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Zucapsaicin (Civamide; cis-Capsaicin) is the cis isomer of capsaicin which is an orally bioactive TRPV1 agonist and a medication used to treat osteoarthritis of the knee and other neuropathic pain. It is applied three times daily for a maximum of three months. It reduces pain, and improves articular functions. It is the cis-isomer of capsaicin. Civamide, manufactured by Winston Pharmaceuticals, is produced in formulations for orally bioavailable, nasal, and topical use (patch and cream). Zucapsaicin has been tested for treatment of a variety of conditions associated with ongoing nerve pain. This includes herpes simplex infections; cluster headaches and migraine; and knee osteoarthritis.
Physicochemical Properties
| Molecular Formula | C18H27NO3 |
| Molecular Weight | 305.4119 |
| Exact Mass | 305.199 |
| Elemental Analysis | C, 70.79; H, 8.91; N, 4.59; O, 15.72 |
| CAS # | 25775-90-0 |
| Related CAS # | Capsaicin;404-86-4 |
| PubChem CID | 1548942 |
| Appearance | Typically exists as white to off-whit solids at room temperature |
| Density | 1.0±0.1 g/cm3 |
| Boiling Point | 511.5±50.0 °C at 760 mmHg |
| Melting Point | 71.5-74.5 |
| Flash Point | 263.1±30.1 °C |
| Vapour Pressure | 0.0±1.4 mmHg at 25°C |
| Index of Refraction | 1.524 |
| LogP | 3.33 |
| Hydrogen Bond Donor Count | 2 |
| Hydrogen Bond Acceptor Count | 3 |
| Rotatable Bond Count | 9 |
| Heavy Atom Count | 22 |
| Complexity | 341 |
| Defined Atom Stereocenter Count | 0 |
| SMILES | O=C(C([H])([H])C([H])([H])C([H])([H])C([H])([H])/C(/[H])=C(/[H])\C([H])(C([H])([H])[H])C([H])([H])[H])N([H])C([H])([H])C1C([H])=C([H])C(=C(C=1[H])OC([H])([H])[H])O[H] |
| InChi Key | YKPUWZUDDOIDPM-VURMDHGXSA-N |
| InChi Code | InChI=1S/C18H27NO3/c1-14(2)8-6-4-5-7-9-18(21)19-13-15-10-11-16(20)17(12-15)22-3/h6,8,10-12,14,20H,4-5,7,9,13H2,1-3H3,(H,19,21)/b8-6- |
| Chemical Name | (Z)-N-(4-hydroxy-3-methoxybenzyl)-8-methylnon-6-enamide |
| Synonyms | Civamide; (Z)-Capsaicin; BRN 4261852; cis-Capsaicin; Zucapsaicin, trade name Civanex.Zucapsaicin; 25775-90-0; cis-Capsaicin; Civamide; Civanex; (Z)-N-(4-Hydroxy-3-methoxybenzyl)-8-methylnon-6-enamide; (Z)-8-Methyl-N-vanillyl-6-nonenamide; |
| HS Tariff Code | 2934.99.9001 |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: This product requires protection from light (avoid light exposure) during transportation and storage. |
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets | TRPV1 receptor |
| ln Vitro | As a TRPV1 agonist, (Z)-capsaicin is the cis isomer of capsaicin. Moreover, (Z)-capsaicin may inhibit calcium channels in neurons [1]. |
| ln Vivo | After oral administration, (Z)-Capsaicin (also known as Zucapsaicin) can significantly reduce nociceptive behavior in rats. In guinea pigs with primary or recurrent experimental genital herpes simplex virus infection, (Z)-capsaicin is also tolerant [1]. |
| Animal Protocol | The mechanism of action and clinical indications of zucapsaicin are similar to that of its naturally occurring isomer, capsaicin. However, in contrast to capsaicin, zucapsaicin is better tolerated. In the future, zucapsaicin could become a valuable drug for treating pain relief. Indeed, it is possible, in addition to providing NP relief, that it may have a use in treating osteoarthritic pain, headaches and pain that accompany intestinal diseases.[1] |
| ADME/Pharmacokinetics |
Absorption, Distribution and Excretion Zucapsaicin displays low systemic absorption and localizes at the area of application. In animal studies, systemic absorption is 0.075%. In rat studies, zucapsaicin and its metabolites are slowly excreted into urine and feces (up to 2/3), with minimal elimination via exhalation following dermal administration. Metabolism / Metabolites In vitro studies demonstrates weak to moderate inhibitiory effects on various cytochrome P450 enzymes, although not clinically significant due to low systemic absorption. Biological Half-Life In rats, the elimination half life of zucapsaicin and its metabolites is approximately 7 to 11 hours. |
