Capsazepine

Last updated
Capsazepine
Capsazepine.png
Capsazepine-3D-balls.png
Names
Preferred IUPAC name
N-[2-(4-Chlorophenyl)ethyl]-7,8-dihydroxy-1,3,4,5-tetrahydro-2H-2-benzazepine-2-carbothioamide
Other names
  • N-(4-Chlorophenethyl)-7,8-dihydroxy-1,3,4,5-tetrahydro-2H-benzo[c]azepine-2-carbothioamide
  • N-(4-Chlorophenethyl)-7,8-dihydroxy-4,5-dihydro-1H-benzo[c]azepine-2(3H)-carbothioamide
Identifiers
3D model (JSmol)
ChEMBL
ChemSpider
PubChem CID
UNII
  • InChI=1S/C19H21ClN2O2S/c20-16-5-3-13(4-6-16)7-8-21-19(25)22-9-1-2-14-10-17(23)18(24)11-15(14)12-22/h3-6,10-11,23-24H,1-2,7-9,12H2,(H,21,25) Yes check.svgY
    Key: DRCMAZOSEIMCHM-UHFFFAOYSA-N Yes check.svgY
  • InChI=1/C19H21ClN2O2S/c20-16-5-3-13(4-6-16)7-8-21-19(25)22-9-1-2-14-10-17(23)18(24)11-15(14)12-22/h3-6,10-11,23-24H,1-2,7-9,12H2,(H,21,25)
    Key: DRCMAZOSEIMCHM-UHFFFAOYAH
  • Clc1ccc(cc1)CCNC(=S)N3Cc2c(cc(O)c(O)c2)CCC3
Properties
C19H21ClN2O2S
Molar mass 376.9 g/mol
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
Yes check.svgY  verify  (what is  Yes check.svgYX mark.svgN ?)

Capsazepine is a synthetic antagonist of capsaicin. [1] It is used as a biochemical tool in the study of TRPV ion channels.

Contents

Pharmacology

Capsazepine blocks the painful sensation of heat caused by capsaicin (the active ingredient of chilli pepper) which activates the TRPV1 ion channel. Capsazepine is therefore considered to be a TRPV1 antagonist. The TRPV1 channel functions as a pain and temperature sensor in mammalians. Capsazepine blocks the activation of TRPV1 channels by other chemicals, but not by other painful stimuli such as heat. Depending on the pharmacological assay, the IC50 is in the nanomolar to low micromolar range. In addition to its effects on TRPV1 channels, it was also shown to activate the noxious chemical sensor TRPA1 channel, [2] inhibit the cold activated TRPM8 channel, [3] voltage-activated calcium channels [4] and nicotinic acetylcholine receptors. [5] It mainly serves as a tool to study the TRPV1 ion channel. [6]

Development

Capsazepine was discovered by a research group working for Novartis. [1] Its synthesis and chemical properties were published in 1994. It was found by modification of the chemical backbone of capsaicin. [7]

Use in biotechnology

By incorporation of an azobenzene unit, a photoswitchable version of capsazepine (AC4) was developed in 2013 that allows for optical control of TRPV1 channels with light. [8] [9]

See also

Related Research Articles

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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.

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 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 tastes, 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.

<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.

<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.

TRPM is a family of transient receptor potential ion channels (M standing for wikt:melastatin). Functional TRPM channels are believed to form tetramers. The TRPM family consists of eight different channels, TRPM1–TRPM8.

<span class="mw-page-title-main">TRPA (ion channel)</span> Family of transport proteins

TRPA is a family of transient receptor potential ion channels. The TRPA family is made up of 7 subfamilies: TRPA1, TRPA- or TRPA1-like, TRPA5, painless, pyrexia, waterwitch, and HsTRPA. TRPA1 is the only subfamily widely expressed across animals, while the other subfamilies are largely absent in deuterostomes.

<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 Wasabi Receptor, is a protein that in humans is encoded by the TRPA1 gene.

<span class="mw-page-title-main">TRPV4</span> Protein-coding gene in humans

Transient receptor potential cation channel subfamily V member 4 is an ion channel protein that in humans is encoded by the TRPV4 gene.

<span class="mw-page-title-main">TRPM8</span> Protein-coding gene in the species Homo sapiens

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.

<i>N</i>-Arachidonoyl dopamine Chemical compound

N-Arachidonoyl dopamine (NADA) is an endocannabinoid that acts as an agonist of the CB1 receptor and the transient receptor potential V1 (TRPV1) ion channel. NADA was first described as a putative endocannabinoid (agonist for the CB1 receptor) in 2000 and was subsequently identified as an endovanilloid (agonist for TRPV1) in 2002. NADA is an endogenous arachidonic acid based lipid found in the brain of rats, with especially high concentrations in the hippocampus, cerebellum, and striatum. It activates the TRPV1 channel with an EC50 of approximately of 50 nM which makes it the putative endogenous TRPV1 agonist.

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

Iodoresiniferatoxin (I-RTX) is a strong competitive antagonist of the Transient Receptor Potential Vanilloid 1 (TRPV1) receptor. I-RTX is derived from resiniferatoxin (RTX).

