TRPV1
Vocacapsaicin hydrochloride targets the transient receptor potential vanilloid 1 (TRPV1) receptor as a potent agonist. TRPV1 is a non-selective cation channel expressed primarily on nociceptive sensory neurons and is activated by capsaicin, heat, and protons. Upon local administration, vocacapsaicin hydrochloride is converted to capsaicin, which activates TRPV1 receptors on C-fibers. This activation induces a long-lasting refractory state of C-fibers, providing sustained analgesia without affecting normal sensory function, proprioception, or muscle strength. The compound is a first-in-class non-opioid TRPV1 agonist.

Vocacapsaicin (CA-008, Conentric Analgesics) – an investigational TRPV agonist being studied for long-lasting pain – works through the same TRPV1 agonism mechanism but its localized delivery is thought to minimize activation of a large array of neurons, such as capsaicin topical products[1].

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In vitro studies demonstrate that vocacapsaicin hydrochloride is a prodrug of capsaicin that acts as a first-in-class non-opioid TRPV1 agonist. As a prodrug, it is designed to be converted to active capsaicin upon administration. The compound activates TRPV1 receptors, leading to calcium influx and desensitization of nociceptive C-fibers. This mechanism provides meaningful and long-lasting pain relief. The prodrug is water-soluble, which may offer advantages for formulation and local administration compared to capsaicin itself. In vitro characterization includes assessment of TRPV1 agonism and prodrug conversion kinetics.

When injected into surgical sites, vocacapsaicin is rapidly converted to lipophilic capsaicin and can cross the membranes to reach the desired amino acid target on TRVP1 channels[1].

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In vivo studies have demonstrated that vocacapsaicin hydrochloride provides meaningful and long-lasting pain relief upon local administration. The compound is being developed as a non-opioid, site-specific treatment for postsurgical pain management. Upon administration, the prodrug is converted to capsaicin, which activates TRPV1 receptors and induces a long-lasting refractory state of C-fibers. This provides sustained analgesia without affecting sensation, proprioception, or muscle strength. The compound has been evaluated in preclinical models for postsurgical pain. Clinical development has been reported for this compound.

For TRPV1 receptor binding and activation assays, cells expressing TRPV1 receptors (e.g., HEK293 cells transfected with TRPV1) are cultured and loaded with calcium-sensitive fluorescent dyes. Vocacapsaicin hydrochloride is dissolved in appropriate buffer and diluted to varying concentrations. Cells are treated with the compound and calcium flux is measured using fluorescence plate readers. TRPV1 activation is assessed by measuring intracellular calcium increases. For prodrug conversion assays, the compound is incubated with appropriate enzymes or tissue homogenates and conversion to capsaicin is quantified by HPLC or LC-MS. IC50 or EC50 values are calculated from dose-response curves. Assays are performed in replicate with vehicle and positive controls (e.g., capsaicin).

For in vitro cellular assays, cells expressing TRPV1 receptors (e.g., HEK293 cells or primary sensory neurons) are cultured in appropriate media under standard conditions (37°C, 5% CO2). Vocacapsaicin hydrochloride is dissolved in DMSO or water and diluted in culture medium to desired concentrations. Cells are treated with compound for specified durations. TRPV1 activation is assessed by measuring intracellular calcium flux using fluorescent indicators. Cell viability and cytotoxicity can also be assessed using MTT or LDH assays. Prodrug conversion can be measured by analyzing culture supernatants for capsaicin formation. Each concentration is tested in replicate wells with vehicle controls and positive controls (e.g., capsaicin).

For in vivo animal studies of vocacapsaicin hydrochloride, preclinical models of postsurgical pain are used. Animals (typically rats or mice) undergo surgical procedures to induce pain, followed by local administration of the compound. Pain behavior is assessed using standard nociceptive tests (e.g., von Frey filaments, paw withdrawal thresholds). The compound is formulated in appropriate vehicles for local administration (e.g., injection at surgical site). Dosing regimens vary by study objective. Blood and tissue samples may be collected for pharmacokinetic analysis and biomarker assessment. Analgesic efficacy and duration of action are evaluated. All procedures follow institutional animal care and use committee guidelines.

Pharmacokinetic properties of vocacapsaicin hydrochloride are characteristic of a water-soluble prodrug. The compound has a molecular weight of 496.08, formula C26H42ClN3O4, and CAS number 1931116-92-5. LogP is 4.2 and tPSA is 79.9 Ų. As a prodrug of capsaicin, it is designed for local administration and conversion to active capsaicin at the site of action. The compound is water-soluble, which may facilitate formulation for injection. Storage: typically at -20°C for powder; in solvent at -80°C. Specific pharmacokinetic parameters such as half-life, clearance, and bioavailability are not extensively reported in publicly available sources.