| References |
[1]. Civamide (cis-capsaicin) for treatment of primary or recurrent experimental genital herpes. Antimicrob Agents Chemother. 1999 Nov;43(11):2685-8. |
| Additional Infomation |
Zucapsaicin is a member of phenols and a member of methoxybenzenes. Zucapsaicin, the cis-isomer of capsaicin, is a topical analgesic used to treat osteoarthritis of the knee and other neuropathic pain. It is a modulator of transient receptor potential cation channel subfamily V member 1 (TRPV-1), also known as the vanilloid or capsaicin receptor 1, that reduces pain and improves articular functions. Zucapsaicin has also been evaluated for the management of several conditions manifested by chronic nerve pain. These conditions include herpes simplex (HSV) infections, cluster headaches, migraine, and osteoarthritis of the knee. Zucapsaicin was approved by the Health Canada in 2010 as topical cream marketed under the brand name Zuacta but currently not FDA-approved. Drug Indication Indicated to be used in conjunction with oral COX-2 inhibitors or NSAIDs for the relief of severe pain in adult patients with osteoarthritis of the knee, not controlled with oral COX-2 inhibitors or NSAIDs alone, for a duration of no more than three months. Mechanism of Action Zucapsaicin excites and desensitizes C-fibers via agonist at TRPV1 on nociceptive neurons. It binds to intracellular sites and initially stimulates the channels, causing burning sensation. Activation of TRPV1 results in calcium influx and sodium, which leads to cell depolarization. Hypersensitization by zucapsaicin is then followed by reduced sensitivity and persistent desensitization (tachyphylaxis) of the channels via various pathways. Densentiziation is thought to be dependent on intraceullar levels of calcium. Decreased TRPV1 channel action and release of inflammatory neuropeptides induces an analgesic effect, and pain relief. Zucapsaicin activates calcineurin and calcium-dependent protein kinase C isoforms which results in phosphorylation of TRPV1. Phosphorylation of TRPV1 enhances reponsivity to zucapsaicin by potentiating capsaicin- or proton-evoked responses and reducing the temperature threshold for TRPV1 activation. Studies suggest that zucapsaicin is involved in activation of phospholipase C with the subsequent phosphatidylinositol 4,5-biphosphate (PIP2) hydrolysis, which results in TRPV1 inactivation. Tachyphylaxis or persistent desensitization is reversible, and involves the downregulation of proalgesic substances (such as SP) and upregulation of analgesic peptides. Pharmacodynamics Zucapsaicin mediates an antinociceptive action via acting as an agonist at TRPV1. TRPV1 play an important physiological role of transducing chemical, mechanical and thermal stimuli as well as pain transduction, and participate in pain modulation and perception. They are mainly distributed in C sensory nerve fibers as well as Aẟ fibers to transmit sensory information involving inflammatory and neuropathic pain, and activation of these channels releasesomatostatin, calcitonin gene-related peptide (CGRP) and other neuropeptides (neurokinin A, kassinin), leading to neurogenic inflammation. Zucapsaicin is also reported to affect the peptidergic afferent neurons via a desensitization mechanism to decrease the levels of dorsal root ganglia and sciatic calcitonin gene-related peptide (CGRP) and substance P (SP). |
Solubility Data
| Solubility (In Vitro) | DMSO : ≥ 125 mg/mL (~409.29 mM) |
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (6.81 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 20.8 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: ≥ 2.08 mg/mL (6.81 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 20.8 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. Solubility in Formulation 3: ≥ 2.08 mg/mL (6.81 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.2743 mL | 16.3714 mL | 32.7429 mL | |
| 5 mM | 0.6549 mL | 3.2743 mL | 6.5486 mL | |
| 10 mM | 0.3274 mL | 1.6371 mL | 3.2743 mL |