Identification

Name
Zucapsaicin
Accession Number
DB09120
Type
Small Molecule
Groups
Approved, Investigational
Description

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 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. It was approved by the Health Canada in 2010 as topical cream marketed under the brand name Zuacta but currently not FDA-approved.

Structure
Thumb
Synonyms
  • (Z)-Capsaicin
  • cis-Capsaicin
  • Civamide
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
ZuactaCream0.075 %TopicalSanofi Aventis2011-08-24Not applicableCanada
International/Other Brands
Civanex
Categories
UNII
15OX67P384
CAS number
25775-90-0
Weight
Average: 305.4119
Monoisotopic: 305.199093735
Chemical Formula
C18H27NO3
InChI Key
YKPUWZUDDOIDPM-VURMDHGXSA-N
InChI
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-
IUPAC Name
(6Z)-N-[(4-hydroxy-3-methoxyphenyl)methyl]-8-methylnon-6-enamide
SMILES
COC1=C(O)C=CC(CNC(=O)CCCC\C=C/C(C)C)=C1

Pharmacology

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.

Associated Conditions
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 [1]. 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) [5].

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 [4]. Decreased TRPV1 channel action and release of inflammatory neuropeptides induces an analgesic effect, and pain relief [1, 2]. 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 [4]. 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 [4]. Tachyphylaxis or persistent desensitization is reversible, and involves the downregulation of proalgesic substances (such as SP) and upregulation of analgesic peptides [1].

TargetActionsOrganism
ATransient receptor potential cation channel subfamily V member 1
agonist
activator
Human
Absorption

Zucapsaicin displays low systemic absorption and localizes at the area of application. In animal studies, systemic absorption is 0.075% [5].

Volume of distribution
Not Available
Protein binding
Not Available
Metabolism

In vitro studies demonstrates weak to moderate inhibitiory effects on various cytochrome P450 enzymes, although not clinically significant due to low systemic absorption.

Route of elimination

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 [5].

Half life

In rats, the elimination half life of zucapsaicin and its metabolites is approximately 7 to 11 hours [5].

Clearance
Not Available
Toxicity

Most common adverse effects involved application site reactions such as transient burning and warm sensation. Other adverse effects observed in clinical trials are eye irritation, arthralgia, aggravated osteoarthritis, burning sensation, headache, cough and sneezing. Oral LD50 in mouse is >87.5 mg/kg in male and <60 mg/kg in females. Oral LD50 in rats is >90 mg/kg in males and >60 mg/kg in females [5].

Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
Not Available
Food Interactions
Not Available

References

Synthesis Reference
  1. Gannett PM, Nagel DL, Reilly PJ, Lawson T, Sharpe J, Toth B: The Capsaicinoids: Their Separation, Synthesis, and Mutagenicity. J. Org. Chem., 1988, 53 (5), pp 1064–1071.
  2. Kaga H, Miura M, Orito K: A facile procedure for synthesis of capsaicin. J. Org. Chem., 1989, 54 (14), pp 3477–3478.
General References
  1. Salat K, Jakubowska A, Kulig K: Zucapsaicin for the treatment of neuropathic pain. Expert Opin Investig Drugs. 2014 Oct;23(10):1433-40. doi: 10.1517/13543784.2014.956079. Epub 2014 Aug 29. [PubMed:25171227]
  2. Derry S, Lloyd R, Moore RA, McQuay HJ: Topical capsaicin for chronic neuropathic pain in adults. Cochrane Database Syst Rev. 2009 Oct 7;(4):CD007393. doi: 10.1002/14651858.CD007393.pub2. [PubMed:19821411]
  3. Studer M, McNaughton PA: Modulation of single-channel properties of TRPV1 by phosphorylation. J Physiol. 2010 Oct 1;588(Pt 19):3743-56. doi: 10.1113/jphysiol.2010.190611. Epub 2010 Aug 6. [PubMed:20693293]
  4. Rosenbaum T, Simon SA: TRPV1 Receptors and Signal Transduction . [PubMed:21204507]
  5. Sanofi Canada: ZUACTA (zucapsaicin cream) product monograph [Link]
External Links
PubChem Compound
1548942
PubChem Substance
310265037
ChemSpider
1265956
ChEBI
135952
ChEMBL
CHEMBL313971
Wikipedia
Zucapsaicin
ATC Codes
M02AB02 — Zucapsaicin
AHFS Codes
  • 28:08.04.92 — Other Nonsteroidal Antiimflammatory Agents

