Riluzole (hydrochloride)
(Synonyms: PK 26124 hydrochloride) 目录号 : GC44841
An inhibitor of glutamatergic transmission
Cas No.:850608-87-6
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
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- Purity: >99.50%
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Cell experiment: | Two-electrode voltage clamp of Xenopus oocytes expressing exogenous GABAA receptors is performed with a CA-1B high performance oocyte clamp. The extracellular recording solution is ND-96 medium. Riluzole hydrochloride is applied from a common tip via a gravity-driven multibarrel drug-delivery system. Data acquisition and analysis are performed with pCLAMP 6 software[1]. |
Animal experiment: | Adult male Sprague-Dawley rats (180 to 350 g) are housed in a temperature-controlled room and maintained on a 12-h day/night cycle with unrestricted access to food and water. Pain behaviors are measured before and 5 h after induction of a mono-arthritis in the left knee joint. To test the effects of systemic (intraperitoneal, i.p.) application of Riluzole hydrochloride, pain behaviors are measured 1 h postinjection of Riluzole hydrochloride in normal and arthritic animals. To determine effects of Riluzole hydrochloride into the amygdala, pain behaviors are measured 15 min after starting Riluzole hydrochloride application through a stereotaxically implanted microdialysis probe. To investigate site of action in the amygdala of systemically applied Riluzole hydrochloride, potassium channel blockers are administered into the amygdala 45 min after systemic application of Riluzole hydrochloride and pain behaviors are measured 15 min later, i.e., 1 h postinjection of riluzole (i.p.)[2]. |
References: [1]. He Y, et al. Neuroprotective agent riluzole potentiates postsynaptic GABA(A) receptor function. Neuropharmacology. 2002 Feb;42(2):199-209. | |
Riluzole hydrochloride is an anticonvulsant drug and belongs to the family of use-dependent Na+ channel blocker which can also inhibit GABA uptake with an IC50 of 43 μM.
Riluzole hydrochloride is an anticonvulsant drug and belongs to the family of use-dependent Na+ channel blocker which can also inhibit GABA uptake with an IC50 of 43 μM. At 20 μM, Riluzole hydrochloride inhibits peak autaptic IPSCs only slightly but prolongs IPSCs reliably. It is also found that Riluzole hydrochloride causes a strong, concentration-dependent, readily reversible enhancement of responses to 2 μM GABA. At higher concentrations of Riluzole hydrochloride, especially 300 μM, GABA currents exhibit apparent desensitization during prolonged co-exposure to 2 μM GABA and Riluzole hydrochloride. The EC50 of Riluzole hydrochloride potentiation of GABA responses is about 60 μM[1].
In normal naïve rats, systemic injection of Riluzole hydrochloride (8 mg/kg, i.p.; n=6 rats) decreases the duration of ultrasonic but not audible vocalizations evoked by noxious stimulation of the knee joint compare to vehicle tested in the same rats (P<0.05). Systemic application of Riluzole hydrochloride (8 mg/kg, i.p.; n=19 rats) decreases the vocalizations of arthritic rats compare to predrug and vehicle significantly (P<0.05 to 0.001). Riluzole hydrochloride administered into the CeA significantly decreases the duration of audible and ultrasonic vocalizations evoked by noxious stimulation of the knee compare to predrug values (n=8 rats; P<0.05 to 0.01)[2].
References:
[1]. He Y, et al. Neuroprotective agent riluzole potentiates postsynaptic GABA(A) receptor function. Neuropharmacology. 2002 Feb;42(2):199-209.
[2]. Thompson JM, et al. Small-conductance calcium-activated potassium (SK) channels in the amygdala mediate pain-inhibiting effects of clinically available riluzole in a rat model of arthritis pain. Mol Pain. 2015 Aug 28;11:51.
| Cas No. | 850608-87-6 | SDF | |
| 别名 | PK 26124 hydrochloride | ||
| Canonical SMILES | NC1=NC2=C(S1)C=C(OC(F)(F)F)C=C2.Cl | ||
| 分子式 | C8H5F3N2OS•HCl | 分子量 | 270.7 |
| 溶解度 | DMF: 30 mg/mL,DMSO: 30 mg/mL,Ethanol: 30 mg/mL,Ethanol:PBS (pH7.2)(1:20): 0.04 mg/mL,Water: Soluble | 储存条件 | Store at -20°C |
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| 5 mM | 0.7388 mL | 3.6941 mL | 7.3883 mL |
| 10 mM | 0.3694 mL | 1.8471 mL | 3.6941 mL |
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The Effects of Riluzole on Cisplatin-induced Ototoxicity
Int Arch Otorhinolaryngol 2019 Jul;23(3):e267-e275.PMID:31360245DOI:10.1055/s-0038-1676654.
