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Purity: ≥98%
TCS-OX2-29 (TCS-OX229, TCS-OX-229), discovered from high throughput screening (HTS), is a potent, selective and non-peptide OX2 (orexin) receptor antagonist with potential usefulness in the treatment of insomnia. It inhibits OX2 with an IC50 of 40 nM and displays >250-fold selectivity for OX2 over OX1. Orexin receptor antagonists are expected to be a new approach for the treatment of insomnia that directly targets sleep/wake regulation. Several such compounds have entered into clinical development, including the dual orexin receptor antagonists, suvorexant and almorexant. TCS-OX2-29 shows selectivity for ion channels, and transporters (<30% inhibition at 10 μM), which includes G-protein coupled receptors associated with food intake including galanin and neuripeptide Y. TCS-OX2-29 Inhibits orexin A induced IP3 accumulation and ERK1/2 phosphorylation in CHO cells transfected with the OX2 receptor.
| Targets |
OX2 Receptor
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| ln Vitro |
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| ln Vivo |
TCS-OX2-29 (5-10 mg/kg; intraperitoneal injection; adult male NMRI mice) treatment significantly suppresses the acquisition and expression of conditioned place preference (CPP) in both naïve and dependent mice[2].
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| Enzyme Assay |
Full assay details are provided in the Supporting Information. 24-hour-old CHO cells that were seeded at a density of 25,000 cells/well and were stably expressing the human orexin-2 receptor were used for cell-based inositol phosphate (Cisbio BioAssays, Codolet, France) and ERK1/2 phosphorylation (Surefire, PerkinElmer, Waltham, MA, USA) functional assays in 96-well plates
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| Cell Assay |
In Krebs assay buffer (8.5 mM HEPES, 1.3 mM CaCl2, 1.2 mM MgSO4, 118 mM NaCl, 4.7 mM KCl, 4 mM NaHCO3, 1.2 mM KH2PO4, 11 mM glucose, pH 7.4), cell membranes from HEK293 cells transiently expressing the human OX2 receptor were incubated with [3H]-EMPA in a total assay volume of 0.25 mL with a final DMSO concentration of 1%. Using a Tomtec cell harvester, the reaction was quickly stopped after 90 minutes of room temperature incubation by filtering through GF/B 96-well glass fiber plates with 5 × 0.25 mL washes with ddH2O. Using Lablogic SafeScint for liquid scintillation, bound radioactivity was ascertained and detected on a microbeta liquid scintillation counter. The amount of non-specific binding was defined as that which persisted when the antagonist EMPA was present at a 10 μM saturating concentration. Membranes (2 μg protein/well) were incubated with a range of concentrations of [3H]-EMPA (0.4 nM–15 nM) in order to perform saturation studies. Using a Beckman LS 6000 liquid scintillation counter and SafeScint, radioligand concentrations were ascertained. In order to conduct competition binding, membranes (2 μg protein/well) were incubated with a range of concentrations of the test compound and 1.5 nM of [3H]-EMPA.
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| Animal Protocol |
440 adult male NMRI mice (25-30 g)
5 mg/kg and 10 mg/kg Intraperitoneal injection (Pharmacokinetic study) |
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| References |
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| Molecular Formula |
C₂₃H₃₁N₃O₃
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| Molecular Weight |
397.51
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| Exact Mass |
397.24
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| Elemental Analysis |
C, 69.49; H, 7.86; N, 10.57; O, 12.07
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| CAS # |
372523-75-6
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| Related CAS # |
TCS-OX2-29 hydrochloride; 1610882-30-8
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| Appearance |
Solid powder
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| SMILES |
CC(C)(C)[C@@H](C(=O)N1CCC2=CC(=C(C=C2C1)OC)OC)NCC3=CC=NC=C3
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| InChi Key |
COFVZFLCAOUMJT-OAQYLSRUSA-N
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| InChi Code |
InChI=1S/C23H31N3O3/c1-23(2,3)21(25-14-16-6-9-24-10-7-16)22(27)26-11-8-17-12-19(28-4)20(29-5)13-18(17)15-26/h6-7,9-10,12-13,21,25H,8,11,14-15H2,1-5H3/t21-/m1/s1
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| Chemical Name |
(2S)-1-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-3,3-dimethyl-2-(pyridin-4-ylmethylamino)butan-1-one
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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 (6.29 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 (6.29 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 (6.29 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 | 2.5157 mL | 12.5783 mL | 25.1566 mL | |
| 5 mM | 0.5031 mL | 2.5157 mL | 5.0313 mL | |
| 10 mM | 0.2516 mL | 1.2578 mL | 2.5157 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.
 Competition kinetics curves for [3H]-EMPA binding to OX2-expressing (HEK293) cell membranes in the presence of increasing concentrations of EMPA, TCS-OX2-29, suvorexant and almorexant.Br J Pharmacol.2014 Jan;171(2):351-63. |
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 Deming linear correlations between (A) kinetically derived pKDand pKIvalues derived from equilibrium competition binding.Br J Pharmacol.2014 Jan;171(2):351-63. |
 Comparison of depression of the orexin-A maximal response in (A) ERK1/2 phosphorylation and (B) inositol phosphate accumulation assays as a function of antagonist concentration.Br J Pharmacol.2014 Jan;171(2):351-63. |
 Effect of increasing concentrations of (A) EMPA, (B) TCS-OX-29, (C) suvorexant and (D) almorexant on orexin-A stimulated ERK1/2 phosphorylation in CHO-hOX2cells.Br J Pharmacol.2014 Jan;171(2):351-63. |
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 Effect of increasing concentrations of (A) EMPA, (B) TCS-OX-29, (C) suvorexant and (D) almorexant on orexin-A stimulated inositol phosphate accumulation in CHO-hOX2cells.Br J Pharmacol.2014 Jan;171(2):351-63. |
 Competition for [3H]–EMPA binding to OX2-expressing HEK293 cell membranes showing the displacement of increasing concentrations by test compounds.
Kinetic binding profile of [3H]–EMPA binding to OX2-expressing HEK293 cell membranes.Br J Pharmacol.2014 Jan;171(2):351-63. |
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