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.

Physicochemical Properties

Molecular Formula	C20H23BRFN3O2
Molecular Weight	436.317927598953
Exact Mass	435.095
CAS #	1191044-58-2
Related CAS #	1191044-58-2
PubChem CID	44463491
Appearance	White to off-white solid powder
Density	1.4±0.1 g/cm3
Boiling Point	575.8±50.0 °C at 760 mmHg
Flash Point	302.1±30.1 °C
Vapour Pressure	0.0±1.6 mmHg at 25°C
Index of Refraction	1.592
LogP	4.41
Hydrogen Bond Donor Count	1
Hydrogen Bond Acceptor Count	5
Rotatable Bond Count	5
Heavy Atom Count	27
Complexity	498
Defined Atom Stereocenter Count	2
SMILES	C[C@H]1CC[C@H](N(C1)C(=O)C2=C(C(=CC=C2)F)OC)CNC3=NC=C(C=C3)Br
InChi Key	TWCRHJLMMAYSTE-ZFWWWQNUSA-N
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
Chemical Name	[(2S,5S)-2-[[(5-bromopyridin-2-yl)amino]methyl]-5-methylpiperidin-1-yl]-(3-fluoro-2-methoxyphenyl)methanone
Synonyms	GSK1059865; GSK-1059865; GSK 1059865
HS Tariff Code	2934.99.9001
Storage	Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month
Shipping Condition	Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Biological Activity

Targets	Orexin 1 receptor
ln Vivo	GSK1059865 treatment dramatically reduces ethanol consumption in CIE-exposed mice in a dose-dependent manner. On the other hand, GSK1059865 only reduces drinking at the maximum dose when given to mice exposed to air. GSK1059865 has no effect on the consumption of sucrose[1]. Non-surmountable antagonism is produced by GSK1059865 (0.3 nM–10 nM), which also causes a dose-dependent rightward shift of the OXA EC50 and a concurrent reduction in the agonist maximal response. The calculated pKB value is 8.77±0.12 for GSK1059865. GSK1059865 (0.1-3.3 μM) generates a classical surmountable profile with a parallel rightward shift of the OXA EC50 without lowering the agonist maximal response[2]. The administration of GSK1059865 intraperitoneally results in a region-specific suppression of the relative cerebral blood volume response induced by yohimbine. In various brain regions, the administration of GSK1059865 alone results in a modest relative increase in cerebral blood volume. Animals pretreated with GSK1059865 have baseline mean arterial blood pressure values that are marginally higher than controls[3].
Animal Protocol	Rats: GSK1059865 is given to rats by gavage at doses of 10 and 30 mg/kg after being dissolved in 0.5% HPMC (w/v) in distilled water. One hour is allowed before having access to extremely appetizing food for the drug or vehicle[2]. Mice: Mice are injected intraperitoneally (0.01 ml/g body weight) with vehicle (saline) 30 minutes prior to ethanol consumption during baseline and the first five test cycles after chronic intermittent ethanol (or air) exposure. Mice are given either vehicle or GSK1059865 (10, 25, 50 mg/kg) on test cycles 6 and 7. After that, they are allowed to choose between ethanol (15 percent v/v) in Test 6 and sucrose (5% w/v) in Test 7, or water. Using TWEEN 80 (0.5 % v/v) as the vehicle, GSK1059865 is dissolved in salted water[1].
References	[1]. The highly selective orexin/hypocretin 1 receptor antagonist GSK1059865 potently reduces ethanol drinking in ethanol dependent mice. Brain Res. 2016 Apr 1;1636:74-80. [2]. Role of orexin-1 receptor mechanisms on compulsive food consumption in a model of binge eating in female rats. Neuropsychopharmacology. 2012 Aug;37(9):1999-2011. [3]. Differential effect of orexin-1 and CRF-1 antagonism on stress circuits: a fMRI study in the rat with the pharmacological stressor Yohimbine. Neuropsychopharmacology. 2013 Oct;38(11):2120-30.

Solubility Data

Solubility (In Vitro)

DMSO: ~200 mg/mL (~458.4 mM) Water: N/A Ethanol: N/A

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.