Introduction Riluzole (2-amino-6-trifluoromethoxy benzothiazole) is known as a neuroprotective, antioxidant, antiapoptotic agent. It may have beneficial effects on neuronal cell death due to cisplatin-induced ototoxicity. Objective To evaluate the effect of Riluzole on cisplatin-induced ototoxicity in guinea pigs. Methods Twenty-four guinea pigs, studied in three groups, underwent auditory brainstem response evaluation using click and 8 kHz tone burst stimuli. Subsequently, 5 mg/kg of cisplatin were administered to all animals for 3 days intraperitoneally (i.p.) to induce ototoxicity. Half an hour prior to cisplatin, groups 1, 2 and 3 received 2 ml of saline i.p., 6 mg/kg of Riluzole hydrochloride i.p., and 8 mg/kg of Riluzole hydrochloride i.p., respectively, for 3 days. The auditory brainstem responses were repeated 24 hours after the last drug administration. The cochleae were analyzed by transmission electron microscopy (TEM). Results After drug administiration, for 8,000 Hz stimulus, group 1 had significantly higher threshold shifts when compared with groups 2 ( p < 0.05) and 3 ( p < 0.05), and there was no significant difference in threshold shifts between groups 2 and 3 ( p > 0.05). Transmission electron microscopy findings demonstrated the protective effect of Riluzole on the hair cells and the stria vascularis, especially in the group treated with 8 mg/kg of Riluzole hydrochloride. Conclusion We can say that Riluzole may have a protective effect on cisplatin- induced ototoxicity. However, additional studies are needed to confirm these results and the mechanisms of action of Riluzole.
Riluzole attenuates the effects of chemoconvulsants acting on glutamatergic and GABAergic neurotransmission in the planarian Dugesia tigrina
Eur J Pharmacol 2013 Oct 15;718(1-3):493-501.PMID:23872399DOI:10.1016/j.ejphar.2013.07.009.
Planarians, the non-parasitic flatworms, display dose-dependent, distinct (C-like and corkscrew-like) hyperkinesias upon exposure to 0.001-10 mM aqueous solutions of glutamatergic agonists (L-glutamate and N-methyl-D-aspartate (NMDA)) and 0.001-5 mM concentrations of the glutamate decarboxylase (GAD) inhibitor (semicarbazide). In the planarian seizure-like activity (PSLA) experiments the three chemoconvulsants displayed the following order of potency (EC50): L-glutamate (0.6mM)>NMDA (1.4 mM)>semicarbazide (4.5mM). Planarian hyperkinesias behavior counting experiments also revealed that Riluzole (0.001 to 1mM), an anti-convulsive agent, displayed no significant behavioral activity by itself, but attenuated hyperkinesias elicited by the three chemoconvulsants targeting either glutamatergic or GABAergic neurotransmission with the following order of potency (IC50): NMDA (44.7 µM)>semicarbazide (88.3 µM)>L-glutamate (160 µM). Further, (+)-MK-801, a specific NMDA antagonist, alleviated 3mM NMDA (47%) or 3mM L-glutamate (27%) induced planarian hyperkinesias. The results provide pharmacological evidence for the presence of glutamatergic receptor-like and semicarbazide sensitive functional GAD enzyme-like proteins in planaria in addition to demonstrating, for the first time, the anti-convulsive effects of Riluzole in an invertebrate model. High performance liquid chromatography coupled with fluorescence detection (HPLC-F) analysis performed on planarian extracts post no drug treatment (control) or treatment with 3mM semicarbazide, combination of 3mM semicarbazide and 0.1 mM Riluzole, or 0.1 mM Riluzole revealed that 3 mM semicarbazide induced 35% decrease in the GABA levels and a combination of 3mM semicarbazide and 0.1 mM Riluzole induced 42% decrease in glutamate levels with respect to the control group.
Crystal structure analysis of the biologically active drug mol-ecule Riluzole and riluzolium chloride
Acta Crystallogr E Crystallogr Commun 2019 Jul 2;75(Pt 8):1084-1089.PMID:31417770DOI:10.1107/S2056989019009022.
This study is an investigation into the crystal structure of the biologically active drug mol-ecule Riluzole [RZ, 6-(tri-fluoro-meth-oxy)-1,3-benzo-thia-zol-2-amine], C8H5F3N2OS, and its derivative, the riluzolium chloride salt [RZHCl, 2-amino-6-(tri-fluoro-meth-oxy)-1,3-benzo-thia-zol-3-ium chloride], C8H6F3N2OS+·Cl-. In spite of repeated efforts to crystallize the drug, its crystal structure has not been reported to date, hence the current study provides a method for obtaining crystals of both Riluzole and its corresponding salt, riluzolium hydro-chloride. The salt was obtained by grinding HCl with the drug and crystallizing the obtained solid from di-chloro-methane. The crystals of Riluzole were obtained in the presence of l-glutamic acid and d-glutamic acid in separate experiments. In the crystal structure of RZHCl, the -OCF3 moiety is perpendicular to the mol-ecular plane containing the riluzolium ion, as can be seen by the torsion angle of 107.4 (3)°. In the case of Riluzole, the torsion angles of the four different mol-ecules in the asymmetric unit show that in three cases the tri-fluoro-meth-oxy group is perpendicular to the Riluzole mol-ecular plane and only in one mol-ecule does the -OCF3 group lie in the same mol-ecular plane. The crystal structure of Riluzole primarily consists of strong N-H⋯N hydrogen bonds along with weak C-H⋯F, C-H⋯S, F⋯F, C⋯C and C⋯S inter-actions, while that of its salt is stabilized by strong [N-H]+⋯Cl- and weak C-H⋯Cl-, N-H⋯S, C-H⋯F, C⋯C, S⋯N and S⋯Cl- inter-actions.
