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Umbellulone
Umbellulone
is a headache-inducing monoterpene ketone found in the leaves of the tree Umbellularia californica, sometimes known as the "headache tree".[1][2] It is hypothesized to cause headaches by influencing the trigeminovascular system via TRPA1.[1]

Space-filling model of umbellulone.

Contents

1 History 2 Structure and reactivity 3 Synthesis 4 Mechanism of action 5 Indications 6 Toxicity 7 Other applications 8 References

History[edit] Umbellularia californica
Umbellularia californica
is a tree native to the coastal forest of California. Menzies was the first to collect the oil at the end of the 18th century. In 1826 this tree was classified as a laurel, Laurus regia, by Douglass. He probably intended to indicate the beauty and splendor of the tree.[original research?] In 1833 the tree got another classification by Hooker and Arnott, Tetranthera californica. Shortly after that the present name was given by Nuttal, Umbellularia californica. In 1875 Heaney obtained a colorless liquid (Oreodaphenol) via fractionation under reduced pressure. This oil of the California laurel possess a pungent odor. Stillman (1880) did a fractionation at 215-216 °C. He discovered that inhalation of its fumes can lead to a painful cold sensation and severe headaches. In earlier times the leaves of the tree were used for cures for headaches or stomachaches and even toothaches. Powers and Lee did in 1904 another fractionation on the oil of the tree at 217-222 °C. This yielded different compounds: pinene, cineol, eugenol, methyl eugenol and a ketone called umbellulone. Umbellulone
Umbellulone
is the chemical responsible for the headaches induced by the tree. They gave umbellulone the following structural formula (Fig. 1).

Figure 1: Strucutural formula according to Powers and Lee, 1904.

Figure 2: (A) Strucutural formula according to Tutin, 1908. (B) Structural formula according to Semmller, 1908.

In 1908 the structural formula was adapted by Tutin (Fig. 2A). This was corrected later that year by Semmller; he gave the structural formula which is accepted today (Fig. 2B). Structure and reactivity[edit] Umbellulone
Umbellulone
is a monoterpene ketone that is found in the leaves of Umbellularia californica. The formula of umbellulone is C10H14O, containing a cyclopropane and cyclopentane ring. There is only one isomer of umbellulone known. Umbellulone
Umbellulone
is a lipophilic liquid (oil) at room temperature. The boiling point of umbellulone is 220 °C and the vapor pressure is 0.159 mm/Hg. Umbellulone
Umbellulone
has a high-affinity binding for thiols. The molecule is reactive with most of the thiols, but not with all.[1] The reaction between the thiol cysteamine and umbellulone, is given in figure 3. A European registered medicine called Cystagon® or Procysbi® contains cysteamine, which can interact with umbellulone.

Figure 3: Reaction between cysteamine and umbellulone.

Synthesis[edit] A possible synthesis of umbellulone is given by the following process[4]. Diazomethyl isopropyl ketone reacts with methyl methacrylate to give 1-carbo-methoxy-2-isobutyryl-1-methylcyclopropane. This reaction gives a yield of 35%. This is then hydrolyzed to a mixture of cis and trans 2-isobutyryl-1-methyl-1-cyclopropane. The trans isomer is isolated and reacts with the cadmium methyl Grignard reagent to 1-acetyl-2-isobutyryl-1-methylcyclopropane. This undergoes an aldol cyclization on treatment with dilute base to umbellulone. Mechanism of action[edit]

Figure 4. TRPA1
TRPA1
channel agonists can activate the TRPA1
TRPA1
channel to release CGRP. CGRP will bind to its receptor and will initiate vasodilation. Umbellulone
Umbellulone
is known to be able to interact with two ion channels, TRPA1
TRPA1
and TRPM8. Umbellulone
Umbellulone
has a high affinity to TRPA1 and a lower affinity to TRPM8.

