SB408124

OX(1)receptor antagonist CAS# 288150-92-5

SB408124

Catalog No. BCC4972----Order now to get a substantial discount!

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Chemical structure

SB408124

3D structure

Chemical Properties of SB408124

Cas No. 288150-92-5 SDF Download SDF
PubChem ID 4331799 Appearance Powder
Formula C19H18F2N4O M.Wt 356.38
Type of Compound N/A Storage Desiccate at -20°C
Solubility DMSO : 50 mg/mL (140.30 mM; Need ultrasonic)
H2O : < 0.1 mg/mL (insoluble)
Chemical Name 1-(6,8-difluoro-2-methylquinolin-4-yl)-3-[4-(dimethylamino)phenyl]urea
SMILES CC1=NC2=C(C=C(C=C2C(=C1)NC(=O)NC3=CC=C(C=C3)N(C)C)F)F
Standard InChIKey JTARFZSNUAGHRB-UHFFFAOYSA-N
Standard InChI InChI=1S/C19H18F2N4O/c1-11-8-17(15-9-12(20)10-16(21)18(15)22-11)24-19(26)23-13-4-6-14(7-5-13)25(2)3/h4-10H,1-3H3,(H2,22,23,24,26)
General tips For obtaining a higher solubility , please warm the tube at 37 ℃ and shake it in the ultrasonic bath for a while.Stock solution can be stored below -20℃ for several months.
We recommend that you prepare and use the solution on the same day. However, if the test schedule requires, the stock solutions can be prepared in advance, and the stock solution must be sealed and stored below -20℃. In general, the stock solution can be kept for several months.
Before use, we recommend that you leave the vial at room temperature for at least an hour before opening it.
About Packaging 1. The packaging of the product may be reversed during transportation, cause the high purity compounds to adhere to the neck or cap of the vial.Take the vail out of its packaging and shake gently until the compounds fall to the bottom of the vial.
2. For liquid products, please centrifuge at 500xg to gather the liquid to the bottom of the vial.
3. Try to avoid loss or contamination during the experiment.
Shipping Condition Packaging according to customer requirements(5mg, 10mg, 20mg and more). Ship via FedEx, DHL, UPS, EMS or other couriers with RT, or blue ice upon request.

Biological Activity of SB408124

DescriptionSelective non-peptide orexin OX1 receptor antagonist (Kb values are 21.7 and 1405 nM for human OX1 and OX2 receptors respectively). Blocks orexin-A induced grooming following oral administration in vivo.

SB408124 Dilution Calculator

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SB408124 Molarity Calculator

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Preparing Stock Solutions of SB408124

1 mg 5 mg 10 mg 20 mg 25 mg
1 mM 2.806 mL 14.03 mL 28.0599 mL 56.1199 mL 70.1498 mL
5 mM 0.5612 mL 2.806 mL 5.612 mL 11.224 mL 14.03 mL
10 mM 0.2806 mL 1.403 mL 2.806 mL 5.612 mL 7.015 mL
50 mM 0.0561 mL 0.2806 mL 0.5612 mL 1.1224 mL 1.403 mL
100 mM 0.0281 mL 0.1403 mL 0.2806 mL 0.5612 mL 0.7015 mL
* Note: If you are in the process of experiment, it's necessary to make the dilution ratios of the samples. The dilution data above is only for reference. Normally, it's can get a better solubility within lower of Concentrations.

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Background on SB408124

SB408124 is a potent and novel nonpeptide antagonist of orexin-1 (OX(1)) receptor with Ki values of 27 nM and 57 nM in membrane formats and in whole cell, respectively. SB408124 was 50-fold selective over the human OX2 receptor [1].

Pre-treated with SB408124 before orexin A in primary astrocyte cultures from the rat cerebral cortex remarkably decreased the orexin A stimulatory activity on forskolin and basal-induced cAMP production [2].

