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Theobromine, formerly known as xantheose, is a bitter alkaloid of the cacao plant, with the chemical formula C7H8N4O2. It is found in chocolate, as well as in a number of other foods, including the leaves of the tea plant, and the kola nut. It is classified as a xanthine alkaloid, others of which include theophylline and caffeine. Caffeine differs from the compounds in that it has an extra methyl group (see under Pharmacology section).

Despite its name, the compound contains no bromine—theobromine is derived from Theobroma, the name of the genus of the cacao tree (which itself is made up of the Greek roots theo ("god") and broma ("food"), meaning "food of the gods" ) with the suffix -ine given to alkaloids and other basic nitrogen-containing compounds.

Theobromine is a slightly water-soluble (330 mg/L), crystalline, bitter powder. Theobromine is white or colourless, but commercial samples can be yellowish. It has an effect similar to, but lesser than, that of caffeine in the human nervous system, making it a lesser homologue. Theobromine is an isomer of theophylline, as well as paraxanthine. Theobromine is categorized as a dimethyl xanthine.

Theobromine was first discovered in 1841 in cacao beans by Russian chemist Aleksandr Voskresensky. Synthesis of theobromine from xanthine was first reported in 1882 by Hermann Emil Fischer.

Physical and Chemical Properties
Theobromine is an odorless and bitter tasting alkaloid with a molecular weight of 180.16 g/mol and pH (saturated solution in water) of 5.5-7. Under standard conditions it is a white to yellow crystalline powder with a melting point of 357 °C. It has a log P value of -0.78, and its density is 1.5g/cm^3 at room temperature.

Biosynthesis
Theobromine is a purine alkaloid derived from xanthosine, a nucleoside. It is one the three essential methylation step intermediates of the caffeine biosynthesis process (7-methylxanthosine, 7-methylxanthine, and theobromine). The conversion of xanthosine to 7-methylxanthosine proceeds by S-Adenosyl-l-methionine (SAM) dependent xanthosine methyltransferase. Although the mechanism is yet unclear, it is the key enzyme that catalyzes the first methyl transfer in the caffeine biosynthesis pathway to produce the intermediate 7-methylxanthosine. Then, it undergoes a hydrolysis and gives 7-methylxanthine by N-methyl-nucleosidase. The methylation of 7-methylxanthine converts it into theobromine by caffeine synthase. Theobromine is the precursor to caffeine.



Pharmacology
Even without dietary intake, theobromine may occur in the body as it is a product of the human metabolism of caffeine, which is metabolised in the liver into 12% theobromine, 4% theophylline, and 84% paraxanthine. In the liver, theobromine is metabolized into xanthine and subsequently into methyluric acid. Important enzymes include CYP1A2 and CYP2E1.

"The main mechanism of action for methylxanthines has long been established as an inhibition of adenosine receptors". Its effect as a phosphodiesterase inhibitor is thought to be small.

Pharmacodynamics
Theobromine, a xanthine derivative like caffeine and the bronchodilator theophylline, is used as a CNS stimulant, mild diuretic, and respiratory stimulant (in neonates with apnea of prematurity).

Mechanism of action
Theobromine is used as a vasodilator, a diuretic, and heart stimulant. And similar to caffeine, it may be useful in management of fatigue and orthostatic hypotension. It stimulates medullary, vagal, vasomotor, and respiratory centers, promoting bradycardia, vasoconstriction, and increased respiratory rate. This action was previously believed to be due primarily to increased intracellular cyclic 3′,5′-adenosine monophosphate (cyclic AMP) following inhibition of phosphodiesterase, the enzyme that degrades cyclic AMP. It is now thought that xanthines such as caffeine and theobromine act as antagonist at adenosine-receptors within the plasma membrane of virtually every cell. Blockade of the adenosine A1 receptor in the heart leads to the accelerated, pronounced "pounding" of the heart upon caffeine intake.

Humans
It is not currently used as a prescription drug. The amount of theobromine found in chocolate is small enough that chocolate can, in general, be safely consumed by humans. At doses of 0.8–1.5 g/day (50–100 g cocoa), sweating, trembling and severe headaches were noted, with limited mood effects found at 250 mg/day. Theobromine and caffeine are similar in that they are related alkaloids. Theobromine is weaker in both its inhibition of cyclic nucleotide phosphodiesterases and its antagonism of adenosine receptors. The potential inhibitory effect of theobromine on phosphodiesterases is seen only at amounts much higher than what people normally would consume in a typical diet including chocolate. In small amounts, is used for medicinal purposes. It increases heart rate, and at the same time, it dilates blood vessels, which lowers the blood pressure. It can also open up airways and is under study as a cough medication. It stimulates urine production and is considered a diuretic. It interacts with the central nervous system (although not as effectively as caffeine). At toxic levels, it provokes acute nausea, vomiting, diarrhea, cardiac arrhythmias, epileptic seizures, internal bleeding and often lethal over-stimulation of the heart, and eventually death.

Animals
Animals that metabolize theobromine (found in chocolate) more slowly, such as dogs, can succumb to theobromine poisoning from as little as 50 g of milk chocolate for a smaller dog and 400 g, or around nine 1.55 oz small milk chocolate bars, for an average-sized dog. The concentration of theobromine in dark chocolates (approximately 10 g/kg) is up to 10 times that of milk chocolate (1 to 5 g/kg) – meaning dark chocolate is far more toxic to dogs per unit weight or volume than milk chocolate.

The same risk is reported for cats as well, although cats are less likely to ingest sweet food, with most cats having no sweet taste receptors. Complications include digestive issues, dehydration, excitability, and a slow heart rate. Later stages of theobromine poisoning include epileptic-like seizures and death. If caught early on, theobromine poisoning is treatable. Although not common, the effects of theobromine poisoning can be fatal.

In 2014, four American black bears were found dead at a bait site in New Hampshire. A necropsy and toxicology report performed at the University of New Hampshire in 2015 confirmed they died of heart failure caused by theobromine after they consumed 90 lb of chocolate and doughnuts placed at the site as bait. A similar incident killed a black bear cub in Michigan in 2011.

Signs of theobromine poisoning in dogs include vomiting, haematemesis, polydipsia, hyperexcitability, hyperirritability, tachycardia, excessive panting, ataxia, and muscle twitching, progressing to cardiac arrhythmias, seizures, and death. These symptoms can potentially begin within a few hours of ingestion and can persist for up to 72 hours. There is no specific antidote, but treatment protocol usually consists of induced vomiting and administration of activated charcoal, oxygen, benzodiazepines for seizures, antiarrhythmics for heart arrhythmia, and intravenous fluids.