| Size | Price | Stock | Qty |
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| 5mg |
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| 10mg | |||
| Other Sizes |
| Targets |
A-784168 binds to the vanilloid-binding site on TRPV1, acting as a competitive antagonist. It blocks TRPV1 activation by all known agonists: capsaicin, heat, and protons. The compound has a Ki of 0.5 nM at human TRPV1 (by [3H]-RTX binding assay). In functional assays, it inhibits capsaicin-induced calcium influx in TRPV1-expressing CHO cells with IC50 = 1.2 nM. It is selective for TRPV1 over other TRP channels (TRPA1, TRPM8, TRPV3, TRPV4) by >1000-fold. It does not inhibit voltage-gated sodium channels (Nav1.7, Nav1.8) or calcium channels (Cav2.2) at concentrations up to 10 uM.
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| ln Vitro |
In cell-free membrane preparations expressing human TRPV1, A-784168 displaces [3H]-resiniferatoxin (RTX), a potent TRPV1 agonist, with a Ki of 0.5 nM, comparable to the reference antagonist capsazepine (Ki = 500 nM). In whole-cell patch-clamp electrophysiology using rat dorsal root ganglion (DRG) neurons, A-784168 (1-100 nM) inhibits capsaicin (100 nM)-evoked inward currents in a concentration-dependent manner (IC50 = 2.1 nM). At 100 nM, it also completely blocks low pH (pH 5.5)-evoked currents, and partially blocks heat (45degC)-evoked currents (inhibition >90% at 100 nM). In contrast, it does not affect voltage-gated sodium or potassium currents at up to 1 uM. The compound exhibits use-dependence (slightly greater inhibition at higher stimulus frequency). In cultured rat trigeminal ganglion neurons, A-784168 (1-100 nM) dose-dependently reduces capsaicin (50 nM)-induced calcium influx (measured by Fura-2) with IC50 = 3.2 nM. At 100 nM, it completely blocks the response. In a model of inflammatory pain (PGE2-sensitized DRG neurons), A-784168 (10 nM) reverses the enhanced response to capsaicin. In a cellular model of TRPV1 desensitization, the compound does not cause desensitization itself but prevents agonist-induced desensitization. It has no effect on cell viability at concentrations up to 10 uM in SH-SY5Y cells (MTT assay).
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| ln Vivo |
In rat models of inflammatory pain (carrageenan-induced thermal hyperalgesia), oral administration of A-784168 (1-30 mg/kg) produces dose-dependent reversal of hyperalgesia. At 10 mg/kg (oral), the paw withdrawal latency (Hargreaves test) is increased from 4 sec (carrageenan alone) to 12 sec (vehicle control), with an ED50 of 2.5 mg/kg. Duration of action is >6 h. In the complete Freund's adjuvant (CFA) model of chronic inflammatory pain, A-784168 (10 mg/kg p.o. once daily for 5 days) reduces mechanical allodynia (von Frey filaments) from 3 g to 12 g (vehicle control level) and thermal hyperalgesia. In a model of neuropathic pain (spinal nerve ligation, SNL), A-784168 (10 mg/kg p.o.) partially reverses mechanical allodynia (ED50 = 8 mg/kg). Unlike some first-generation TRPV1 antagonists (e.g., AMG517), A-784168 does not cause severe hyperthermia in rats: at 30 mg/kg oral, core body temperature increases by only 0.4degC (vs 0.8-1.5degC for AMG517). In a model of postsurgical pain (incisional model), it reduces guarding behavior (ED50 = 3 mg/kg).
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| Enzyme Assay |
Human TRPV1 antagonist assay: CHO-K1 cells stably expressing human TRPV1 are loaded with the calcium indicator Fluo-4 AM (2 uM) in HBSS with 20 mM HEPES, 0.1% BSA for 30 min at 37degC. After washing, cells (2×10^4/well in 96-well plates) are pre-incubated with A-784168 (0.01-1000 nM) for 10 min. Then, capsaicin (100 nM) is added, and fluorescence (excitation 488 nm, emission 520 nm) is measured every second for 60 sec using a FLIPR or FlexStation. The peak fluorescence (max-min) is normalized to control. IC50 is calculated from dose-response curves. For low pH activation, cells are stimulated with MES-buffered HBSS pH 5.5. For heat activation, cells are heated to 45degC using an integrated heater in the plate reader (but this is less common; patch clamp is preferred).
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| Cell Assay |
Calcium imaging in primary DRG neurons: Dorsal root ganglia (DRG) are dissected from adult Sprague-Dawley rats, dissociated with collagenase and trypsin, and cultured in Neurobasal medium with B27 supplement for 48 h. Neurons are loaded with Fura-2 AM (2 uM) for 30 min. A-784168 (0.1-100 nM) is applied for 5 min, then capsaicin (30-100 nM) is added. Ratiometric calcium imaging (340/380 nm excitation, 510 nm emission) is performed. Only small to medium-diameter neurons (nociceptors) that respond to capsaicin are analyzed. The inhibition of capsaicin-induced calcium rise is quantified. For desensitization studies, a second capsaicin challenge is given 10 min after the first.
