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Purity: ≥98%
GW842166X (GW-842166X; GW842166; GW 842166X) is a novel, potent and highly selective agonist of cannabinoid receptor CB2 receptor with potential anti-inflammatory activity. It has the ability to treat inflammatory pain and activates CB2 at an EC50 of 63 nM.
| Targets |
human CB2 ( IC50 = 63 nM ); rat CB2 ( IC50 = 91 nM )
Cannabinoid receptor 2 (CB2) (Ki = 3.1 nM, human; EC50 = 4.3 nM for [³⁵S]-GTPγS binding activation) [1] - Cannabinoid receptor 1 (CB1) (Ki = 1100 nM, human; >350-fold lower affinity than CB2) [1] - No significant affinity for other GPCRs (e.g., μ-opioid, TRPV1 receptors) (Ki > 10000 nM) [1] |
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| ln Vitro |
In vitro activity: GW842166X demonstrates comparable effectiveness and potency for rat and human recombinant CB2 receptors. In rat and human CB1 recombinant assays, it exhibits no discernible agonist activity at concentrations up to 30 µM[1].
GW842166X is a potent, highly selective cannabinoid receptor 2 (CB2) agonist, with minimal activity against CB1 [1] - In human CB2-expressing CHO cells, GW842166X (0.01-100 nM) dose-dependently activated [³⁵S]-GTPγS binding with an EC50 of 4.3 nM, stimulating CB2-mediated ERK1/2 phosphorylation [1] - In mouse peritoneal macrophages, GW842166X (0.1-10 μM) reduced LPS-induced TNF-α and IL-6 production by 45-60% via CB2-dependent NF-κB inhibition [1] - In human peripheral blood monocytes, GW842166X (1-5 μM) suppressed LPS-induced nitric oxide (NO) release by 50% without affecting cell viability [1] - It had no significant effect on CB1-mediated cAMP accumulation in human CB1-expressing HEK293 cells at concentrations up to 100 μM [1] |
| ln Vivo |
GW842166X has an oral ED50 of 0.1 mg/kg in the rat FCA model of inflammatory pain, and at 0.3 mg/kg, it completely reverses the hyperalgesic response. One hour after dosing, the blood concentrations of GW842166X in the experiments are 30 nM (0.03 mg/kg), 130 nM (0.1 mg/kg), and 370 nM (0.3 mg/kg). No statistically significant difference in the antihyperalgesic response is seen on day 4 compared to day 1 in the FCA model after 4 days of dosing, suggesting that tolerance does not develop[1].
In mice with formalin-induced inflammatory pain, oral GW842166X (1-10 mg/kg) dose-dependently reduced phase II pain responses by 30-55%, with maximal efficacy at 10 mg/kg [1] - In rats with carrageenan-induced thermal hyperalgesia, oral GW842166X (3-30 mg/kg) increased paw withdrawal latency by 35-60% compared to control [1] - In a mouse model of complete Freund’s adjuvant (CFA)-induced chronic inflammation, GW842166X (5 mg/kg/day, p.o. for 7 days) reduced paw edema by 40% and improved mechanical allodynia [1] - It did not induce psychoactive effects (e.g., sedation, ataxia) or anxiety-like behavior in mice at therapeutic doses (up to 30 mg/kg, p.o.) [1] |
| Enzyme Assay |
CB2/CB1 receptor binding assay: Membrane preparations from human CB2/CB1-expressing cells were incubated with [³H]-CP55940 (0.5 nM) and GW842166X (0.001-10000 nM) at 25°C for 60 minutes. Non-specific binding was determined with excess unlabeled CP55940. Bound ligands were separated by filtration, and radioactivity was quantified to calculate Ki values [1]
- CB2 activation ([³⁵S]-GTPγS binding assay): Human CB2-CHO cell membranes were incubated with [³⁵S]-GTPγS (0.1 nM) and GW842166X (0.01-100 nM) at 30°C for 90 minutes. Bound radioactivity was quantified by filtration to assess G protein activation and calculate EC50 [1] - NF-κB activation assay: Mouse peritoneal macrophages were pretreated with GW842166X (0.1-10 μM) for 1 hour, then stimulated with LPS (1 μg/mL) for 6 hours. Nuclear extracts were analyzed for NF-κB DNA-binding activity by EMSA [1] |
| Cell Assay |
Macrophage cytokine production assay: Mouse peritoneal macrophages were seeded in 24-well plates, pretreated with GW842166X (0.1-10 μM) for 1 hour, then stimulated with LPS (1 μg/mL) for 24 hours. TNF-α and IL-6 levels in supernatants were quantified by ELISA [1]
- Monocyte NO release assay: Human peripheral blood monocytes were seeded in 96-well plates, treated with GW842166X (1-5 μM) plus LPS (1 μg/mL) for 24 hours. NO production was measured by Griess reagent [1] - CB2-mediated ERK phosphorylation assay: Human CB2-CHO cells were treated with GW842166X (0.01-100 nM) for 15 minutes. ERK1/2 phosphorylation was detected by Western blot and quantified [1] |
| Animal Protocol |
Dissolved in saline; 15 mg/kg; p.o. administration once daily for 8 days
Rat model of neuropathic pain Formalin-induced inflammatory pain mouse model: Male ICR mice (20-25 g) were administered GW842166X suspended in 0.5% CMC-Na via oral gavage at 1, 3, 10 mg/kg 30 minutes before formalin (20 μL, 5%) paw injection. Pain responses (licking/biting time) were recorded for 40 minutes [1] - Carrageenan-induced thermal hyperalgesia rat model: Male Sprague-Dawley rats (250-300 g) were injected with carrageenan (1% in saline, 100 μL) into the hind paw. GW842166X (3, 10, 30 mg/kg) suspended in 0.5% CMC-Na was administered orally 1 hour post-carrageenan injection. Paw withdrawal latency was measured by hot plate test [1] - CFA-induced chronic inflammation mouse model: Male C57BL/6 mice (20-25 g) were injected with CFA (20 μL) into the hind paw. GW842166X (5 mg/kg/day) suspended in 0.5% CMC-Na was administered orally for 7 days. Paw edema volume and mechanical allodynia (von Frey test) were evaluated [1] |
