Zucapsaicin

Last updated

Zucapsaicin
Zucapsaicin.svg
Clinical data
Trade names Civanex
Other namesCivamide; (Z)-Capsaicin; cis-Capsaicin
Routes of
administration 		Topical
ATC code
Legal status
Legal status
Identifiers
  • (Z)-N-[(4-Hydroxy-3-methoxyphenyl)methyl]-8-methylnon-6-enamide
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.164.527 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C18H27NO3
Molar mass 305.418 g·mol−1
3D model (JSmol)
  • Oc1ccc(cc1OC)CNC(CCCC\C=C/C(C)C)=O
  • 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-
  • Key:YKPUWZUDDOIDPM-VURMDHGXSA-N

Zucapsaicin (Civanex) is a medication used to treat osteoarthritis of the knee and other neuropathic pain. Zucapsaicin is a member of phenols and a member of methoxybenzenes. [2] 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. [3] [ unreliable medical source? ] [4] It is the cis-isomer of capsaicin. Civamide, manufactured by Winston Pharmaceuticals, is produced in formulations for oral, nasal, and topical use (patch and cream). [5] [6]

Contents

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. [7] [ dead link ] It was approved by the Health Canada in 2010 as topical cream sold under the brand name Zuacta. [3] It has a melting point of 71.5–74.5 °C. [3]

Pharmacology

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 releases somatostatin, calcitonin gene-related peptide (CGRP) and other neuropeptides (neurokinin A, kassinin), leading to neurogenic inflammation [A19720]. 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) [L877]. [3]

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 releases somatostatin, calcitonin gene-related peptide (CGRP) and other neuropeptides (neurokinin A, kassinin), leading to neurogenic inflammation. [6] 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). [3]

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. [4] The mechanism of pharmacological action of zucapsaicin has not been fully understood yet. It is suggested that this compound, similarly to its trans isomer, is an agonist of the vanilloid receptor VR1 (TRPV1) and a neuronal calcium channel blocker. [8] [9] Capsaicin is able to excite and desensitize C-fibers. As such, it is not only able to cause pain, but also exhibit analgesic properties. Initially, it stimulates TRPV1, which is responsible for a burning sensation. This effect is followed by a longlasting refractory state – ‘desensitization’ – during which the previously excited sensory neurons become unresponsive to capsaicin and other stimuli. It was shown that desensitization and tachyphylaxis of TRPV1 channels contribute to capsaicin-induced pain relief. [10] Desensitization of TRPV1 represents the main mechanism of its inhibitory function.

Three distinct pathways of capsaicin-induced desensitization have been described: i) activation of calcineurin, which results in dephosphorylation of TRPV1; ii) activation of phospholipase C with the subsequent phosphatidylinositol 4,5-biphosphate hydrolysis (rather controversial) and iii) activation of calcium-dependent protein kinase C isoforms and subsequent channel phosphorylation. [11] [12] Desensitization involves both tachyphylaxis (short-term desensitization) and long-term, persistent, desensitization. [13] [14] [15] It is suggested that the downregulation of proalgesic substances (such as SP) and upregulation of analgesic peptides are implicated in desensitization. [16] The exhaustion of SP reserves renders neurons desensitized and refractory. These mechanisms of desensitization are not fully understood. It is thought that the short-term desensitization is related to capsaicin's ability to block the intra-axonal transport of NGF, SP and somatostatin. [17]

The desensitization is a reversible phenomenon. It begins a few hours after capsaicin application and may last even several weeks. [16] The reversible desensitization was found useful in the treatment of pain, whereas the site-specific ablation of sensory nerves transmitting pain stimuli is a promising approach (‘molecular scalpel’) to achieve a permanent pain relief in patients suffering from bone cancer pain or HIV-induced neuropathies. [13] [14] Desensitization and depletion of pronociceptive neurotransmitters induce chemical denervation with a loss of function, which is clinically used in osteoarthritis, diabetic neuropathy, psoriasis and others. [18] [19] [20] In dorsal root ganglia and the sciatic nerve, zucapsaicin decreases levels of SP and CGRP, indicating that it influences peptidergic afferent neurons via a desensitization mechanism [21] [41]. When administered topically, the intended targets for zucapsaicin are the neurons that innervate the local area of application. These neurons transmit pain toward the CNS.