TRPA1 Umbellulone
Umbellulone
can cause severe headaches by activating transient receptor potential cation channel, subfamily A, member 1 (TRPA1) and influencing the trigeminovascular system via calcitonin gene-related peptide (CGRP). Once inhaled, umbellulone will diffuse from the nasal mucosa into the blood circulation. Because of the high lipid solubility of umbellulone, the molecule will quickly pass through the epithelial cells and will quickly be absorbed in the blood. From there on, umbellulone is able to reach the perivascular sensory nerve endings of the meningeal vessels. Stimulation of these nerve fibers will eventually lead to the release of CGRP, a nociceptor known for its ability to induce migraine and cluster headache attacks.[1] Activation of TRPA1
TRPA1
by umbellulone results in the opening of this ion channel. Calcium
Calcium
will enter the cell and the cell membrane will be depolarised. Depolarisation of the membrane will result in the release of CGRP1. Released CGRP can bind to its CGRP-receptor. This will induce a CGRP-dependent local vasodilation (Fig. 4) of the cerebral blood vessels. Vasodilation of the cerebral blood vessels will increase the blood flow to the brain's outer membranes. CGRP binding to its receptor will also promote mast cell degranulation and infiltration by neutrophils and other immune cells. The increase in immune cells and its inflammatory response is thought to be the main cause of the occurrence of migraine. Its is still being discussed if vasodilation of the cerebral blood vessels contributes to the cause of the migraine and headaches. Still, the vasodilatory effect and the blood flow increase can be used as an indirect indication for the release of CGRP and therefore for the presence of the migraine and headaches. TRPM8 Transient receptor potential cation channel, subfamily M, member 8 (TRPM8) is an ion channel that is able to induce an intensely cold sensation when activated. Menthol
Menthol
is the primary ligand of TRPM8, but since umbellulone has some structural similarities with menthol, umbellulone is also able to activate TRPM8. But this is a weak interaction. Indications[edit] Exposure to umbellularia is likely to result in an intense cold sensation in the nasal cavity. When combined with a headache, an increase in plasma CGRP or irritation of the eyes, the possibility for the person to have been exposed to umbellulone increases. Toxicity[edit] The oil of Umbellularia californica
Umbellularia californica
contains 40% to 60% of umbellulone. It possesses an effect similar to atropine on the nerves and muscle fibers. Contact with the oil, or even expose to the vapors, can cause:

Headache Irritation to eyes Irritation to the nose Irritation of the mucous membrane Loss of concentration Lowering blood pressure Difficulty with respiration

Umbellulone
Umbellulone
induces rapid production of methemoglobine. Methemoglobine is a globin in the blood which mainly consists of ferric (Fe3+) haemoglobin instead of the usual ferrous (Fe2+) haemoglobin. Methemoglobin has a decreased ability to bind oxygen. But in combination with the 3 other ferrous irons on the hemoglobin unit, the oxygen release is also decreased. Red blood cells will be less able to nurture organs with oxygen. Therefore, the probability for a hypoxia increases. Methemoglobin lethality is possible at concentrations higher than 50% of the substance in red blood cells. Umbellularia californica
Umbellularia californica
should not be mistaken for the conventional bay leaf (Laurus nobilis), which is devoid of these toxic effects. Other applications[edit] In 2013 a new possible application of Umbellularia californica
Umbellularia californica
came to light. The essential oil was used for its mosquito biting deterrent and larvicidal activity. This encourages further investigation of this oil. Not only as a natural repellent for other arthropods, but also for medical and veterinary importance. This could lead to a new molecular-based approach to ethnopharmacological investigation of essential oils for pest control.[citation needed] References[edit]

^ a b c d Nassini, R.; Materazzi, S.; Vriens, J.; Prenen, J.; Benemei, S.; De Siena, G.; La Marca, G.; Andrè, E.; Preti, D.; Avonto, C.; Sadofsky, L.; Di Marzo, V.; De Petrocellis, L.; Dussor, G.; Porreca, F.; Taglialatela-Scafati, O.; Appendino, G.; Nilius, B.; Geppetti, P. (2011). "The 'headache tree' via umbellulone and TRPA1
TRPA1
activates the trigeminovascular system". Brain. 135 (Pt 2): 376–390. doi:10.1093/brain/awr272. PMID 22036959.  ^ Rachel Ehrenberg (November 3, 2011). " Headache
Headache
tree is a pain in the brain: Bay laurel swells cranial blood vessels". ScienceNews. Retrieved 2011-11-07. 

3. Drake, M.; Stuhr, E.; (1934) "Some pharmacological and bactericidal properties of umbellulone" [1]. Retrieved 2016-03-10. 4. Synthesis of an Isomer of Umbellulone
Umbellulone
(1956) [2]. Retrieved 2016-03-10.

v t e

Types of Terpenes and Terpenoids (# of isoprene units)

Basic forms:

Acyclic (linear, cis and trans forms) Monocyclic (single ring) Bicyclic (2 rings) Iridoids (cyclopentane ring) Iridoid
Iridoid
glycosides (iridoids bound to a sugar) Steroids (4 rings)

Hemiterpenoids (1)

Isoprene
Isoprene
(C5H8) Prenol Isovaleric acid

Monoterpene
Monoterpene
(C10H16)(2)

