Umbellulone is a headache-inducing monoterpene ketone found in the leaves of the tree Umbellularia californica, sometimes known as the "headache tree".
It is hypothesized to cause headaches by influencing the trigeminovascular system via TRPA1.
The 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.
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 laural possess a pungent odor.
Stillman (1880) did a fractionation at 215-216 °C. He discovered that inhalation of its fumes can lead to 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. The 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 (Fig. 1).
In 1908 the structural formula was adapted by Tutin (Fig. 2A).
This was correct later that year by Semmller, he gave the structural formula which is accepted today (Fig. 2B).
Umbellulone is a monoterpene ketone that is found in the leaves of the 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, it's a liquid (oil) at room temperature. The boiling point of umbellulone is 220 °C and the vapor pressure is 0.159 mm/Hg. Due to this extremely low vapor pressure, umbellulone fumes are easily created. This makes the substance easily inhaled. Umbellulone has a high-affinity binding for thiols. The molecule is reactive with most of the thiols, but not with all. 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.
A possible synthesis of Umbellulone is given by the following process. 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.
At room temperature umbellulone is an liquid (oil). Due to its low vapor pressure, umbellulone fumes are easily created. Physical contact with the substance can be accomplished by direct skin contact of the oil or inhalation of the vapors.
Umbellulone is known to be able to react on two ion channels, TRPA1 and TRPM8. Umbellulone has a high affinity to TRPA1 and a lower affinity to TRPM8.
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 structure 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, an 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 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 vasodilatation (Fig. 4) of the cerebral blood vessels. Vasodilation of the cerebral blood vessels will increase the blood flow to the brain 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 vasodil