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| Targets |
Trpvicin specifically targets the Transient Receptor Potential Vanilloid 3 (TRPV3) ion channel. It acts as an antagonist by stabilizing the channel in a closed state, thereby preventing its activation. Its mechanism involves binding to the VSLD-PD site, which locks the channel in a non-conductive conformation. In the context of the pathogenic G573S mutant, Trpvicin accesses an additional binding pocket within the central cavity, remodeling channel symmetry and physically blocking the pore to inhibit the channel's constitutive open state.
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| ln Vitro |
Trpvicin (0-100 μM) dose-dependently inhibited the currents of TRPV3-WT and hTRPV3-G573S channels expressed in HEK293T cells, achieving almost complete inhibition at a concentration of 10 μM, with efficacy comparable to Ruthenium Red [1]. Trpvicin (10 μM, 24 hours) rescued the viability of HEK293T cells expressing the cytotoxic hTRPV3-G573S mutant, indicating that it has a functional blocking effect on constitutive active channels [1]. Trpvicin (0-100 μM) dose-dependently inhibited the currents of heterologously expressed hTRPV3-G568V and mTRPV3-G568V channels in HEK293T cells [1]. Trpvicin effectively inhibited heterologous expression of wild-type mouse TRPV3 (mTRPV3-WT) and gain-of-function mutant mTRPV3-G568V in HEK293T cells, with IC50 values of 0.38 μM and 0.42 μM, respectively [1]. The potency of Trpvicin against hTRPV3 A556V, A560T and F601A mutants was significantly reduced compared to the wild-type channel (reduced by 158-fold, 162-fold and 208-fold, respectively), indicating that these residues are key determinants of Trpvicin binding [1]. The efficacy of Trpvicin against the double mutants hTRPV3-G573S-F666A, hTRPV3-G573S-F666Y and hTRPV3-G573S-T665A was reduced by 17-fold, 12-fold and 16-fold, respectively, indicating that these residues have important drug-binding functions in the central cavity region, and their role exceeds their primary VSLD-PD binding site [1].
Trpvicin is a highly potent and selective inhibitor of TRPV3, with remarkable subtype selectivity. Its in vitro activity is characterized by its IC50 values: 0.41 microM for the human wild-type TRPV3 (hTRPV3-WT) and 0.22 microM for the hTRPV3-G573S mutant. It exhibits minimal activity against other TRP family members, including TRPV1, TRPV2, TRPV4, TRPV5, TRPV6, TRPA1, and TRPM8. It dose-dependently inhibits TRPV3 currents in HEK293T cells expressing either wild-type or gain-of-function mutants (e.g., G568V), achieving near-complete inhibition at 10 microM. |
| ln Vivo |
Trpvicin (10 and 100 µM, intradermal injection, sprayed 30 minutes before SLIGRL injection) significantly reduced acute scratching behavior in mice induced by SLIGRL [1]. Trpvicin (30 and 100 mg/kg, oral gavage, laboratory daily for 12 days starting 5 days before MC903 modeling) achieved chronic scratching and ear swelling in a MC903-induced mouse dermatitis model [1]. Trpvicin (1 wt%, topical, daily formulation for 16 days starting 50 days after birth) effectively improved hair loss in female and Trpv3+/G568V knock-in mice [1].
In vivo, Trpvicin exhibits pharmacological efficacy in mouse models relevant to TRPV3 function. When administered intradermally (10 and 100 microM), it significantly reduces acute scratching behavior induced by the Trpvicin peptide SLIGRL, demonstrating its anti-itch effects. In a mouse model of chronic dermatitis induced by MC903, oral administration of Trpvicin (30 and 100 mg/kg) for 12 days dose-dependently inhibits chronic scratching and ear swelling, highlighting its potential for treating inflammatory skin conditions. Furthermore, it has been shown to inhibit hair loss in mouse models. |
| Enzyme Assay |
General in vitro TRPV3 binding/activity assay: The primary method to evaluate Trpvicin's activity is a patch-clamp electrophysiology assay using HEK293T cells heterologously expressing human TRPV3 (WT or mutant). Cells are cultured and voltage-clamped at -60 mV. Trpvicin is applied at various concentrations (0-100 microM) via bath perfusion. The TRPV3 channel is activated by bath application of a known agonist, such as 2-APB (200 uM). The whole-cell current is measured before and after compound application. The percentage inhibition is calculated, and dose-response curves are generated.
