Umbellulone

Umbellulone
Names
	IUPAC name 4-Methyl-1-(propan-2-yl)bicyclo[3.1.0]hex-3-en-2-one
	Other names Thujenone; Thujen-2-one; Umbellulon
Identifiers
CAS Number	24545-81-1 ; 546-78-1 (1R,5S) ;
3D model (JSmol)	Interactive image ;
ChemSpider	82348 ;
PubChem CID	91195 ;
UNII	X5YT6KCX2U ;
	InChI InChI=1S/C10H14O/c1-6(2)10-5-8(10)7(3)4-9(10)11/h4,6,8H,5H2,1-3H3 Key: LTTVJAQLCIHAFV-UHFFFAOYSA-N; InChI=1/C10H14O/c1-6(2)10-5-8(10)7(3)4-9(10)11/h4,6,8H,5H2,1-3H3 Key: LTTVJAQLCIHAFV-UHFFFAOYAU;
	SMILES O=C1\C=C(\C)C2C1(C(C)C)C2;
Properties
Chemical formula	C10H14O
Molar mass	150.221 g·mol−1
	Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa). Infobox references

Last updated November 15, 2023

Umbellulone is a headache-inducing monoterpene ketone found in the leaves of the tree Umbellularia californica , sometimes known as the "headache tree".^[1]^[2]

History

Umbellularia californica is a tree native to California and Southern Oregon.^[3]

Botanist Archibald 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 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 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 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 and cyclopentane 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.^[1]

Synthesis

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

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 (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 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 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, 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.^[5] This encourages further investigation of this oil.

Related Research Articles

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 the genus Umbellularia.

<span class="mw-page-title-main">Vasodilation</span> Widening of blood vessels

Vasodilation, also known as vasorelaxation, 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, which is the narrowing of blood vessels.

<span class="mw-page-title-main">Sumatriptan</span> 5-HT receptor agonist medication used for migraines & cluster headaches

Sumatriptan, sold commonly under brand names Imitrex and Treximet among others, is a medication used to treat migraine headaches and cluster headaches. It is taken orally, intranasally, or by subcutaneous injection. Therapeutic effects generally occur within three hours.

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

Tyramine, also known under several other names, is a naturally occurring trace amine derived from the amino acid tyrosine. Tyramine acts as a catecholamine releasing agent. Notably, it is unable to cross the blood-brain barrier, resulting in only non-psychoactive peripheral sympathomimetic effects following ingestion. A hypertensive crisis can result, however, from ingestion of tyramine-rich foods in conjunction with the use of monoamine oxidase inhibitors (MAOIs).

<span class="mw-page-title-main">Triptan</span> Class of pharmaceutical drugs

Triptans are a family of tryptamine-based drugs used as abortive medication in the treatment of migraines and cluster headaches. This drug class was first commercially introduced in the 1990s. While effective at treating individual headaches, they do not provide preventive treatment and are not considered a cure. They are not effective for the treatment of tension–type headache, except in persons who also experience migraines. Triptans do not relieve other kinds of pain.

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 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.

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.

Vasomotor refers to actions upon a blood vessel which alter its diameter. More specifically, it can refer to vasodilator action and vasoconstrictor action.

Methysergide, sold under the brand names Deseril and Sansert, is a monoaminergic medication of the ergoline and lysergamide groups which is used in the prophylaxis and treatment of migraine and cluster headaches. It has been withdrawn from the market in the United States and Canada due to adverse effects. It is taken by mouth.

Eletriptan, sold under the brand name Relpax and used in the form of eletriptan hydrobromide, is a second generation triptan medication intended for treatment of migraine headaches. It is used as an abortive medication, blocking a migraine attack which is already in progress. Eletriptan is marketed and manufactured by Pfizer Inc.

<span class="mw-page-title-main">Isometheptene</span> Sympathomimetic amine

Isometheptene is a sympathomimetic amine sometimes used in the treatment of migraines and tension headaches due to its vasoconstricting properties; that is, it causes constriction (narrowing) of blood vessels. Along with paracetamol and dichloralphenazone, it is one of the constituents of Amidrine.

alpha-1 (α₁) adrenergic receptors are G protein-coupled receptors (GPCRs) associated with the G_q heterotrimeric G protein. α₁-adrenergic receptors are subdivided into three highly homologous subtypes, i.e., α_1A-, α_1B-, and α_1D-adrenergic receptor subtypes. There is no α_1C receptor. At one time, there was a subtype known as α_1C, but it was found to be identical to the previously discovered α_1A receptor subtype. To avoid confusion, naming was continued with the letter D. Catecholamines like norepinephrine (noradrenaline) and epinephrine (adrenaline) signal through the α₁-adrenergic receptors in the central and peripheral nervous systems. The crystal structure of the α_1B-adrenergic receptor subtype has been determined in complex with the inverse agonist (+)-cyclazosin.

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).

Antimigraine drugs are medications intended to reduce the effects or intensity of migraine headache. They include drugs for the treatment of acute migraine symptoms as well as drugs for the prevention of migraine attacks.

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.

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.

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.

The trigeminovascular system (TVS) refers to neurons and their axonal projections within the trigeminal nerve that project to the cranial meninges and meningeal blood vessels residing on the brain's surface. The term, introduced in 1983 denotes also the neuropeptides contained within axons that are released into the meninges to target vessels and surrounding cells.

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

Wasabi receptor toxin (WaTx) is the active component of the venom of the Australian black rock scorpion Urodacus manicatus. WaTx targets TRPA1, also known as the wasabi receptor or irritant receptor. WaTx is a cell-penetrating toxin that stabilizes the TRPA1 channel open state while reducing its Ca²⁺-permeability, thereby eliciting pain and pain hypersensitivity without the neurogenic inflammation that typically occurs in other animal toxins.

References

1 2 3 4 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 activates the trigeminovascular system". Brain. 135 (Pt 2): 376–390. doi: 10.1093/brain/awr272 . PMID 22036959.
↑ Rachel Ehrenberg (November 3, 2011). "Headache tree is a pain in the brain: Bay laurel swells cranial blood vessels". ScienceNews. Retrieved 2011-11-07.
↑ Howard, Janet L. (1992). "Index of Species Information, Umbellularia californica". US Forest Service, Fire Effects Information System (FEIS) . Retrieved November 14, 2023.
↑ Smith, Howard E.; Eastman, Richard H. (1956). "Synthesis of an Isomer of Umbellulone". Journal of Organic Chemistry. 21 (7): 830. doi:10.1021/jo01113a019. ISSN 0022-3263.
↑ Tabanca, Nurhayat; Avonto, Cristina; Wang, Mei; Parcher, Jon F.; Ali, Abbas; Demirci, Betul; Raman, Vijayasankar; Khan, Ikhlas A. (2013). "Comparative Investigation of Umbellularia californica and Laurus nobilis Leaf Essential Oils and Identification of Constituents Active against Aedes aegypti". Journal of Agricultural and Food Chemistry. 61 (50): 12283–12291. doi:10.1021/jf4052682. PMID 24266426.