Icilin

Last updated
Icilin
Icilin.svg
Names
Preferred IUPAC name
3-(2-Hydroxyphenyl)-6-(3-nitrophenyl)-3,4-dihydropyrimidin-2(1H)-one
Other names
1-(2-Hydroxyphenyl)-4-(3-nitrophenyl)-3,6-dihydropyrimidin-2-one
AG-3-5
Identifiers
3D model (JSmol)
ChemSpider
ECHA InfoCard 100.164.593 OOjs UI icon edit-ltr-progressive.svg
PubChem CID
UNII
  • InChI=1S/C16H13N3O4/c20-15-7-2-1-6-14(15)18-9-8-13(17-16(18)21)11-4-3-5-12(10-11)19(22)23/h1-8,10,20H,9H2,(H,17,21) X mark.svgN
    Key: RCEFMOGVOYEGJN-UHFFFAOYSA-N X mark.svgN
  • InChI=1/C16H13N3O4/c20-15-7-2-1-6-14(15)18-9-8-13(17-16(18)21)11-4-3-5-12(10-11)19(22)23/h1-8,10,20H,9H2,(H,17,21)
    Key: RCEFMOGVOYEGJN-UHFFFAOYAQ
  • O=C3N(c1c(O)cccc1)C/C=C(/c2cccc([N+]([O-])=O)c2)N3
Properties
C16H13N3O4
Molar mass 311.29 g/mol
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
X mark.svgN  verify  (what is  Yes check.svgYX mark.svgN ?)

Icilin (AG-3-5) is a synthetic super-agonist of the transient receptor potential M8 (TRPM8) ion channel. Although structurally not related to menthol, it produces an extreme sensation of cold, both in humans and animals. It is almost 200 times more potent than menthol, and 2.5 times more efficacious. [1] Despite their similar effects, icilin activates the TRPM8 receptor in a different way than menthol does. [2] Icilin has been shown to be effective in the treatment of pruritus in an experimental model of itch. [3] It is now used as a research tool for the study of TRP channels, although despite its high potency it is less selective for TRPM8 over other related ion channels than are other compounds such as WS-12.

Related Research Articles

<span class="mw-page-title-main">Menthol</span> Organic compound used as flavouring and analgesic

Menthol is an organic compound, more specifically a monoterpenoid, made synthetically or obtained from the oils of corn mint, peppermint, or other mints. It is a waxy, clear or white crystalline substance, which is solid at room temperature and melts slightly above.

<span class="mw-page-title-main">Itch</span> Sensation that causes desire or reflex to scratch

Itch is a sensation that causes a strong desire or reflex to scratch. Itches have resisted many attempts to be classified as any one type of sensory experience. Itches have many similarities to pain, and while both are unpleasant sensory experiences, their behavioral response patterns are different. Pain creates a withdrawal reflex, whereas itches leads to a scratch reflex.

<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.

Antipruritics, abirritants, or anti-itch drugs, are medications that inhibit the itching often associated with sunburns, allergic reactions, eczema, psoriasis, chickenpox, fungal infections, insect bites and stings like those from mosquitoes, fleas, and mites, and contact dermatitis and urticaria caused by plants such as poison ivy or stinging nettle. It can also be caused by chronic kidney disease and related conditions.

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.

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">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">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">TRPM2</span> Protein-coding gene in the species Homo sapiens

Transient receptor potential cation channel, subfamily M, member 2, also known as TRPM2, is a protein that in humans is encoded by the TRPM2 gene.

<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.

<span class="mw-page-title-main">TRPV3</span> Protein-coding gene in the species Homo sapiens

Transient receptor potential cation channel, subfamily V, member 3, also known as TRPV3, is a human gene encoding the protein of the same name.

<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.

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

Umbellulone is a headache-inducing monoterpene ketone found in the leaves of the tree Umbellularia californica, sometimes known as the "headache tree".

Diana M. Bautista is an American neuroscientist known for her work on the molecular mechanisms underlying itch, touch and pain. She is a full professor of cell and developmental biology in the Department of Molecular and Cell Biology and is affiliated with the Helen Wills Neuroscience Institute at the University of California, Berkeley.

<span class="mw-page-title-main">WS-12</span> Chemical compound

WS-12 is a chemical compound that acts as a potent and selective activator of the TRPM8 calcium channel, which is responsible for the sensation of coldness produced by menthol. It is slightly less potent as a TRPM8 activator compared to icilin, but is much more selective for TRPM8 over related calcium channels. It produces analgesic and antiinflammatory effects in animal models with similar efficacy to menthol and a reduced side effect profile.

<span class="mw-page-title-main">PF-05105679</span> Chemical compound

PF-05105679 is a drug which acts as a potent and selective blocker of the TRPM8 ion channel, which is the main receptor responsible for the sensation of cold. It was developed as a potential analgesic, and blocks the sensation of cold in both animals and human trials. It also lowers core body temperature in small mammals, but does not produce this effect in humans in the normal dosage range.

<span class="mw-page-title-main">RQ-00203078</span> Chemical compound

RQ-00203078 is a drug which acts as a potent and selective blocker of the TRPM8 ion channel, which is the main receptor responsible for the sensation of cold. It was developed as a potential analgesic, and blocks the development of hyperalgesia following exposure to cold temperatures or chronic morphine administration.

<span class="mw-page-title-main">AMG-333</span> Drug which acts as a potent and selective blocker of the TRPM8 ion channel

AMG-333 is a drug which acts as a potent and selective blocker of the TRPM8 ion channel, which is the main receptor responsible for the sensation of cold. It was developed as a potential treatment for migraine.

References

  1. Wei ET, Seid DA (1983). "AG-3-5: a chemical producing sensations of cold". J. Pharm. Pharmacol. 35 (2): 110–2. doi:10.1111/j.2042-7158.1983.tb04279.x. PMID   6131976. S2CID   42844929.
  2. Andersson DA, Chase HW, Bevan S (2004). "TRPM8 activation by menthol, icilin, and cold is differentially modulated by intracellular pH". J. Neurosci. 24 (23): 5364–9. doi: 10.1523/JNEUROSCI.0890-04.2004 . PMC   6729305 . PMID   15190109.
  3. Biró, T; Ko, MC; Bromm, B; et al. (2005). "How best to fight that nasty itch - from new insights into the neuroimmunological, neuroendocrine, and neurophysiological bases of pruritus to novel therapeutic approaches". Experimental Dermatology. 14 (3): 225–40. doi: 10.1111/j.0906-6705.2005.0321a.x . PMID   15740597. S2CID   23665244.