Pharmacokinetics

Absorption

Zucapsaicin displays low systemic absorption and localizes at the area of application. In animal studies, systemic absorption is 0.075%. [22] [ unreliable medical source? ] [23] [24]

Metabolism

In vitro studies demonstrates weak to moderate inhibitory effects on various cytochrome P450 enzymes, although not clinically significant due to low systemic absorption. [23]

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. [22] [23]

Half life

In rats, the elimination half life of zucapsaicin and its metabolites is approximately 7 to 11 hours. [22] [23]

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. [22]

Chemical and Physical Properties

Computed properties

Property NameProperty Value [25]
Molecular Weight305.418 g/mol
XLogP3-AA3.6
Hydrogen Bond Donor Count2
Hydrogen Bond Acceptor Count3
Rotatable Bond Count9
Exact Mass305.199 g/mol
Monoisotopic Mass305.199 g/mol
Topological Polar Surface Area58.6 A^2
Heavy Atom Count22
Formal Charge0
Complexity341
Isotope Atom Count0
Defined Atom Stereocenter Count0
Undefined Atom Stereocenter Count0
Defined Bond Stereocenter Count1
Undefined Bond Stereocenter Count0
Covalently-Bonded Unit Count1
Compound Is CanonicalizedYes

Related Research Articles

<span class="mw-page-title-main">Thermoreceptor</span> Receptive portion of a sensory neuron

A thermoreceptor is a non-specialised sense receptor, or more accurately the receptive portion of a sensory neuron, that codes absolute and relative changes in temperature, primarily within the innocuous range. In the mammalian peripheral nervous system, warmth receptors are thought to be unmyelinated C-fibres, while those responding to cold have both C-fibers and thinly myelinated A delta fibers. The adequate stimulus for a warm receptor is warming, which results in an increase in their action potential discharge rate. Cooling results in a decrease in warm receptor discharge rate. For cold receptors their firing rate increases during cooling and decreases during warming. Some cold receptors also respond with a brief action potential discharge to high temperatures, i.e. typically above 45 °C, and this is known as a paradoxical response to heat. The mechanism responsible for this behavior has not been determined.

<span class="mw-page-title-main">Nociceptor</span> Sensory neuron that detects pain

A nociceptor is a sensory neuron that responds to damaging or potentially damaging stimuli by sending "possible threat" signals to the spinal cord and the brain. The brain creates the sensation of pain to direct attention to the body part, so the threat can be mitigated; this process is called nociception.

Transient receptor potential channels are a group of ion channels located mostly on the plasma membrane of numerous animal cell types. Most of these are grouped into two broad groups: Group 1 includes TRPC, TRPV, TRPVL, TRPM, TRPS, TRPN, and TRPA. Group 2 consists of TRPP and TRPML. Other less-well categorized TRP channels exist, including yeast channels and a number of Group 1 and Group 2 channels present in non-animals. Many of these channels mediate a variety of sensations such as pain, temperature, different kinds of taste, pressure, and vision. In the body, some TRP channels are thought to behave like microscopic thermometers and used in animals to sense hot or cold. Some TRP channels are activated by molecules found in spices like garlic (allicin), chili pepper (capsaicin), wasabi ; others are activated by menthol, camphor, peppermint, and cooling agents; yet others are activated by molecules found in cannabis or stevia. Some act as sensors of osmotic pressure, volume, stretch, and vibration. Most of the channels are activated or inhibited by signaling lipids and contribute to a family of lipid-gated ion channels.

Neuropathic pain is pain caused by a lesion or disease of the somatosensory nervous system. Neuropathic pain may be associated with abnormal sensations called dysesthesia or pain from normally non-painful stimuli (allodynia). It may have continuous and/or episodic (paroxysmal) components. The latter resemble stabbings or electric shocks. Common qualities include burning or coldness, "pins and needles" sensations, numbness and itching.

Neurogenic inflammation is inflammation arising from the local release by afferent neurons of inflammatory mediators such as Substance P, Calcitonin Gene-Related Peptide (CGRP), neurokinin A (NKA), and endothelin-3 (ET-3). In such neurons, release of these pro-inflammatory mediators is thought to be triggered by the activation of ion channels that are the principal detectors of noxious environmental stimuli. In particular, the heat/capsaicin receptor TRPV1 and the irritant/wasabi receptor TRPA1. TRPA1 channels stimulated by lipopolysaccharide (LPS) may also cause acute neurogenic inflammation. Once released, these neuropeptides induce the release of histamine from adjacent mast cells. In turn, histamine evokes the release of substance P and calcitonin gene-related peptide; thus, a bidirectional link between histamine and neuropeptides in neurogenic inflammation is established.

