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| 25mg |
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Purity: ≥98%
GSK189254A (also known as GSK189254) is a novel histamine H(3) receptor antagonist with high affinity for human (pK(i) = 9.59 -9.90) and rat (pK(i) = 8.51-9.17) H(3) receptors. It has the potential for the treatment of narcolepsy. GSK189254 demonstrated strong functional antagonism (pA(2) = 9.06 versus agonist-induced changes in cAMP) and inverse agonism (pIC(50) = 8.20 versus basal guanosine 5'-O-(3-[(35)S]thio)triphosphate binding) at the human recombinant H(3) receptor, demonstrating its >10,000-fold selectivity for human H(3) receptors over other targets tested. Specific binding of [(3)H]GSK189254 was shown by in vitro autoradiography in the cortex and hippocampus of rats and humans. For the symptomatic treatment of dementia in Alzheimer's disease and other cognitive disorders, GSK189254 may have therapeutic potential.
| Targets |
H3, human ( pKi = 9.59-9.90 ); H3, rat ( pIC50 = 8.51-9.17 )
GSK189254A was not mentioned in the provided literature; the only related substance was coffee polyphenol extract (CPE), which targets enteroendocrine cells to regulate GLP-1 secretion via cAMP-dependent pathway, [1] |
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| ln Vitro |
In vitro activity: GSK189254A possesses a strong affinity for native H3 receptors found in the cerebral cortex of various species as well as recombinant H3 receptors expressed in HEK-293-MSR-II cells. In comparison to rat, mouse, and dog H3 receptors, GSK189254 typically demonstrates a higher affinity for human and pig H3 receptors. [3H] Rat and human brain regions such as the cortex and hippocampus are binding sites for GSK189254. For the symptomatic treatment of dementia in Alzheimer's disease and other cognitive disorders, GSK189254 may have therapeutic potential [1]. 1. CPE augmented active glucagon-like peptide-1 (GLP-1(7-36)) amide secretion from human enteroendocrine NCI-H716 cells in a dose-dependent manner (0–0.1% CPE, 2 h incubation, n=14–16 per group, P<0.001/P<0.01 vs 0% CPE by one-way ANOVA + Dunnett's test) [1] 2. CPE increased intracellular cyclic AMP (cAMP) levels in NCI-H716 cells in a dose-dependent manner (0–0.1% CPE, 20 min incubation, n=3–4 per group, P<0.05/P<0.01/P<0.001 vs 0% CPE by one-way ANOVA + Dunnett's test); this effect was not mediated by G protein-coupled receptor 119 (GPR119), as shown by no significant cAMP elevation in GPR119-transfected CHO-K1 cells treated with CPE [1] |
| ln Vivo |
GSK189254 (0.3-3 mg/kg p.o.) enhances the release of dopamine, noradrenaline, and acetylcholine in the dorsal hippocampus and the anterior cingulate cortex. Rats' performance in a variety of cognitive paradigms, such as object recognition, water maze, passive avoidance, and attentional set shift, is considerably improved by GSK189254[1]. Acute GSK189254 administration enhances W and reduces paradoxical and slow wave sleep in Ox+/+ and Ox−/− mice in a manner akin to modafinil, while in Ox−/− mice it lessens narcoleptic episodes[2].
1. Oral administration of CPE alone to C57BL/6J mice increased active GLP-1(7-36) amide levels in portal blood (10/30 min post-gastric administration, n=6–8 per group, P<0.05 vs control by Student's t test) [1] 2. Oral administration of CPE combined with glucose/starch + glyceryl trioleate (TO) to C57BL/6J mice augmented diet-induced active GLP-1 secretion (10/30 min post-administration, n=7–11 per group, P<0.05 vs control by Student's t test/one-way ANOVA + Fisher's PLSD) and decreased glucose-dependent insulinotropic polypeptide (GIP) release [1] 3. CPE administration did not affect diet-induced insulin secretion in C57BL/6J mice but reduced postprandial hyperglycaemia (portal blood glucose levels measured at 10/30 min post-administration, n=7–11 per group, P<0.05 vs control by Student's t test/one-way ANOVA + Fisher's PLSD) [1] |
| Enzyme Assay |
1. Intracellular cAMP measurement assay: NCI-H716 cells and GPR119-transfected CHO-K1 cells were incubated with 0–0.1% CPE for 20 min; intracellular cAMP levels were quantified to evaluate the activation of cAMP-dependent pathway, with Dunnett's test/Student's t test used for statistical analysis [1]
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| Cell Assay |
1. NCI-H716 cell GLP-1 secretion assay: Human enteroendocrine NCI-H716 cells were seeded and incubated with 0–0.1% CPE for 2 h; culture supernatants were collected to measure active GLP-1(7-36) amide levels, with one-way ANOVA + Dunnett's test used to compare with control group (0% CPE) [1]
2. Glucose/fatty acid-induced GLP-1 secretion assay: NCI-H716 cells were incubated with glucose (50–500 mM) or fatty acids (0.4/0.8 mM) for 2 h; GLP-1 secretion levels were measured to establish the baseline response of enteroendocrine cells to nutrient stimulation (P<0.001/P<0.01 vs control by one-way ANOVA + Dunnett's test) [1] |
| Animal Protocol |
Rats: GSK189254 pharmacokinetic studies are carried out in male Sprague-Dawley rats that are conscious. GSK189254 (n=3) is infused intravenously into the animals over the course of one hour at a nominal dose level of 1 mg of free base/kg through the use of a femoral vein cannula (10 mL/h/kg). To achieve the target concentration of 0.1 mg free base/mL, GSK189254 is dissolved in 0.9% (w/v) saline and filtered through a 0.22-mm Millex-GV filter prior to administration. The same rats were given a single oral dose of GSK189254 by gastric gavage after a period of at least two days, with the aim of achieving a dose of 2 mg of free base/kg. GSK189254 is designed to have a target concentration of 0.4 mg free base/mL in 1% (w/v) aqueous methylcellulose[1].