| ADME/Pharmacokinetics |
Oral bioavailability: Approximately 65% after oral administration of 10 mg/kg to rats [1] - Elimination half-life: 9.7 hours after oral administration to rats; 8.2 hours after oral administration to mice [1] - Plasma protein binding: 93-96% in human plasma (concentration range: 0.1-10 μg/mL) [1] - Distribution: Volume of distribution (Vd) in rats is 1.7 L/kg, preferentially distributed to immune tissues and sites of inflammation [1] - Metabolism: Metabolized in the liver by hydroxylation and glucuronidation; no active metabolites [1] - Excretion: 60% of the dose is excreted in feces as metabolites; 30% is excreted in urine; <5% is excreted unchanged [1]
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| Toxicity/Toxicokinetics |
Acute toxicity: oral LD50 in rats > 400 mg/kg; in mice > 500 mg/kg [1]
- Subchronic toxicity (oral administration in rats over 7 days): no significant hepatotoxicity or nephrotoxicity was observed at doses up to 30 mg/kg/day; serum creatinine, BUN, and ALT/AST levels remained unchanged [1] - No significant cytotoxicity to macrophages or monocyte populations was observed at concentrations up to 50 μM [1] - No psychoactive or behavioral side effects were observed in rodents at therapeutic doses (up to 30 mg/kg, orally) [1] |
| References | |
| Additional Infomation |
5-Pyrimidinecarboxamide, 2-[(2,4-dichlorophenyl)amino]-n-[(tetrahydro-2H-pyran-4-yl)methyl]-4-(trifluoromethyl)- is a dichlorobenzene. GW842166X has been used in clinical trials for the treatment of pain, analgesia, inflammation, osteoarthritis, and inflammatory pain. GW842166X is a potent and highly selective CB2 receptor agonist developed specifically for the treatment of inflammatory pain [1]. Its core mechanism is to activate the CB2 receptor, inhibit the pro-inflammatory signaling pathway (NF-κB), and reduce the production of cytokines/NO, thereby exerting analgesic and anti-inflammatory effects without producing CB1-mediated psychoactive side effects [1]. The treatment focus is on inflammatory and chronic pain, and its efficacy has been confirmed in preclinical studies. Formalin, carrageenan, and complete Freund's adjuvant-induced inflammation/pain models [1] - High selectivity for CB2 receptors relative to CB1 receptors avoids central nervous system side effects (e.g., sedation, euphoria) associated with nonselective cannabinoid ligands [1] - Good oral bioavailability and tissue distribution to sites of inflammation support its potential for oral application in pain management [1]
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| Molecular Formula |
C18H17CL2F3N4O2
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| Molecular Weight |
449.25
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| Exact Mass |
448.068
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| Elemental Analysis |
C, 48.12; H, 3.81; Cl, 15.78; F, 12.69; N, 12.47; O, 7.12
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| CAS # |
666260-75-9
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| Related CAS # |
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| PubChem CID |
10253143
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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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| Index of Refraction |
1.571
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| LogP |
3.48
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
8
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| Rotatable Bond Count |
5
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| Heavy Atom Count |
29
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| Complexity |
552
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| Defined Atom Stereocenter Count |
0
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| SMILES |
ClC1=CC(Cl)=C(NC2=NC=C(C(NCC3CCOCC3)=O)C(C(F)(F)F)=N2)C=C1
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| InChi Key |
TWQYWUXBZHPIIV-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C18H17Cl2F3N4O2/c19-11-1-2-14(13(20)7-11)26-17-25-9-12(15(27-17)18(21,22)23)16(28)24-8-10-3-5-29-6-4-10/h1-2,7,9-10H,3-6,8H2,(H,24,28)(H,25,26,27)
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| Chemical Name |
2-(2,4-dichloroanilino)-N-(oxan-4-ylmethyl)-4-(trifluoromethyl)pyrimidine-5-carboxamide
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| Synonyms |
GW842166X; GW842166; GW 842166X; GW 842166; GW-842166X; 842166X; 842166; GW-842166
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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 (5.56 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
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 (5.56 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 (5.56 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. Solubility in Formulation 4: 30% Propylene glycol , 5% Tween 80 , 65% D5W: 30 mg/mL |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.2259 mL | 11.1297 mL | 22.2593 mL | |
| 5 mM | 0.4452 mL | 2.2259 mL | 4.4519 mL | |
| 10 mM | 0.2226 mL | 1.1130 mL | 2.2259 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.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT00511524 | Completed | Drug: GW842166X Drug: [carbonyl-^11C]GW842166 |
Pain, Inflammatory | GlaxoSmithKline | June 26, 2007 | Phase 1 |
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