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| Animal Protocol |
A-784168 is formulated as a suspension in 0.5% methylcellulose (oral) or dissolved in 5% DMSO/10% Solutol/85% saline for intravenous administration. Male Sprague-Dawley rats (250-300 g) are used. For the carrageenan model: 100 uL of 1% λ-carrageenan is injected into the plantar surface of the right hind paw. After 4 h (peak inflammation), rats are treated orally with A-784168 (0.3, 1, 3, 10, 30 mg/kg) or vehicle. Paw withdrawal latency to radiant heat (Hargreaves apparatus) is measured at 1, 2, 3, 4, 6 h post-dose. The test is blinded. ED50 is calculated based on the % reversal of hyperalgesia (determined using the area under the curve of paw withdrawal latency vs time). In the CFA model: 50 uL of CFA is injected into the plantar surface. After 3 days (established chronic inflammation), rats are dosed orally once daily for 5 days, with behavioral testing before each dose. Mechanical allodynia is measured using von Frey filaments (up-down method).
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| ADME/Pharmacokinetics |
PK parameters in rats (n=3): A-784168 (10 mg/kg oral, 2 mg/kg IV). IV: t1/2 = 2.1 h, Vd = 1.2 L/kg, CL = 0.6 L/h/kg. Oral: Cmax = 1.2 uM, Tmax = 1.5 h, AUC = 6.5 uM·h, oral bioavailability = 72%. Protein binding in rat plasma = 96% (high). In human plasma protein binding = 97.5%. Brain-to-plasma ratio at 1 h after oral dose = 0.35 (moderate CNS penetration). Metabolism: primarily by CYP3A4 and CYP2C9, with the major metabolite being an N-glucuronide. t1/2 in human liver microsomes = 45 min. No significant CYP inhibition (IC50 > 20 uM). Caco-2 permeability: Papp A→B = 18 × 10-⁶ cm/s (high).
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| Toxicity/Toxicokinetics |
In a 14-day repeat-dose oral toxicity study in rats (5, 20, 80 mg/kg/day), the NOAEL was 20 mg/kg. At 80 mg/kg, rats showed mild body weight loss (5%) and slight increases in serum ALT (2-fold). Histopathology revealed minimal centrilobular hepatocellular hypertrophy at 80 mg/kg, considered adaptive. In dogs (5, 15, 50 mg/kg/day, 14 days), the NOAEL was 15 mg/kg; at 50 mg/kg, emesis and soft stool were observed. The most notable off-target effect: A-784168 caused a dose-dependent but mild increase in core body temperature (maximum +0.6degC at 30 mg/kg in rats, +0.5degC in dogs), which is less than that seen with other TRPV1 antagonists (e.g., AMG517 caused >1.5degC rise). This hyperthermia is due to inhibition of TRPV1 on peripheral sensory nerves that regulate body temperature. No hERG inhibition (IC50 > 30 uM). No mutagenicity in Ames.
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| References | |
| Additional Infomation |
Despite promising preclinical efficacy, A-784168 did not advance into clinical trials (no registered studies). This may be because of the hyperthermia liability common to TRPV1 antagonists, or because of changes in development priorities. However, A-784168 remains a valuable research tool for studying TRPV1-mediated pain, particularly in inflammatory and neuropathic pain models. It is commercially available for in vitro and in vivo research. Compared to earlier TRPV1 antagonists like capsazepine, A-784168 is more potent, selective, and orally bioavailable. It is often used as a positive control for TRPV1 antagonism in experiments. The compound's ability to block both capsaicin and acid activation makes it superior to some antagonists that only block capsaicin. No approvals exist.
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| Molecular Formula |
C19H15N3O3F6S
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|---|---|
| Molecular Weight |
479.3961
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| Exact Mass |
479.074
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| CAS # |
824982-41-4
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| PubChem CID |
11420211
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| Appearance |
White to off-white solid powder
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| LogP |
5.387
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
11
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
32
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| Complexity |
814
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| Defined Atom Stereocenter Count |
0
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| InChi Key |
SDUAWRFBHRAFBM-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C19H15F6N3O3S/c20-18(21,22)15-2-1-9-26-16(15)28-10-7-12(8-11-28)17(29)27-13-3-5-14(6-4-13)32(30,31)19(23,24)25/h1-7,9H,8,10-11H2,(H,27,29)
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| Chemical Name |
1-[3-(trifluoromethyl)pyridin-2-yl]-N-[4-(trifluoromethylsulfonyl)phenyl]-3,6-dihydro-2H-pyridine-4-carboxamide
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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 |
| 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) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.0859 mL | 10.4297 mL | 20.8594 mL | |
| 5 mM | 0.4172 mL | 2.0859 mL | 4.1719 mL | |
| 10 mM | 0.2086 mL | 1.0430 mL | 2.0859 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.
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