Acyclic

Ocimene Myrcenes

Monocyclic

Limonene Terpinene Phellandrene Umbellulone

Bicyclic

Pinene
Pinene
(β and α Camphene Thujene Sabinene Carene

Monoterpenoids (2,modified)

Acyclic

Linalool Citronellal Citral Citronellol Geraniol Geranyl pyrophosphate

Monocyclic

Grapefruit mercaptan menthol p-Cymene thymol Perillyl alcohol Carvacrol

Bicyclic

Camphor Borneol Eucalyptol Halomon Eucalyptol Pinene Ascaridole

Sesquiterpenoids
Sesquiterpenoids
(3)

Farnesyl pyrophosphate Artemisinin Bisabolol

Diterpenoids (4)

Geranylgeranyl pyrophosphate Gibberellin Retinol Retinal Phytol Taxol Forskolin Aphidicolin Salvinorin A

Sesterterpenoids (5)

geranylfarnesol

Triterpenoids (6)

Steroids

Phytosterols

Campesterol beta Sitosterol gamma sitosterol Stigmasterol

Tocopherols Cholesterol Testosterone Cholecalciferol
Cholecalciferol
(Vit D) Ecdysones

Other

Saponins Squalane Lanosterol Acids

Oleanolic acid Ursolic acid Betulinic acid Moronic acid

Sesquarterpenes/oids (7)

ferrugicadiol tetraprenylcurcumene

Tetraterpenoids (Carotenoids) (8)

Carotenes

Alpha-Carotene Beta-Carotene Gamma-Carotene Delta-Carotene Lycopene Neurosporene Phytofluene Phytoene

Xanthophylls:

Canthaxanthin Cryptoxanthin Zeaxanthin Astaxanthin Lutein Rubixanthin

Polyterpenoids (many)

sap, resins, latex of many plants, e.g. rubber

Norisoprenoids (modified)

3-oxo-α-ionol 7,8-dihydroionone

Synthesis

Terpene
Terpene
synthase enzymes (many), having in common a Terpene
Terpene
synthase N terminal domain (protein domain)

Activated isoprene forms

Isopentenyl pyrophosphate
Isopentenyl pyrophosphate
(IPP) Dimethylallyl pyrophosphate
Dimethylallyl pyrophosphate
(DMAPP)

v t e

TRP channel modulators

TRPA

Activators

4-Hydroxynonenal 4-Oxo-2-nonenal 4,5-EET 12S-HpETE 15-Deoxy-Δ12,14-prostaglandin J2 α- Sanshool
Sanshool
(ginger, Sichuan and melegueta peppers) Acrolein Allicin
Allicin
(garlic) Allyl isothiocyanate
Allyl isothiocyanate
(mustard, radish, horseradish, wasabi) AM404 Bradykinin Cannabichromene
Cannabichromene
(cannabis) Cannabidiol
Cannabidiol
(cannabis) Cannabigerol
Cannabigerol
(cannabis) Cinnamaldehyde
Cinnamaldehyde
(cinnamon) CR gas
CR gas
(dibenzoxazepine; DBO) CS gas
CS gas
(2-chlorobenzal malononitrile) Curcumin
Curcumin
(turmeric) Dehydroligustilide (celery) Diallyl disulfide Dicentrine
Dicentrine
( Lindera
Lindera
spp.) Farnesyl thiosalicylic acid Formalin Gingerols (ginger) Hepoxilin A3 Hepoxilin B3 Hydrogen peroxide Icilin Isothiocyanate Ligustilide (celery, Angelica acutiloba) Linalool
Linalool
(Sichuan pepper, thyme) Methylglyoxal Methyl salicylate
Methyl salicylate
(wintergreen) N-Methylmaleimide Nicotine
Nicotine
(tobacco) Oleocanthal
Oleocanthal
(olive oil) Paclitaxel
Paclitaxel
(Pacific yew) Paracetamol
Paracetamol
(acetaminophen) PF-4840154 Phenacyl chloride Polygodial
Polygodial
(Dorrigo pepper) Shogaols (ginger, Sichuan and melegueta peppers) Tear gases Tetrahydrocannabinol
Tetrahydrocannabinol
(cannabis) Thiopropanal S-oxide
Thiopropanal S-oxide
(onion) Umbellulone
Umbellulone
(Umbellularia californica) WIN 55,212-2

Blockers

Dehydroligustilide (celery) Nicotine
Nicotine
(tobacco) Ruthenium red

TRPC

Activators

Adhyperforin
Adhyperforin
(St John's wort) Diacyl glycerol GSK1702934A Hyperforin
Hyperforin
(St John's wort) Substance P

