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Umbellulone is a
headache Headache is the symptom of pain in the face, head, or neck. It can occur as a migraine, tension-type headache, or cluster headache. There is an increased risk of depression in those with severe headaches. Headaches can occur as a result ...
-inducing
monoterpene Monoterpenes are a class of terpenes that consist of two isoprene units and have the molecular formula C10H16. Monoterpenes may be linear (acyclic) or contain rings (monocyclic and bicyclic). Modified terpenes, such as those containing oxygen funct ...
ketone In organic chemistry, a ketone is a functional group with the structure R–C(=O)–R', where R and R' can be a variety of carbon-containing substituents. Ketones contain a carbonyl group –C(=O)– (which contains a carbon-oxygen double bo ...
found in the leaves of the tree ''
Umbellularia californica ''Umbellularia californica'' is a large hardwood tree native to coastal forests and the Sierra foothills of California, and to coastal forests extending into Oregon. It is endemic to the California Floristic Province. It is the sole species in th ...
'', sometimes known as the "headache tree". It is hypothesized to cause headaches by influencing the
trigeminovascular system The trigeminovascular system consists of neurons in the trigeminal nerve that innervate cerebral blood vessels. It has been hypothesized that the trigeminovascular system may be involved in some types of headaches. See also * Umbellulone Umbel ...
via
TRPA1 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'' (and in mice and rats by the ''Trpa1' ...
.


History

''
Umbellularia californica ''Umbellularia californica'' is a large hardwood tree native to coastal forests and the Sierra foothills of California, and to coastal forests extending into Oregon. It is endemic to the California Floristic Province. It is the sole species in th ...
'' is a tree native to the coastal forest of California. Botanist
Archibald Menzies Archibald Menzies ( ; 15 March 1754 – 15 February 1842) was a Scottish surgeon, botanist and naturalist. He spent many years at sea, serving with the Royal Navy, private merchants, and the Vancouver Expedition. He was the first recorded Euro ...
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 botanist David Douglas. In 1833 the tree received 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 Fractionation is a separation process in which a certain quantity of a mixture (of gases, solids, liquids, enzymes, or isotopes, or a suspension) is divided during a phase transition, into a number of smaller quantities (fractions) in which the ...
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 Pinene is a collection of unsaturated bicyclic monoterpenes. Two geometric isomers of pinene are found in nature, α-pinene and β-pinene. Both are chiral. As the name suggests, pinenes are found in pines. Specifically, pinene is the major comp ...
,
cineol Eucalyptol is a monoterpenoid. A colorless liquid, it is a bicyclic ether. Eucalyptol has a fresh mint-like smell and a spicy, cooling taste. It is insoluble in water, but miscible with organic solvents. Eucalyptol makes up ~70% - 90% of eucal ...
,
eugenol Eugenol is an allyl chain-substituted guaiacol, a member of the allylbenzene class of chemical compounds. It is a colorless to pale yellow, aromatic oily liquid extracted from certain essential oils especially from clove, nutmeg, cinnamon, basil ...
,
methyl eugenol Methyl eugenol (allylveratrol) is a natural chemical compound classified as a phenylpropene, a type of phenylpropanoid. It is the methyl ether of eugenol and is important to insect behavior and pollination. It is found in various essential oils. ...
and a ketone called umbellulone. Umbellulone is the chemical responsible for the headaches induced by the tree. They gave umbellulone the following structural formula: : In 1908 the structural formula was adapted by Tutin, which was corrected later that year by Semmller to give the structural formula which is accepted today: :


Structure and reactivity

Umbellulone is a monoterpene ketone that is found in the leaves of ''Umbellularia californica''. The formula of umbellulone is C10H14O, containing a
cyclopropane Cyclopropane is the cycloalkane with the molecular formula (CH2)3, consisting of three methylene groups (CH2) linked to each other to form a ring. The small size of the ring creates substantial ring strain in the structure. Cyclopropane itself ...
and
cyclopentane Cyclopentane (also called C pentane) is a highly flammable alicyclic hydrocarbon with chemical formula C5H10 and CAS number 287-92-3, consisting of a ring of five carbon atoms each bonded with two hydrogen atoms above and below the plane. It occur ...
ring. There is only one isomer of umbellulone known. 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 has a high-affinity binding for thiols. The molecule is reactive with most of the thiols, such as cysteamine, but not with all. :


Synthesis

A possible synthesis of umbellulone is given by the following process. Diazomethyl isopropyl ketone reacts with
methyl methacrylate Methyl methacrylate (MMA) is an organic compound with the formula CH2=C(CH3)COOCH3. This colorless liquid, the methyl ester of methacrylic acid (MAA), is a monomer produced on a large scale for the production of poly(methyl methacrylate) (PMMA ...
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


TRPA1

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 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 produ ...
(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. Activation of TRPA1 by umbellulone results in the opening of this ion channel. Calcium will enter the cell and the cell membrane will be depolarized. Depolarization 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 Vasodilation is the widening of blood vessels. It results from relaxation of smooth muscle cells within the vessel walls, in particular in the large veins, large arteries, and smaller arterioles. The process is the opposite of vasoconstriction, ...
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. It 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 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

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

The oil of ''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 exposure 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 induces rapid production of methemoglobine. Methemoglobine is a globin in the blood that mainly consists of ferric (Fe3+)
haemoglobin Hemoglobin (haemoglobin BrE) (from the Greek word αἷμα, ''haîma'' 'blood' + Latin ''globus'' 'ball, sphere' + ''-in'') (), abbreviated Hb or Hgb, is the iron-containing oxygen-transport metalloprotein present in red blood cells (erythrocyte ...
, instead of the usual ferrous (Fe2+) haemoglobin. Methemoglobin has a decreased ability to bind oxygen, but, in combination with the 3 other ferrous ions 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 hypoxia increases. Methemoglobin lethality is possible at concentrations higher than 50% of the substance in red blood cells. ''Umbellularia californica'' should not be mistaken for the conventional bay leaf (''Laurus nobilis''), which is devoid of these toxic effects.


Other applications

In 2013, a new potential application of ''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.


References


Further reading

* {{Transient receptor potential channel modulators Ketones Monoterpenes Cycloalkenes Cyclopropanes Isopropyl compounds