<span class="mw-page-title-main">Resiniferatoxin</span> Chemical compound

Resiniferatoxin (RTX) is a naturally occurring chemical found in resin spurge, a cactus-like plant commonly found in Morocco, and in Euphorbia poissonii found in northern Nigeria. It is a potent functional analog of capsaicin, the active ingredient in chili peppers.

<i>Euphorbia resinifera</i> Species of plant

Euphorbia resinifera, the resin spurge, is a species of spurge native to Morocco, where it occurs on the slopes of the Atlas Mountains. The dried latex of the plant was used in ancient medicine. It contains resiniferatoxin, an extremely potent capsaicin analog tested as an analgesic since 1997.

<span class="mw-page-title-main">Calcitonin gene-related peptide</span> Peptide hormone in animals

Calcitonin gene-related peptide (CGRP) is a member of the calcitonin family of peptides consisting of calcitonin, amylin, adrenomedullin, adrenomedullin 2 (intermedin) and calcitonin‑receptor‑stimulating peptide. Calcitonin is mainly produced by thyroid C cells whilst CGRP is secreted and stored in the nervous system. This peptide, in humans, exists in two forms: CGRP alpha, and CGRP beta. α-CGRP is a 37-amino acid neuropeptide and is formed by alternative splicing of the calcitonin/CGRP gene located on chromosome 11. β-CGRP is less studied. In humans, β-CGRP differs from α-CGRP by three amino acids and is encoded in a separate, nearby gene. The CGRP family includes calcitonin (CT), adrenomedullin (AM), and amylin (AMY).

<span class="mw-page-title-main">TRPV1</span> Human protein for regulating body temperature

The transient receptor potential cation channel subfamily V member 1 (TRPV1), also known as the capsaicin receptor and the vanilloid receptor 1, is a protein that, in humans, is encoded by the TRPV1 gene. It was the first isolated member of the transient receptor potential vanilloid receptor proteins that in turn are a sub-family of the transient receptor potential protein group. This protein is a member of the TRPV group of transient receptor potential family of ion channels. Fatty acid metabolites with affinity for this receptor are produced by cyanobacteria, which diverged from eukaryotes at least 2000 million years ago (MYA). The function of TRPV1 is detection and regulation of body temperature. In addition, TRPV1 provides a sensation of scalding heat and pain (nociception). In primary afferent sensory neurons, it cooperates with TRPA1 to mediate the detection of noxious environmental stimuli.

<span class="mw-page-title-main">TRPV</span> Subgroup of TRP cation channels named after the vanilloid receptor

TRPV is a family of transient receptor potential cation channels in animals. All TRPVs are highly calcium selective.

<span class="mw-page-title-main">Capsazepine</span> Chemical compound

Capsazepine is a synthetic antagonist of capsaicin. It is used as a biochemical tool in the study of TRPV ion channels.

<span class="mw-page-title-main">Group C nerve fiber</span> One of three classes of nerve fiber in the nervous system

Group C nerve fibers are one of three classes of nerve fiber in the central nervous system (CNS) and peripheral nervous system (PNS). The C group fibers are unmyelinated and have a small diameter and low conduction velocity, whereas Groups A and B are myelinated. Group C fibers include postganglionic fibers in the autonomic nervous system (ANS), and nerve fibers at the dorsal roots. These fibers carry sensory information.

<span class="mw-page-title-main">TRPA1</span> Protein and coding gene in humans

Transient receptor potential cation channel, subfamily A, member 1, also known as transient receptor potential ankyrin 1, TRPA1, or The Mustard and Wasabi Receptor, is a protein that in humans is encoded by the TRPA1 gene.

<span class="mw-page-title-main">TRPM8</span> Protein-coding gene in humans

Transient receptor potential cation channel subfamily M (melastatin) member 8 (TRPM8), also known as the cold and menthol receptor 1 (CMR1), is a protein that in humans is encoded by the TRPM8 gene. The TRPM8 channel is the primary molecular transducer of cold somatosensation in humans. In addition, mints can desensitize a region through the activation of TRPM8 receptors.

<span class="mw-page-title-main">Hydroxy-α-sanshool</span> Chemical compound

Hydroxy-α-sanshool is a molecule found in plants from the genus Zanthoxylum. It is believed to be responsible for the numbing and tingling sensation caused by eating food cooked with Sichuan peppercorns and Uzazi.

