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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
GSK1059865 HCl (referred to as GSK1059865 in literature) targets orexin/hypocretin 1 receptor (OX1R) (highly selective for OX1R over OX2R, with inhibition of OX2R requiring micromolar concentrations while OX1R inhibition occurs at nanomolar concentrations) [2] |
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| ln Vitro |
1. In rat basophil leukemia (RBL) cells expressing rat OX1R (rOX1R), GSK1059865 inhibited orexin-A-induced [³H]inositol phosphates (IPs) accumulation at nanomolar concentrations (0.3, 1, 3.3, 10 nM), demonstrating potent antagonism of OX1R; in RBL cells expressing rat OX2R (rOX2R), GSK1059865 only inhibited orexin-A-induced IPs accumulation at micromolar concentrations (0.1, 0.3, 1, 3.3 μM), indicating highly selective binding to OX1R [2]
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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].
1. In ethanol-dependent mice exposed to chronic intermittent ethanol (CIE), treatment with GSK1059865 significantly decreased voluntary ethanol intake in a dose-dependent manner; in air-exposed non-dependent control mice, GSK1059865 reduced ethanol intake only at the highest dose tested, and had no effect on sucrose intake in either group [1] 2. In a binge eating (BE) model of female rats, GSK1059865 administered by gavage at doses of 10 and 30 mg/kg selectively reduced compulsive consumption of highly palatable food (HPF) without affecting standard food pellet intake, and these doses did not induce sleep in parallel polysomnography experiments [2] 3. In rats treated with the pharmacological stressor yohimbine (0.75 mg/kg i.v.), pretreatment with GSK1059865 robustly inhibited the yohimbine-induced relative cerebral blood volume (rCBV) response in fronto-hippocampal regions and key components of the extended amygdala; GSK1059865 did not prevent yohimbine-induced plasma corticosterone release, confirming a central mechanism of action [3] |
| Enzyme Assay |
1. Receptor activity assay for OX1R/OX2R antagonism: Rat basophil leukemia (RBL) cells stably expressing rat OX1R (rOX1R) or OX2R (rOX2R) were cultured and treated with different concentrations of GSK1059865 (0.3, 1, 3.3, 10 nM for rOX1R; 0.1, 0.3, 1, 3.3 μM for rOX2R) prior to stimulation with orexin-A; the accumulation of [³H]inositol phosphates (IPs), a downstream marker of orexin receptor activation, was measured by quantifying radioactive emissions; Schild's linear regression analysis was performed on the data from rOX2R experiments to characterize the antagonistic properties of GSK1059865 [2]
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| Animal Protocol |
1. Ethanol dependence and intake assay in mice: Mice were first evaluated for baseline ethanol intake, then exposed to cycles of chronic intermittent ethanol (CIE) or air in inhalation chambers, with ethanol intake tested after each cycle; once CIE-exposed mice showed increased voluntary ethanol intake, GSK1059865 was administered (route not specified) at different doses, and ethanol intake (g/kg) and sucrose intake (ml) were measured; control groups included air-exposed mice treated with GSK1059865 or vehicle [1]
2. Binge eating assay in female rats: A binge eating model was established by subjecting female rats to three cycles of food restriction followed by stress (15 min of HPF exposure without access); GSK1059865 was administered by gavage at 10 and 30 mg/kg, while JNJ-10397049 (OX2R antagonist) was given intraperitoneally and SB-649868 (dual OX1/OX2R antagonist) by gavage; topiramate was used as a reference compound; polysomnography was conducted in parallel to measure sleep-inducing dose thresholds of OXR antagonists; HPF and standard food pellet intake were recorded [2] 3. fMRI stress circuit assay in rats: Functional magnetic resonance imaging (fMRI) was used to assess brain activation in rats pretreated with GSK1059865 (administration route not specified) followed by intravenous injection of yohimbine (0.75 mg/kg) as a pharmacological stressor; relative cerebral blood volume (rCBV) was measured to map brain region activation; plasma corticosterone levels were quantified at the end of the fMRI session (30 min post-yohimbine challenge) to evaluate peripheral stress responses [3] |
| References |
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| Additional Infomation |
1. The orexin/hypothalamic secretin system regulates alcohol craving and intake via OX1R; GSK1059865 is a highly selective OX1R antagonist that effectively reduces high ethanol intake in a dependence model, but has limited effect on moderate ethanol or sucrose intake, suggesting that OX1R may be a potential target for treating compulsive reward-seeking disorders such as alcoholism [1] 2. The OX1R mechanism plays an important role in binge eating behavior; selective OX1R antagonism using GSK1059865 is a novel pharmacological strategy for treating binge eating disorder and other eating disorders with compulsive components, unlike OX2R antagonists, which are ineffective for binge eating disorder [2] 3. Corticotropin-releasing factor type 1 receptor (CRF1R) and OX1R antagonists regulate stress response through different central nervous system pathways; GSK1059865 primarily inhibits stress-induced activation in the frontal-hippocampal and extended amygdala regions, while CRF1R antagonists act on the amygdala, striatum, and cingulate gyrus [3].
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| Molecular Formula |
C20H23BRFN3O2
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| Molecular Weight |
436.317927598953
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| Exact Mass |
435.095
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| CAS # |
1191044-58-2
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| Related CAS # |
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| PubChem CID |
44463491
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| Appearance |
White to off-white solid powder
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| Density |
1.4±0.1 g/cm3
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| Boiling Point |
575.8±50.0 °C at 760 mmHg
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| Flash Point |
302.1±30.1 °C
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| Vapour Pressure |
0.0±1.6 mmHg at 25°C
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| Index of Refraction |
1.592
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| LogP |
4.41
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
5
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
27
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| Complexity |
498
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| Defined Atom Stereocenter Count |
2
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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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| 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: 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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