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| Cell Assay |
Cell Cytotoxicity Assay[1]
Cell Types: HEK293T cells Tested Concentrations: 10 μM Incubation Duration: 24 h Experimental Results: Rescued the cell viability of HEK293T cells expressing the cytotoxic hTRPV3-G573S mutant. General in vitro cell viability assay: HEK293T cells expressing the constitutively active cytotoxic hTRPV3-G573S mutant are seeded in 96-well plates. After 24 hours, they are treated with 10 microM Trpvicin for an additional 24 hours. Cell viability is then measured using a standard MTT assay. Treatment with Trpvicin rescues the viability of these cells, confirming its functional blockade of the pathogenic channel. For selectivity, a similar patch-clamp assay can be performed on HEK293T cells expressing other TRP channels (e.g., TRPV1, TRPA1). Trpvicin shows minimal effects on these channels. |
| Animal Protocol |
Animal/Disease Models: Adult wild-type male C57BL/6J mice (8-12 weeks old) topically treated with 20 μL of 100 μM MC903 on both ears, daily for 7 days[1]
Doses: 30 and 100 mg/kg Route of Administration: p.o., daily starting from 5 days before MC903 for 12 days Experimental Results: Reduced the scratching behavior at a dose of 100 mg/kg, compared to the vehicle-treated control mice in the MC903-induced chronic itch model. Reduced the percentage of ear thickness increase induced by MC903. Animal/Disease Models: Adult wild-type male C57BL/6J mice (8-12 weeks old) intradermally injected with SLIGRL (50 µg)[1] Doses: 10 and 100 µM Route of Administration: i.d., 30 min pre-SLIGRL Experimental Results: Exhibited fewer scratching bouts elicited by SLIGRL at both 10 and 100 µM. Animal/Disease Models: Trpv3+/G568V knock-in mice[1] Doses: 1 wt% Route of Administration: topically, daily from postnatal day 50 (P50) for 16 days Experimental Results: Showed substantially longer hair shafts and less hair shedding throughout the period. Demonstrated efficacy in rescuing hair loss in both male and female mouse models. General in vivo animal protocol for efficacy: To assess anti-itch effects, male C57BL/6J mice are used. Trpvicin (10 and 100 microM) is injected intradermally in a volume of 20 microL. Thirty minutes later, the pruritogenic agent SLIGRL (100 microM) is injected into the same site. The mice are then placed in an observation chamber, and their scratching behavior is recorded for 30 minutes. For the dermatitis model, mice are treated with MC903 on their ears for 12 days to induce atopic dermatitis-like skin inflammation. Trpvicin (30 and 100 mg/kg) is administered daily by oral gavage for the duration of the study. Spontaneous scratching behavior is monitored, and ear swelling is measured with a caliper. |
| ADME/Pharmacokinetics |
As a small, lipophilic molecule, Trpvicin (MW 478.45) is orally bioavailable, as evidenced by its efficacy when administered via oral gavage. Its pharmacokinetic profile has not been fully detailed in the source literature, but its distribution to dermal sites after oral dosing is implied by its in vivo activity in suppressing scratching and ear swelling. For research purposes, it is supplied as a solid powder. A 10 mM stock solution can be prepared in DMSO and stored at -80degC for up to 6 months.
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| Toxicity/Toxicokinetics |
No extensive, formal toxicology studies are reported in the provided reference literature. However, in the described mouse models, Trpvicin was administered both intradermally (up to 100 uM) and orally (up to 100 mg/kg) without reports of overt toxicity or significant body weight loss, suggesting a tolerable safety profile at efficacious doses. As a research chemical, it is not a drug and has no FDA approvals or warnings. For its use as an impurity reference standard, it is not a genotoxic impurity and would be controlled according to standard ICH Q3A/B guidelines.
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| References | |
| Additional Infomation |
TRPV3 is a calcium-permeable non-selective cation channel predominantly expressed in skin keratinocytes. It plays critical roles in skin barrier formation, hair growth, thermosensation, and inflammatory responses. Dysfunction of TRPV3, particularly the G573S gain-of-function mutation, is linked to the rare skin disorder Olmsted syndrome, which is characterized by palmoplantar keratoderma and periorificial hyperkeratosis. Trpvicin was identified in a 2022 study published in Nature Chemical Biology, which used cryogenic electron microscopy (cryo-EM) to solve the structure of the TRPV3-Trpvicin complex, providing a structural basis for its inhibitory mechanism. The compound's ability to inhibit both wild-type and disease-associated mutants makes it a valuable tool for validating TRPV3 as a therapeutic target for skin diseases, inflammatory conditions, and pruritus.
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| Molecular Formula |
C20H17F3N6O3S
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| Molecular Weight |
478.45
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| Exact Mass |
478.103
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| CAS # |
2019994-90-0
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| PubChem CID |
122589101
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| Appearance |
White to off-white solid powder
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| Hydrogen Bond Donor Count |
1
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
33
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| Complexity |
736
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| Defined Atom Stereocenter Count |
0
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| SMILES |
CC(C)(C#N)C1=NC=CC(=C1)C2=C(N=C(S2)NC(=O)C3=C(N=CN=C3OC)OC)C(F)(F)F
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| InChi Key |
CPIDEBBXBVMQOC-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C20H17F3N6O3S/c1-19(2,8-24)11-7-10(5-6-25-11)13-14(20(21,22)23)28-18(33-13)29-15(30)12-16(31-3)26-9-27-17(12)32-4/h5-7,9H,1-4H3,(H,28,29,30)
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| Chemical Name |
N-[5-[2-(2-cyanopropan-2-yl)-4-pyridinyl]-4-(trifluoromethyl)-1,3-thiazol-2-yl]-4,6-dimethoxypyrimidine-5-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) |
DMSO : ~25 mg/mL (~52.25 mM; with sonication)
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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 | 2.0901 mL | 10.4504 mL | 20.9008 mL | |
| 5 mM | 0.4180 mL | 2.0901 mL | 4.1802 mL | |
| 10 mM | 0.2090 mL | 1.0450 mL | 2.0901 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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