Ropinirole hydrochloride remedy for amyotrophic lateral sclerosis - Protocol for a randomized, double-blind, placebo-controlled, single-center, and open-label continuation phase I/IIa clinical trial (ROPALS trial)
Regen Ther 2019 Jul 26;11:143-166.PMID:31384636DOI:10.1016/j.reth.2019.07.002.
Introduction: Amyotrophic lateral sclerosis (ALS) is an intractable and incurable neurological disease. It is a progressive disease characterized by muscle atrophy and weakness caused by selective vulnerability of upper and lower motor neurons. In disease research, it has been common to use mouse models carrying mutations in responsible genes for familial ALS as pathological models of ALS. However, there is no model that has reproduced the actual conditions of human spinal cord pathology. Thus, we developed a method of producing human spinal motor neurons using human induced pluripotent stem cells (iPSCs) and an innovative experimental technique for drug screening. As a result, ropinirole hydrochloride was eventually discovered after considering such results as its preferable transitivity in the brain and tolerability, including possible adverse reactions. Therefore, we explore the safety, tolerability and efficacy of ropinirole hydrochloride as an ALS treatment in this clinical trial. Methods: The ROPALS trial is a single-center double-blind randomized parallel group-controlled trial of the safety, tolerability, and efficacy of the ropinirole hydrochloride extended-release tablet (Requip CR) at 2- to 16-mg doses in patients with ALS. Twenty patients will be recruited for the active drug group (fifteen patients) and placebo group (five patients). All patients will be able to receive the standard ALS treatment of Riluzole if not changed the dosage during this trial. The primary outcome will be safety and tolerability at 24 weeks, defined from the date of randomization. Secondary outcome will be the efficacy, including any change in the ALS Functional Rating Scale-Revised (ALSFRS-R), change in the Combined Assessment of Function and Survival (CAFS), and the composite endpoint as a sum of Z-transformed scores on various clinical items. Notably, we will perform an explorative search for a drug effect evaluation using the patient-derived iPSCs to prove this trial concept. Eligible patients will have El Escorial Possible, clinically possible and laboratory-supported, clinically probable, or clinically definite amyotrophic lateral sclerosis with disease duration less than 60 months (inclusive), an ALSFRS-R score ≥2 points on all items and age from 20 to 80 years. Conclusion: Patient recruitment began in December 2018 and the last patient is expected to complete the trial protocol in November 2020. Trial registration: Current controlled trials UMIN000034954 and JMA-IIA00397. Protocol version: version 1.6 (Date; 5/Apr/2019).
Clemizole hydrochloride is a novel and potent inhibitor of transient receptor potential channel TRPC5
Mol Pharmacol 2014 Nov;86(5):514-21.PMID:25140002DOI:10.1124/mol.114.093229.
Canonical transient receptor potential channel 5 (TRPC5) is a nonselective, Ca(2+)-permeable cation channel that belongs to the large family of transient receptor potential channels. It is predominantly found in the central nervous system with a high expression density in the hippocampus, the amygdala, and the frontal cortex. Several studies confirm that TRPC5 channels are implicated in the regulation of neurite length and growth cone morphology. We identified clemizole as a novel inhibitor of TRPC5 channels. Clemizole efficiently blocks TRPC5 currents and Ca(2+) entry in the low micromolar range (IC50 = 1.0-1.3 µM), as determined by fluorometric intracellular free Ca(2+) concentration ([Ca(2+)]i) measurements and patch-clamp recordings. Clemizole blocks TRPC5 currents irrespectively of the mode of activation, for example, stimulation of G protein-coupled receptors, hypo-osmotic buffer conditions, or by the direct activator Riluzole. Electrophysiological whole-cell recordings revealed that the block was mostly reversible. Moreover, clemizole was still effective in blocking TRPC5 single channels in excised inside-out membrane patches, hinting to a direct block of TRPC5 by clemizole. Based on fluorometric [Ca(2+)]i measurements, clemizole exhibits a sixfold selectivity for TRPC5 over TRPC4β (IC50 = 6.4 µM), the closest structural relative of TRPC5, and an almost 10-fold selectivity over TRPC3 (IC50 = 9.1 µM) and TRPC6 (IC50 = 11.3 µM). TRPM3 and M8 as well as TRPV1, V2, V3, and V4 channels were only weakly affected by markedly higher clemizole concentrations. Clemizole was not only effective in blocking heterologously expressed TRPC5 homomers but also TRPC1:TRPC5 heteromers as well as native TRPC5-like currents in the U-87 glioblastoma cell line.