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| 25mg |
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GSK1059865 is a novel, potent and highly selective OX1R antagonist. Treatment with GSK1059865 significantly decreased ethanol drinking in a dose-dependent manner in CIE-exposed mice. GSK1059865, on the other hand, only reduced drinking at the maximum dose when given to mice exposed to air. GSK1059865 had no effect on the amount of sucrose consumed. Therefore, using a highly-selective antagonist to block the OX1R, ORX signaling has a significant impact on high levels of alcohol consumption induced in a dependence paradigm, but has little to no effect on moderate alcohol consumption or sucrose consumption. These findings suggest that treating disorders of compulsive reward seeking, like alcoholism and other addictions with highly elevated motivation, may benefit from targeting the ORX system.
| Targets |
Orexin 1 receptor
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| ln Vivo |
GSK1059865 treatment significantly reduced ethanol drinking in CIE-exposed mice in a dose-dependent manner. In contrast, GSK1059865 reduced alcohol consumption in air-exposed mice only at the highest dose. GSK1059865 has no effect on sucrose intake [1]. GSK1059865 (0.3 nM-10 nM) produced insurmountable antagonism with a dose-dependent right shift of OXA EC50 and a concomitant decrease in the maximal agonist response. The calculated pKB value of GSK1059865 is 8.77±0.12. GSK1059865 (0.1-3.3 μM) produces a classic surmountable curve with a parallel shift of the OXA EC50 to the right without reducing the maximal agonist response [2]. Intraperitoneal administration of GSK1059865 produced a region-dependent inhibition of yohimbine-induced relative cerebral blood volume responses. Administration of GSK1059865 itself produced weak relative cerebral blood volume increases in several brain regions. GSK1059865-pretreated animals exhibited slightly higher baseline mean arterial blood pressure values than controls [3].
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| References |
| Molecular Formula |
C₂₀H₂₃BRFN₃O₂
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| Molecular Weight |
436.32
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| CAS # |
1191044-58-2
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| Related CAS # |
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| Appearance |
White to off-white solid powder
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| SMILES |
C[C@H]1CC[C@H](N(C1)C(=O)C2=C(C(=CC=C2)F)OC)CNC3=NC=C(C=C3)Br
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| InChi Key |
TWCRHJLMMAYSTE-ZFWWWQNUSA-N
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| InChi Code |
InChI=1S/C20H23BrFN3O2/c1-13-6-8-15(11-24-18-9-7-14(21)10-23-18)25(12-13)20(26)16-4-3-5-17(22)19(16)27-2/h3-5,7,9-10,13,15H,6,8,11-12H2,1-2H3,(H,23,24)/t13-,15-/m0/s1
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| Chemical Name |
[(2S,5S)-2-[[(5-bromopyridin-2-yl)amino]methyl]-5-methylpiperidin-1-yl]-(3-fluoro-2-methoxyphenyl)methanone
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| Synonyms |
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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: 3.33 mg/mL (7.63 mM) in 30 % SBE-β-CD (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication.
Solubility in Formulation 2: 5 mg/mL (11.46 mM) in 30% PEG300 70% (10% HP-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2919 mL | 11.4595 mL | 22.9190 mL | |
| 5 mM | 0.4584 mL | 2.2919 mL | 4.5838 mL | |
| 10 mM | 0.2292 mL | 1.1459 mL | 2.2919 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.
 Voluntary sucrose intake (ml) for EtOH and CTL mice that received GSK1059865 treatment before drinking sucrose.Brain Res.2016 Apr 1;1636:74-80. |
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 Voluntary ethanol intake (g/kg) for EtOH and CTL mice that received GSK1059865 treatment before drinking ethanol.Brain Res.2016 Apr 1;1636:74-80. |
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