Relief from chronic pain remains a recognized unmet medical need. Consequently, the search for new analgesic agents is being intensively studied by the pharmaceutical industry. The TRPV1 receptor is a ligand gated ion channel that has been implicated in mediation of many types of pain and therefore studied most extensively. The first competitive antagonist, capsazepine, was first described in 1990; since then, several TRPV1 antagonists have entered clinical trials as analgesic agents. Should these new chemical entities relieve symptoms of chronic pain, then this class of compounds may offer one of the first novel mechanisms for the treatment of pain in many years.

<span class="mw-page-title-main">Rostral ventromedial medulla</span> Group of neurons in medulla of brain

The rostral ventromedial medulla (RVM), or ventromedial nucleus of the spinal cord, is a group of neurons located close to the midline on the floor of the medulla oblongata. The rostral ventromedial medulla sends descending inhibitory and excitatory fibers to the dorsal horn spinal cord neurons. There are 3 categories of neurons in the RVM: on-cells, off-cells, and neutral cells. They are characterized by their response to nociceptive input. Off-cells show a transitory decrease in firing rate right before a nociceptive reflex, and are theorized to be inhibitory. Activation of off-cells, either by morphine or by any other means, results in antinociception. On-cells show a burst of activity immediately preceding nociceptive input, and are theorized to be contributing to the excitatory drive. Neutral cells show no response to nociceptive input.

Calcitonin gene-related peptide (CGRP) receptor antagonists are a class of drugs that act as antagonists of the calcitonin gene-related peptide receptor (CGRPR).

RhTx is a small peptide toxin from Scolopendra subspinipes mutilans, also called the Chinese red-headed centipede. RhTx binds to the outer pore region of the temperature regulated TRPV1 ion channel, preferably in activated state, causing a downwards shift in the activation threshold temperature, which leads to the immediate onset of heat pain.

<span class="mw-page-title-main">Double-knot toxin</span>

Double-knot toxin (DkTx), also known as Tau-theraphotoxin-Hs1a or Tau-TRTX-Hs1a, is a toxin found in the venom of the Chinese Bird spider, a tarantula species primarily living in the Guangxi province of China. This toxin, characterized by its bivalent structure of two Inhibitor Cysteine Knots (ICK), is thought to induce excruciating and long-lasting pain by activating the transient receptor potential vanilloid 1 (TRPV1) channel.