Blockers

DCDPC DHEA-S Flufenamic acid GSK417651A GSK2293017A Meclofenamic acid N-(p-amylcinnamoyl)anthranilic acid Niflumic acid Pregnenolone sulfate Progesterone Pyr3 Tolfenamic acid

TRPM

Activators

ADP-ribose BCTC Calcium
Calcium
(intracellular) Cold Coolact P Cooling Agent 10 CPS-369 Eucalyptol
Eucalyptol
(eucalyptus) Frescolat MGA Frescolat ML Geraniol Hydroxycitronellal Icilin Linalool Menthol
Menthol
(mint) PMD 38 Pregnenolone sulfate Rutamarin (Ruta graveolens) Steviol glycosides (e.g., stevioside) (Stevia rebaudiana) Sweet tastants (e.g., glucose, fructose, sucrose; indirectly) Thio-BCTC WS-3 WS-12 WS-23

Blockers

Capsazepine Clotrimazole DCDPC Flufenamic acid Meclofenamic acid Mefenamic acid N-(p-amylcinnamoyl)anthranilic acid Nicotine
Nicotine
(tobacco) Niflumic acid Ruthenium red Rutamarin (Ruta graveolens) Tolfenamic acid TPPO

TRPML

Activators

MK6-83 PI(3,5)P2 SF-22

TRPP

Activators

Triptolide
Triptolide
(Tripterygium wilfordii)

Blockers

Ruthenium red

TRPV

Activators

2-APB 5',6'-EET 9-HODE 9-oxoODE 12S-HETE 12S-HpETE 13-HODE 13-oxoODE 20-HETE α- Sanshool
Sanshool
(ginger, Sichuan and melegueta peppers) Allicin
Allicin
(garlic) AM404 Anandamide Bisandrographolide (Andrographis paniculata) Camphor
Camphor
(camphor laurel, rosemary, camphorweed, African blue basil, camphor basil) Cannabidiol
Cannabidiol
(cannabis) Cannabidivarin
Cannabidivarin
(cannabis) Capsaicin
Capsaicin
(chili pepper) Carvacrol
Carvacrol
(oregano, thyme, pepperwort, wild bergamot, others) DHEA Diacyl glycerol Dihydrocapsaicin
Dihydrocapsaicin
(chili pepper) Estradiol Eugenol
Eugenol
(basil, clove) Evodiamine
Evodiamine
(Euodia ruticarpa) Gingerols (ginger) GSK1016790A Heat Hepoxilin A3 Hepoxilin B3 Homocapsaicin
Homocapsaicin
(chili pepper) Homodihydrocapsaicin
Homodihydrocapsaicin
(chili pepper) Incensole
Incensole
(incense) Lysophosphatidic acid Low pH (acidic conditions) Menthol
Menthol
(mint) N-Arachidonoyl dopamine N-Oleoyldopamine N-Oleoylethanolamide Nonivamide
Nonivamide
(PAVA) (PAVA spray) Nordihydrocapsaicin
Nordihydrocapsaicin
(chili pepper) Paclitaxel
Paclitaxel
(Pacific yew) Paracetamol
Paracetamol
(acetaminophen) Phorbol esters
Phorbol esters
(e.g., 4α-PDD) Piperine
Piperine
(black pepper, long pepper) Polygodial
Polygodial
(Dorrigo pepper) Probenecid Protons RhTx Rutamarin (Ruta graveolens) Resiniferatoxin
Resiniferatoxin
(RTX) (Euphorbia resinifera/pooissonii) Shogaols (ginger, Sichuan and melegueta peppers) Tetrahydrocannabivarin
Tetrahydrocannabivarin
(cannabis) Thymol
Thymol
(thyme, oregano) Tinyatoxin
Tinyatoxin
(Euphorbia resinifera/pooissonii) Tramadol Vanillin
Vanillin
(vanilla) Zucapsaicin

Blockers

α- Spinasterol
Spinasterol
( Vernonia
Vernonia
tweediana) AMG-517 Asivatrep BCTC Cannabigerol
Cannabigerol
(cannabis) Cannabigerolic acid (cannabis) Cannabigerovarin (cannabis) Cannabinol
Cannabinol
(cannabis) Capsazepine DCDPC DHEA DHEA-S Flufenamic acid GRC-6211 HC-067047 Lanthanum Meclofenamic acid N-(p-amylcinnamoyl)anthranilic acid NGD-8243 Niflumic acid Pregnenolone sulfate RN-1734 RN-9893 Ruthenium red SB-705498 Tivanisiran Tolfenamic acid

See also: Receptor/signaling modulators • Ion channe

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