According to available safety information, vocacapsaicin hydrochloride is intended for research use only and not for human therapeutic applications outside of clinical development. As a TRPV1 agonist, it may cause local irritation or burning sensation upon activation of TRPV1 receptors. Standard laboratory safety precautions should be followed when handling this compound, including the use of appropriate personal protective equipment (gloves, lab coat, safety goggles). The compound should be handled in a well-ventilated area. Avoid dust formation and inhalation. In case of skin contact, wash with plenty of soap and water. In case of eye contact, rinse cautiously with water for several minutes. No clinical toxicity data are available.

[1]. Olivia Higgins, et al. Analgesics of the Future: The Potential of Vocacapsaicin Injections for Knee Pain. 12 Articles in Volume 21, Issue #2.

recently completed Phase II clinical trial of vocacapsaicin showed that the drug significantly reduced pain in patients undergoing total knee arthroplasty (TKA). The study was randomized, double-blind, placebo-controlled. All TKA patients received standard treatment, including spinal anesthesia, ketorolac, acetaminophen, and ropivacaine, administered via intra-articular block, femoral nerve block, and IPACK block, respectively. The trial was divided into two intervention groups, receiving 36 mg vocacapsaicin (n = 61) and 60 mg vocacapsaicin (n = 62), respectively, via surgical site infiltration. The control group (n = 64) received standard treatment and, as needed, opioid analgesia. The primary efficacy endpoint was pain reduction recorded using the Numerical Rating Scale (NRS). The NRS uses an 11-point scale, with 0 indicating no pain and 10 indicating unbearable pain. Patients verbally selected a number based on their pain level over the past 24 hours. Table I shows the pain reduction at rest (after administration of 36 mg vocacapsaicin). Table II shows the pain reduction during activity (after administration of 36 mg vocacapsaicin). At 96 and 168 hours post-administration, the opioid dosage was significantly reduced in the vocacapsaicin 36 mg group. Concentric Analgesics noted that the efficacy of the vocacapsaicin 36 mg group was consistently superior to that of the vocacapsaicin 60 mg group. Regarding side effects, all parameters were consistent between the intervention and control groups. No local or systemic safety issues were observed in the Phase II clinical trial.¹⁴ As this research paper has not yet been published, further data interpretation, including inclusion and exclusion criteria, AUC definition, specific adverse events, and their incidence, is not available. We welcome further information to fully evaluate the use of this therapy.

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Vocacapsaicin hydrochloride (CA-008 hydrochloride) is a first-in-class, non-opioid prodrug of capsaicin and a TRPV1 agonist. It is being developed as a rapidly releasing, water-soluble prodrug for site-specific treatment of postsurgical pain management. Upon local administration, it is converted to capsaicin, which activates TRPV1 receptors and induces a long-lasting refractory state of C-fibers, providing sustained analgesia without affecting sensation, proprioception, or muscle strength. The compound has been evaluated in preclinical models and is in clinical development. No regulatory approvals have been reported to date.

C26H42CLN3O4

496.08

495.28638

C, 62.95; H, 8.53; Cl, 7.15; N, 8.47; O, 12.90

1931116-92-5

Vocacapsaicin;1931116-86-7

132169136

Typically exists as solid at room temperature

3

5

13

34

610

0

CC(C)/C=C/CCCCC(=O)NCC1=CC(=C(C=C1)OC(=O)N2CCCCC2CNC)OC.Cl

WOJDHHAJADLOCK-RVDQCCQOSA-N

InChI=1S/C26H41N3O4.ClH/c1-20(2)11-7-5-6-8-13-25(30)28-18-21-14-15-23(24(17-21)32-4)33-26(31)29-16-10-9-12-22(29)19-27-3;/h7,11,14-15,17,20,22,27H,5-6,8-10,12-13,16,18-19H2,1-4H3,(H,28,30);1H/b11-7+;

(E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-((methylamino)methyl)piperidine-1-carboxylate hydrochloride

Vocacapsaicin hydrochloride; CA-008 HYDROCHLORIDE; 1931116-92-5; Vocacapsaicin (hydrochloride); Vocacapsaicin hydrochloride (USAN); Vocacapsaicin hydrochloride [USAN]; CHEMBL4594295; SCHEMBL19643643;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

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

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.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*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).

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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)]
*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.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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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).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)