In rats, SB408124 at dose of 30 μg/10 μl together with orexin-A after histamine (HA) or hypertonic saline injection could prevent the orexin-A-induced reduction in vasopressin (VP) concentration increase [3].

References:
[1] Langmead CJ1, Jerman JC, Brough SJ, Scott C, Porter RA, Herdon HJ.Characterisation of the binding of [3H]-SB-674042, a novel nonpeptide antagonist, to the human orexin-1 receptor. Br J Pharmacol. 2004 Jan;141(2):340-6.
[2] Woldan-Tambor A1, Biegańska K, Wiktorowska-Owczarek A, Zawilska JB. Activation of orexin/hypocretin type 1 receptors stimulates cAMP synthesis in primary cultures of rat astrocytes. Pharmacol Rep. 2011;63(3):717-23.
[3] Kis GK1, Molnár AH, Daruka L, Gardi J, Rákosi K, László F, László FA, Varga C.The osmotically and histamine-induced enhancement of the plasma vasopressin level is diminished by intracerebroventricularly administered orexin in rats. Pflugers Arch. 2012 Apr;463(4):531-6.

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References on SB408124

Activation of orexinergic and histaminergic pathway involved in therapeutic effect of histamine H4 receptor antagonist against cisplatin-induced anorexia in mice.[Pubmed:30919010]

Naunyn Schmiedebergs Arch Pharmacol. 2019 Mar 27. pii: 10.1007/s00210-019-01646-x.

We previously reported that hypothalamic tumor necrosis factor-alpha (TNF-alpha) mRNA expression via histamine H4 receptors contributes to the development of cisplatin-induced anorexia; however, its precise mechanisms remain unclear. It has been reported that chemotherapeutic agents induce the suppression of orexin neuron activity, and the administration of orexin inhibits chemotherapeutic agent-induced gastric discomfort. Other studies demonstrated that the central administration of TNF-alpha impairs the orexinergic system, and that orexin excites the histaminergic system. We investigated the involvement of orexinergic and histaminergic systems in the therapeutic effect of an H4 receptor antagonist against cisplatin-induced anorexia. Cisplatin decreased the expression of prepro-orexin mRNA, which encodes precursors of orexin, in the hypothalamus of mice. The period of expression decreased in parallel with the onset of anorexia, and treatment with an H4 receptor antagonist (JNJ7777120, 10 mg/kg) inhibited the decrease in expression. The effect of the H4 receptor antagonist on cisplatin-induced anorexia in mice was antagonized by an orexin OX2 receptor antagonist (JNJ10397049, 5 mg/kg) rather than an orexin OX1 receptor antagonist (SB408124, 30 mg/kg). Although an OX2 receptor agonist (YNT-185, 20 mg/kg) or a histamine H3 receptor inverse agonist (ciproxifan, 1 mg/kg) inhibited the cisplatin-induced anorexia, the inhibitory effect of the OX2 receptor agonist was antagonized by an H3 receptor silent antagonist (VUF5681, 5 mg/kg). The combination of JNJ7777120 (10 mg/kg) and ciproxifan (0.5 mg/kg) completely resolved the cisplatin-induced anorexia. These results suggest that activation of the orexinergic and histaminergic pathway is involved in the therapeutic effect of an H4 receptor antagonist against cisplatin-induced anorexia.

Orexin A increases sympathetic nerve activity through promoting expression of proinflammatory cytokines in Sprague Dawley rats.[Pubmed:28872777]

Acta Physiol (Oxf). 2018 Feb;222(2).

