Recent studies revealed that Ralfinamide, a Na(+) channel blocker, suppressed tetrodotoxin-resistant Na(+) currents in dorsal root ganglion (DRG) neurons and reduced pain reactions in animal models of inflammatory and neuropathic pain. Here, we investigated the effects of Ralfinamide on Na(+) currents; firing properties and action potential (AP) parameters in capsaicin-responsive and -unresponsive DRG neurons from adult rats in the presence of TTX (0.5 microM). Ralfinamide inhibited TTX-resistant Na(+) currents in a frequency- and voltage-dependent manner. Small to medium sized neurons exhibited different firing properties during prolonged depolarizing current pulses (600 ms). One group of neurons fired multiple spikes (tonic), while another group fired four or less APs (phasic). In capsaicin-responsive tonic firing neurons, Ralfinamide (25 microM) reduced the number of APs from 10.6+/-1.8 to 2.6+/-0.7 APs/600 ms, whereas in capsaicin-unresponsive tonic neurons, the drug did not significantly change firing (8.4+/-0.9 in control to 6.6+/-2.0 APs/600 ms). In capsaicin-responsive phasic neurons, substance P and 4-aminopyridine induced multiple spikes, an effect that was reversed by Ralfinamide (25 microM). In addition to effects on firing, Ralfinamide increased the threshold, decreased the overshoot, and increased the rate of rise of the AP. To conclude, Ralfinamide suppressed afferent hyperexcitability selectively in capsaicin-responsive, presumably nociceptive neurons, but had no measurable effects on firing in CAPS-unresponsive neurons. The action of Ralfinamide to selectively inhibit tonic firing in nociceptive neurons very likely contributes to the effectiveness of the drug in reducing inflammatory and neuropathic pain as well as bladder overactivity.
Disposition and metabolism of Ralfinamide, a novel Na-channel blocker, in healthy male volunteers
Pharmacology 2010;86(5-6):297-305.PMID:21071997DOI:10.1159/000321322.
Ralfinamide is an α-aminoamide derivative with ion channel blocking properties, acting both peripherally and centrally through different molecular targets important in pain control. Absorption, blood and plasma time courses, and urinary and faecal excretion of total radioactivity were assessed in 6 male healthy volunteers administered a single oral dose of 320 mg ¹⁴C-(S)-ralfinamide. Pharmacokinetics of the parent drug were investigated over 120 h, urinary and plasma metabolites up to 192 h post-dose. ¹⁴C-(S)-ralfinamide was rapidly and completely absorbed. Ralfinamide and the dealkylated Ralfinamide metabolite (NW-1716) represented the majority of plasma radioactivity. Plasma elimination of the parent compound occurred mono-exponentially (half-life approx. 15 h). ¹⁴C-radioactivity was eliminated in a bi-phasic manner (terminal half-life of 60 and 24 h for plasma and whole blood, respectively). Plasma-concentrations of unchanged Ralfinamide were significantly lower than radioactivity concentrations, indicating metabolism of the parent compound. At 192 h post-dose the total balance of radioactivity was almost complete (95%). The main route of excretion was via the kidneys (94% of the dose). Major metabolites identified in urine and plasma were the N-dealkylated acid of Ralfinamide and deaminated Ralfinamide acid (NW-1799). Other metabolites, in particular the product of glucuronide conjugation N-dealkylated-β-glucuronide, were identified.
The anti-nociceptive agent Ralfinamide inhibits tetrodotoxin-resistant and tetrodotoxin-sensitive Na+ currents in dorsal root ganglion neurons
Eur J Pharmacol 2005 Mar 14;510(3):197-208.PMID:15763243DOI:10.1016/j.ejphar.2005.01.030.
Tetrodotoxin-resistant and tetrodotoxin-sensitive Na+ channels contribute to the abnormal spontaneous firing in dorsal root ganglion neurons associated with neuropathic pain. Effects of the anti-nociceptive agent Ralfinamide on tetrodotoxin-resistant and tetrodotoxin-sensitive currents in rat dorsal root ganglion neurons were therefore investigated by patch clamp experiments. Ralfinamide inhibition was voltage-dependent showing highest potency towards inactivated channels. IC50 values for tonic block of half-maximal inactivated tetrodotoxin-resistant and tetrodotoxin-sensitive currents were 10 microM and 22 microM. Carbamazepine, an anticonvulsant used in the treatment of pain, showed significantly lower potency. Ralfinamide produced a hyperpolarising shift in the steady-state inactivation curves of both currents confirming the preferential interaction with inactivated channels. Additionally, Ralfinamide use and frequency dependently inhibited both currents and significantly delayed repriming from inactivation. All effects were more pronounced for tetrodotoxin-resistant than tetrodotoxin-sensitive currents. The potency and mechanisms of actions of Ralfinamide provide a hypothesis for the anti-nociceptive properties found in animal models.