References

  1. ↑ "Zuacta PI". Health Canada . 17 July 2020. Retrieved 15 October 2024.
  2. ↑ "zucapsaicin (CHEBI:135952)". Chemical Entities of Biological Interest (ChEBI). EMBL-EBI. Retrieved 25 June 2019.
  3. 1 2 3 4 5 "Zucapsaicin". DrugBank. Retrieved 25 June 2019.
  4. 1 2 Studer M, McNaughton PA (October 2010). "Modulation of single-channel properties of TRPV1 by phosphorylation". The Journal of Physiology. 588 (Pt 19): 3743–56. doi:10.1113/jphysiol.2010.190611. PMC   2998224 . PMID   20693293.
  5. ↑ "Civamide". Winston Pharmaceuticals. Archived from the original on 25 April 2012. Retrieved 16 November 2011.
  6. 1 2 Sałat K, Jakubowska A, Kulig K (October 2014). "Zucapsaicin for the treatment of neuropathic pain". Expert Opinion on Investigational Drugs. 23 (10): 1433–40. doi:10.1517/13543784.2014.956079. PMID   25171227. S2CID   2969900.
  7. ↑ Zucapsaicin information from the National Library of Medicine http://druginfo.nlm.nih.gov/drugportal
  8. ↑ Bevan SJ, Docherty RJ (1993). "Cellular mechanisms of the action of capsaicin.". In Wood J (ed.). Capsaicin in the study of pain. London, England: Academic Press. pp. 27–44.
  9. ↑ Anand P, Bley K (October 2011). "Topical capsaicin for pain management: therapeutic potential and mechanisms of action of the new high-concentration capsaicin 8% patch". British Journal of Anaesthesia. 107 (4): 490–502. doi:10.1093/bja/aer260. PMC   3169333 . PMID   21852280.
  10. ↑ St Pierre M, Reeh PW, Zimmermann K (June 2009). "Differential effects of TRPV channel block on polymodal activation of rat cutaneous nociceptors in vitro". Experimental Brain Research. 196 (1): 31–44. doi:10.1007/s00221-009-1808-3. PMID   19404626. S2CID   25823889.
  11. ↑ Stucky CL, Dubin AE, Jeske NA, et al. Roles of transient receptor potential channels in pain. Brain Res Rev 2009;60(1):2-23
  12. ↑ Nilius B, Owsianik G (2013). "Transient Receptor Potential Family of Ion Channels". Encyclopedia of Pain. Vol. 12. Springer Berlin Heidelberg. p. 4037. doi:10.1007/978-3-642-28753-4_202324. ISBN   978-3-642-28752-7. PMC   3129667 . PMID   21401968.{{cite encyclopedia}}: |journal= ignored (help)
  13. 1 2 Szallasi A, Sheta M (September 2012). "Targeting TRPV1 for pain relief: limits, losers and laurels". Expert Opinion on Investigational Drugs. 21 (9): 1351–69. doi:10.1517/13543784.2012.704021. PMID   22780443. S2CID   32934502.
  14. 1 2 Trevisani M (26 July 2010). "Targeting TRPV1: Challenges and Issues in Pain Management" (PDF). The Open Drug Discovery Journal. 2 (3): 37–49. doi: 10.2174/1877381801002030037 (inactive 1 November 2024). ISSN   1877-3818.{{cite journal}}: CS1 maint: DOI inactive as of November 2024 (link)
  15. ↑ Khairatkar-Joshi N, Szallasi A (January 2009). "TRPV1 antagonists: the challenges for therapeutic targeting". Trends in Molecular Medicine. 15 (1): 14–22. doi:10.1016/j.molmed.2008.11.004. PMID   19097938.
  16. 1 2 Brederson JD, Kym PR, Szallasi A. Targeting TRP channels for pain relief. Eur J Pharmacol 2013;716:61-76
  17. ↑ Papoiu AD, Yosipovitch G (June 2010). "Topical capsaicin. The fire of a 'hot' medicine is reignited". Expert Opinion on Pharmacotherapy. 11 (8): 1359–71. doi: 10.1517/14656566.2010.481670 . PMID   20446852.
  18. ↑ Palazzo E, Luongo L, de Novellis V, Berrino L, Rossi F, Maione S (October 2010). "Moving towards supraspinal TRPV1 receptors for chronic pain relief". Molecular Pain. 6: 1744-8069–6-66. doi: 10.1186/1744-8069-6-66 . PMC   2959024 . PMID   20937102.
  19. ↑ Lambert DG (February 2009). "Capsaicin receptor antagonists: a promising new addition to the pain clinic". British Journal of Anaesthesia. 102 (2): 153–5. doi: 10.1093/bja/aen354 . PMID   19151045.
  20. ↑ Lambert GA, Davis JB, Appleby JM, Chizh BA, Hoskin KL, Zagami AS (October 2009). "The effects of the TRPV1 receptor antagonist SB-705498 on trigeminovascular sensitisation and neurotransmission". Naunyn-Schmiedeberg's Archives of Pharmacology. 380 (4): 311–25. doi:10.1007/s00210-009-0437-5. PMID   19690836. S2CID   11113986.
  21. ↑ Holzer P (March 1988). "Local effector functions of capsaicin-sensitive sensory nerve endings: involvement of tachykinins, calcitonin gene-related peptide and other neuropeptides". Neuroscience. 24 (3): 739–68. doi:10.1016/0306-4522(88)90064-4. PMID   3288903. S2CID   35325223.
  22. 1 2 3 4 "Zuacta (zucapsaicin cream) product monograph" (PDF). Sanofi Canada.
  23. 1 2 3 4 WO 2011100668,Bernstein JE,"Method and compositions of civamide to treat disease of the intestines.",published 2011
  24. ↑ Schnitzer TJ, Pelletier JP, Haselwood DM, Ellison WT, Ervin JE, Gordon RD, et al. (March 2012). "Civamide cream 0.075% in patients with osteoarthritis of the knee: a 12-week randomized controlled clinical trial with a longterm extension". The Journal of Rheumatology. 39 (3): 610–20. doi: 10.3899/jrheum.110192 . PMID   22089461.
  25. ↑ "Zucapsaicin. Computed Properties". PubChem. U.S. National Library of Medicine. Retrieved 23 August 2019.
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