AIM: Accumulating evidence suggests that orexin signalling is involved in the regulation of blood pressure and cardiovascular function. However, the underlying mechanisms are not clear. Here, we test the hypothesis that upregulated orexin A signalling in the paraventricular nucleus (PVN) increases sympathetic nerve activity (SNA) through stimulating expression of proinflammatory cytokines (PICs). METHODS: In vivo sympathetic nerve recordings were performed to test the impact of PVN orexin signalling on sympathetic outflow in Sprague Dawley (SD) rats. Real-time PCR was carried out to assess effects of central administration of orexin A on PVN PICs expression in SD rats. To test whether orexin A-induced increases in PICs were exclusively mediated by orexin receptor 1 (OX1R), OX1R-expressing PC12 (PC12-OX1R) cells were incubated with different dose of orexin A, and then, PICs mRNA and immunoreactivity were measured. RESULTS: Orexin A microinjection (25 pmol) into the PVN significantly increased splanchnic SNA (93.5%) and renal SNA (83.3%) in SD rats, and these increases were attenuated by OX1R antagonist SB408124. Intracerebroventricular injection of orexin A (0.2 nmol) into SD rats increased mRNA levels of PICs including IL-1-beta (2.7-fold), IL-6 (1.7-fold) and TNF-alpha (1.5-fold), as well as Fra1 (1.6-fold) in the PVN. Orexin A treatment in PC12-OX1R cells resulted in a dose- and time-dependent increase in the expression of PICs and Fra1, a subunit of AP1 transcriptional factor. The increase in the PICs was blocked by AP1 blocker curcumin. CONCLUSION: Paraventricular nucleus orexin system activation is involved in SNA regulation maybe through triggering AP1-PICs pathway.

Characterisation of the binding of [3H]-SB-674042, a novel nonpeptide antagonist, to the human orexin-1 receptor.[Pubmed:14691055]

Br J Pharmacol. 2004 Jan;141(2):340-6.

1. This study characterises the binding of a novel nonpeptide antagonist radioligand, [(3)H]SB-674042 (1-(5-(2-fluoro-phenyl)-2-methyl-thiazol-4-yl)-1-((S)-2-(5-phenyl-(1,3,4)oxadiazo l-2-ylmethyl)-pyrrolidin-1-yl)-methanone), to the human orexin-1 (OX(1)) receptor stably expressed in Chinese hamster ovary (CHO) cells in both a whole cell assay and in a cell membrane-based scintillation proximity assay (SPA) format. 2. Specific binding of [(3)H]SB-674042 was saturable in both whole cell and membrane formats. Analyses suggested a single high-affinity site, with K(d) values of 3.76+/-0.45 and 5.03+/-0.31 nm, and corresponding B(max) values of 30.8+/-1.8 and 34.4+/-2.0 pmol mg protein(-1), in whole cell and membrane formats, respectively. Kinetic studies yielded similar K(d) values. 3. Competition studies in whole cells revealed that the native orexin peptides display a low affinity for the OX(1) receptor, with orexin-A displaying a approximately five-fold higher affinity than orexin-B (K(i) values of 318+/-158 and 1516+/-597 nm, respectively). 4. SB-334867, SB-408124 (1-(6,8-difluoro-2-methyl-quinolin-4-yl)-3-(4-dimethylamino-phenyl)-urea) and SB-410220 (1-(5,8-difluoro-quinolin-4-yl)-3-(4-dimethylamino-phenyl)-urea) all displayed high affinity for the OX(1) receptor in both whole cell (K(i) values 99+/-18, 57+/-8.3 and 19+/-4.5 nm, respectively) and membrane (K(i) values 38+/-3.6, 27+/-4.1 and 4.5+/-0.2 nm, respectively) formats. 5. Calcium mobilisation studies showed that SB-334867, SB-408124 and SB-410220 are all functional antagonists of the OX(1) receptor, with potencies in line with their affinities, as measured in the radioligand binding assays, and with approximately 50-fold selectivity over the orexin-2 receptor. 6. These studies indicate that [(3)H]SB-674042 is a specific, high-affinity radioligand for the OX(1) receptor. The availability of this radioligand will be a valuable tool with which to investigate the physiological functions of OX(1) receptors.

Description

SB408124 is a non-peptide antagonist for OX1 receptor with Ki of 57 nM and 27 nM in both whole cell and membrane, respectively; exhibits 50-fold selectivity over OX2 receptor.

Keywords:

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