Mice: The vehicle is made up of 0.05 mL of 0.9% NaCl and 1% methylcellulose. It dissolves GSK189254 in the vehicle solution. GSK189254 is administered acutely and repeatedly to wild-type (Ox+/+) and orexin-knockout (Ox−/−) mice to examine its effects on the sleep-wake cycle. In Ox+/+ and Ox−/− mice, GSK189254 (3 and 10 mg/kg, p.o.) is dosed at 10 h during the sleep-wake cycle. GSK189254 is administered orally at a dose of 10 mg/kg[2].
1. C57BL/6J mouse gastric administration assay: C57BL/6J mice were subjected to gastric administration of CPE alone (0–0.1%), CPE + glucose (2 g/kg body weight), or CPE + starch (waxy maize) + glyceryl trioleate (TO, 1/2 g/kg body weight); portal blood samples were collected at 10 min and 30 min post-administration to measure glucose, insulin, GLP-1, and GIP levels (n=5–11 per group), with Student's t test/one-way ANOVA + Fisher's PLSD used for statistical analysis [1] 2. Time-course analysis of nutrient-induced GLP-1 secretion: C57BL/6J mice were given glucose (2 g/kg), TO (2 g/kg), glucose + TO (1/1 or 2/2 g/kg) via gastric administration; portal blood GLP-1 levels were measured at different time points to evaluate the effect of nutrients on GLP-1 release (n=5 per group) [1] |
| References | |
| Additional Infomation |
1. GLP-1 is a key gut hormone that stimulates glucose-induced insulin secretion; sustained activation of GLP-1 can alleviate diabetes, therefore GLP-1 secretagogues are potential targets for the treatment of type 2 diabetes [1]
2. Epidemiological studies have shown that increasing coffee intake can reduce the risk of diabetes; CPE enhances the secretion of gut-derived active GLP-1 through a cAMP-dependent pathway (independent of GPR119), which may help reduce the risk of type 2 diabetes [1] 3. CPE reduces postprandial hyperglycemia in C57BL/6J mice by increasing insulin sensitivity (without affecting insulin secretion), which may be mediated by elevated GLP-1 levels [1] |
| Molecular Formula |
C21H25N3O2
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| Molecular Weight |
351.44
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| Exact Mass |
351.194
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| Elemental Analysis |
C, 71.77; H, 7.17; N, 11.96; O, 9.10
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| CAS # |
720690-73-3
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| Related CAS # |
945493-87-8 (HCl); 720690-73-3
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| PubChem CID |
9798547
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| Appearance |
White to off-white solid powder
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| Density |
1.2±0.1 g/cm3
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| Boiling Point |
545.0±50.0 °C at 760 mmHg
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| Flash Point |
283.4±30.1 °C
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| Vapour Pressure |
0.0±1.5 mmHg at 25°C
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| Index of Refraction |
1.605
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| LogP |
3.29
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
26
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| Complexity |
482
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
WROHEWWOCPRMIA-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C21H25N3O2/c1-22-21(25)17-6-8-20(23-14-17)26-19-7-5-15-9-11-24(18-3-2-4-18)12-10-16(15)13-19/h5-8,13-14,18H,2-4,9-12H2,1H3,(H,22,25)
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| Chemical Name |
6-[(3-cyclobutyl-1,2,4,5-tetrahydro-3-benzazepin-7-yl)oxy]-N-methylpyridine-3-carboxamide
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (7.11 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (7.11 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (7.11 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.8454 mL | 14.2272 mL | 28.4544 mL | |
| 5 mM | 0.5691 mL | 2.8454 mL | 5.6909 mL | |
| 10 mM | 0.2845 mL | 1.4227 mL | 2.8454 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
Effects of acute and repeat administration of GSK189254 on mean duration (±SEM) of sleep–wake stages in a 4 h recording within the lights-on period in (A) wild-type (Ox+/+) and (B) Ox−/− mice (n= 14 per group). GSK189254 (3 and 10 mg·kg−1) significantly increased wakefulness (W) and decreased slow wave sleep (SWS) and paradoxical sleep (PS) following acute dosing.Br J Pharmacol.2009 May;157(1):104-17. |
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Effects of acute and repeat administration of GSK189254 on mean duration (±SEM) of sleep–wake stages in a 4 h recording within the lights-off period in (A) wild-type (Ox+/+) and (B) Ox−/− mice (n= 14 per group). GSK189254 (3 and 10 mg·kg−1) significantly increased wakefulness (W) and decreased slow wave sleep (SWS) and paradoxical sleep (PS) following acute dosing.Br J Pharmacol.2009 May;157(1):104-17. |
H3(left panels) and H1(right panels) receptor binding in Ox+/+ and Ox−/− mice measured using [3H]-GSK189254 and [3H]-mepyramine respectively, with real-time autoradiography.
Effects of acute and repeat administration of GSK189254 and effect of acute administration of modafinil on narcoleptic attacks in Ox−/− mice in the lights-off period compared with vehicle-treated mice.Br J Pharmacol.2009 May;157(1):104-17. |
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