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">David Julius</span> American physiologist and Nobel laureate 2021

David Jay Julius is an American physiologist and Nobel Prize laureate known for his work on molecular mechanisms of pain sensation and heat, including the characterization of the TRPV1 and TRPM8 receptors that detect capsaicin, menthol, and temperature. He is a professor at the University of California, San Francisco.

Zucapsaicin (Civanex) is 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. Zucapsaicin is a member of phenols and a member of methoxybenzenes. 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. It is the cis-isomer of capsaicin. Civamide, manufactured by Winston Pharmaceuticals, is produced in formulations for oral, nasal, and topical use.

<span class="mw-page-title-main">Vanilloid</span> Chemical compounds containing a vanillyl group

The vanilloids are compounds which possess a vanillyl group. They include vanillyl alcohol, vanillin, vanillic acid, acetovanillon, vanillylmandelic acid, homovanillic acid, capsaicin, etc. Isomers are the isovanilloids.

The transient receptor potential Ca2+ channel (TRP-CC) family (TC# 1.A.4) is a member of the voltage-gated ion channel (VIC) superfamily and consists of cation channels conserved from worms to humans. The TRP-CC family also consists of seven subfamilies (TRPC, TRPV, TRPM, TRPN, TRPA, TRPP, and TRPML) based on their amino acid sequence homology:

  1. the canonical or classic TRPs,
  2. the vanilloid receptor TRPs,
  3. the melastatin or long TRPs,
  4. ankyrin (whose only member is the transmembrane protein 1 [TRPA1])
  5. TRPN after the nonmechanoreceptor potential C (nonpC), and the more distant cousins,
  6. the polycystins
  7. and mucolipins.

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">AMG-517</span> Chemical compound

AMG-517 is a drug which acts as a potent and selective blocker of the TRPV1 ion channel. It was developed as a potential treatment for chronic pain, but while it was an effective analgesic in animal studies it was dropped from human clinical trials at Phase I due to producing hyperthermia as a side effect, as well as poor water solubility. It is still used in scientific research into the function of the TRPV1 channel and its role in pain and inflammation, and has been used as a template for the design of several newer analogues which have improved properties.

<span class="mw-page-title-main">SB-705498</span> Chemical compound

SB-705498 is a drug which acts as a potent and selective blocker of the TRPV1 ion channel. It has been evaluated in clinical trials for the treatment of rhinitis and chronic cough.

References

  1. 1 2 Bevan S, Hothi S, Hughes G, James IF, Rang HP, Shah K, Walpole CS, Yeats JC (October 1992). "Capsazepine: a competitive antagonist of the sensory neurone excitant capsaicin". British Journal of Pharmacology. 107 (2): 544–52. doi:10.1111/j.1476-5381.1992.tb12781.x. PMC   1907893 . PMID   1422598.
  2. ↑ Kistner K, Siklosi N, Babes A, Khalil M, Selescu T, Zimmermann K, Wirtz S, Becker C, Neurath MF, Reeh PW, Engel MA (June 2016). "Systemic desensitization through TRPA1 channels by capsazepine and mustard oil - a novel strategy against inflammation and pain". Scientific Reports. 6: 28621. doi:10.1038/srep28621. PMC   4928060 . PMID   27356469.
  3. ↑ Behrendt HJ, Germann T, Gillen C, Hatt H, Jostock R (February 2004). "Characterization of the mouse cold-menthol receptor TRPM8 and vanilloid receptor type-1 VR1 using a fluorometric imaging plate reader (FLIPR) assay". British Journal of Pharmacology. 141 (4): 737–45. doi:10.1038/sj.bjp.0705652. PMC   1574235 . PMID   14757700.
  4. ↑ Docherty RJ, Yeats JC, Piper AS (August 1997). "Capsazepine block of voltage-activated calcium channels in adult rat dorsal root ganglion neurones in culture". British Journal of Pharmacology. 121 (7): 1461–7. doi:10.1038/sj.bjp.0701272. PMC   1564831 . PMID   9257928.
  5. ↑ Liu L, Simon SA (May 1997). "Capsazepine, a vanilloid receptor antagonist, inhibits nicotinic acetylcholine receptors in rat trigeminal ganglia". Neuroscience Letters. 228 (1): 29–32. doi:10.1016/S0304-3940(97)00358-3. PMID   9197280.
  6. ↑ Valenzano KJ, Sun Q (December 2004). "Current perspectives on the therapeutic utility of VR1 antagonists". Current Medicinal Chemistry. 11 (24): 3185–202. doi:10.2174/0929867043363686. PMID   15579007. Archived from the original on 2013-04-14.
  7. ↑ Walpole CS, Bevan S, Bovermann G, Boelsterli JJ, Breckenridge R, Davies JW, Hughes GA, James I, Oberer L, Winter J (June 1994). "The discovery of capsazepine, the first competitive antagonist of the sensory neuron excitants capsaicin and resiniferatoxin". Journal of Medicinal Chemistry. 37 (13): 1942–54. doi:10.1021/jm00039a006. PMID   8027976.
  8. ↑ Stein M, Breit A, Fehrentz T, Gudermann T, Trauner D (September 2013). "Optical control of TRPV1 channels". Angewandte Chemie. 52 (37): 9845–8. doi:10.1002/anie.201302530. PMID   23873837.
  9. ↑ Optical switches: Putting the fire out with light LMU Munich, 07/25/2013
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