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1CompletedBasic ScienceHealthy Volunteers1
1RecruitingTreatmentKnee Osteoarthritis (Knee OA)1
1TerminatedBasic ScienceHealthy Volunteers1
2CompletedTreatmentPostherpetic Neuralgia1
3CompletedTreatmentEpisodic Cluster Headache2
3CompletedTreatmentKnee Osteoarthritis (Knee OA)2
3Not Yet RecruitingPreventionEpisodic Cluster Headache1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
CreamTopical0.075 %
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)71.5-74.5Product monograph
water solubilityInsolubleProduct monograph
Predicted Properties
PropertyValueSource
Water Solubility0.00841 mg/mLALOGPS
logP3.8ALOGPS
logP3.75ChemAxon
logS-4.6ALOGPS
pKa (Strongest Acidic)9.93ChemAxon
pKa (Strongest Basic)-0.52ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area58.56 Å2ChemAxon
Rotatable Bond Count9ChemAxon
Refractivity90.32 m3·mol-1ChemAxon
Polarizability35.34 Å3ChemAxon
Number of Rings1ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available
MS/MS Spectrum - , positiveLC-MS/MSsplash10-000i-1900000000-b2bcbe6ef314218a9fca

Taxonomy

Description
This compound belongs to the class of organic compounds known as methoxyphenols. These are compounds containing a methoxy group attached to the benzene ring of a phenol moiety.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Phenols
Sub Class
Methoxyphenols
Direct Parent
Methoxyphenols
Alternative Parents
Phenoxy compounds / Methoxybenzenes / Anisoles / Alkyl aryl ethers / 1-hydroxy-2-unsubstituted benzenoids / N-acyl amines / Secondary carboxylic acid amides / Organopnictogen compounds / Organonitrogen compounds / Organic oxides
show 2 more
Substituents
Methoxyphenol / Phenoxy compound / Anisole / Methoxybenzene / Phenol ether / Alkyl aryl ether / 1-hydroxy-2-unsubstituted benzenoid / Monocyclic benzene moiety / Fatty acyl / Fatty amide
show 14 more
Molecular Framework
Aromatic homomonocyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Yes
Actions
Agonist
Activator
General Function
Transmembrane signaling receptor activity
Specific Function
Ligand-activated non-selective calcium permeant cation channel involved in detection of noxious chemical and thermal stimuli. Seems to mediate proton influx and may be involved in intracellular aci...
Gene Name
TRPV1
Uniprot ID
Q8NER1
Uniprot Name
Transient receptor potential cation channel subfamily V member 1
Molecular Weight
94955.33 Da
References
  1. Yang F, Xiao X, Cheng W, Yang W, Yu P, Song Z, Yarov-Yarovoy V, Zheng J: Structural mechanism underlying capsaicin binding and activation of the TRPV1 ion channel. Nat Chem Biol. 2015 Jul;11(7):518-24. doi: 10.1038/nchembio.1835. Epub 2015 Jun 8. [PubMed:26053297]
  2. Smutzer G, Devassy RK: Integrating TRPV1 Receptor Function with Capsaicin Psychophysics. Adv Pharmacol Sci. 2016;2016:1512457. doi: 10.1155/2016/1512457. Epub 2016 Jan 14. [PubMed:26884754]

Enzymes

Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced flavin or flavoprotein as one donor, and incorporation of one atom of oxygen
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP1A2
Uniprot ID
P05177
Uniprot Name
Cytochrome P450 1A2
Molecular Weight
58293.76 Da
References
  1. Sanofi Canada: ZUACTA (zucapsaicin cream) product monograph [Link]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Steroid hydroxylase activity
Specific Function
Responsible for the metabolism of a number of therapeutic agents such as the anticonvulsant drug S-mephenytoin, omeprazole, proguanil, certain barbiturates, diazepam, propranolol, citalopram and im...
Gene Name
CYP2C19
Uniprot ID
P33261
Uniprot Name
Cytochrome P450 2C19
Molecular Weight
55930.545 Da
References
  1. Zuacta Monograph [File]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
Curator comments
Enzyme action is based on in vitro data. There is limited information in the literature supporting this enzyme action, however, the monograph indicates this enzyme action.
General Function
Steroid hydroxylase activity
Specific Function
Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It oxidizes a variety of structurally un...
Gene Name
CYP2C9
Uniprot ID
P11712
Uniprot Name
Cytochrome P450 2C9
Molecular Weight
55627.365 Da
References
  1. Zuacta Monograph [File]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
Actions
Inhibitor
General Function
Steroid hydroxylase activity
Specific Function
Metabolizes several precarcinogens, drugs, and solvents to reactive metabolites. Inactivates a number of drugs and xenobiotics and also bioactivates many xenobiotic substrates to their hepatotoxic ...
Gene Name
CYP2E1
Uniprot ID
P05181
Uniprot Name
Cytochrome P450 2E1
Molecular Weight
56848.42 Da
References
  1. Sanofi Canada: ZUACTA (zucapsaicin cream) product monograph [Link]
  2. Sanofi Canada: ZUACTA (zucapsaicin cream, 0.075% w/w) Prescribing Information [File]

Drug created on September 22, 2015 15:09 / Updated on November 16, 2018 11:27