Hordenine
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Hordenine is an
alkaloid Alkaloids are a class of basic, naturally occurring organic compounds that contain at least one nitrogen atom. This group also includes some related compounds with neutral and even weakly acidic properties. Some synthetic compounds of similar ...
of the
phenethylamine Phenethylamine (PEA) is an organic compound, natural monoamine alkaloid, and trace amine, which acts as a central nervous system stimulant in humans. In the brain, phenethylamine regulates monoamine neurotransmission by binding to trace amin ...
class that occurs naturally in a variety of plants, taking its name from one of the most common,
barley Barley (''Hordeum vulgare''), a member of the grass family, is a major cereal grain grown in temperate climates globally. It was one of the first cultivated grains, particularly in Eurasia as early as 10,000 years ago. Globally 70% of barley pr ...
(''Hordeum'' species). Chemically, hordenine is the ''N''-methyl
derivative In mathematics, the derivative of a function of a real variable measures the sensitivity to change of the function value (output value) with respect to a change in its argument (input value). Derivatives are a fundamental tool of calculus. F ...
of ''N''-methyltyramine, and the ''N'',''N''-dimethyl derivative of the well-known biogenic amine
tyramine Tyramine ( ) (also spelled tyramin), 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-b ...
, from which it is biosynthetically derived and with which it shares some pharmacological properties (see below). , hordenine is widely sold as an ingredient of nutritional supplements, with the claims that it is a stimulant of the central nervous system, and has the ability to promote weight loss by enhancing metabolism. In experimental animals, given sufficiently large doses parenterally (by injection), hordenine does produce an increase in blood pressure, as well as other disturbances of the cardiovascular, respiratory, and nervous systems. These effects are generally not reproduced by oral administration of the drug in test animals, and virtually no scientific reports of the effects of hordenine in human beings have been published.


Occurrence

The first report of the isolation from a natural source of the compound which is now known as hordenine was made by Arthur Heffter in 1894, who extracted this alkaloid from the cactus ''Anhalonium fissuratus'' (now reclassified as '' Ariocarpus fissuratus''), naming it "anhalin". Twelve years later, E. Léger independently isolated an alkaloid which he named hordenine from germinated
barley Barley (''Hordeum vulgare''), a member of the grass family, is a major cereal grain grown in temperate climates globally. It was one of the first cultivated grains, particularly in Eurasia as early as 10,000 years ago. Globally 70% of barley pr ...
(''Hordeum vulgare'') seeds. Ernst Späth subsequently showed that these alkaloids were identical and proposed the correct molecular structure for this substance, for which the name "hordenine" was ultimately retained. Hordenine is present in a fairly wide range of plants, notably amongst the cacti, but has also been detected in some algae and fungi. It occurs in grasses, and is found at significantly high concentrations in the seedlings of cereals such as
barley Barley (''Hordeum vulgare''), a member of the grass family, is a major cereal grain grown in temperate climates globally. It was one of the first cultivated grains, particularly in Eurasia as early as 10,000 years ago. Globally 70% of barley pr ...
(''
Hordeum vulgare Barley (''Hordeum vulgare''), a member of the grass family, is a major cereal grain grown in temperate climates globally. It was one of the first cultivated grains, particularly in Eurasia as early as 10,000 years ago. Globally 70% of barley pr ...
'') (about 0.2%, or 2000 μg/g),
proso millet ''Panicum miliaceum'' is a grain crop with many common names, including proso millet, broomcorn millet, common millet, hog millet, Kashfi millet, red millet, and white millet. Archaeobotanical evidence suggests millet was first domesticated abou ...
('' Panicum miliaceum'') (about 0.2%), and
sorghum ''Sorghum'' () is a genus of about 25 species of flowering plants in the grass family (Poaceae). Some of these species are grown as cereals for human consumption and some in pastures for animals. One species is grown for grain, while many othe ...
(''
Sorghum vulgare ''Sorghum bicolor'', commonly called sorghum () and also known as great millet, broomcorn, guinea corn, durra, imphee, jowar, or milo, is a grass species cultivated for its grain, which is used for food for humans, animal feed, and ethanol produc ...
'') (about 0.1%). Reti, in his 1953 review of naturally occurring phenethylamines, notes that the richest source of hordenine is the cactus ''Trichocereus candicans'' (now reclassified as '' Echinopsis candicans''), which was found to contain 0.5–5.0% of the alkaloid. Since barley, via its conversion to
malt Malt is germinated cereal grain that has been dried in a process known as " malting". The grain is made to germinate by soaking in water and is then halted from germinating further by drying with hot air. Malted grain is used to make beer, wh ...
, is used extensively in the production of
beer Beer is one of the oldest and the most widely consumed type of alcoholic drink in the world, and the third most popular drink overall after water and tea. It is produced by the brewing and fermentation of starches, mainly derived from ce ...
, beer and malt have been examined by several groups of investigators for the presence of hordenine. Citing a 1965 study by McFarlane, Poocharoen reported that beer contained ~ 12–24 mg/L, wort contained about 11–13 mg/L, and malt contained about 67 μg/g of hordenine. The hordenine content of various malts and malt fractions was extensively studied by Poocharoen himself, who also provided a good coverage of related literature up to 1983. This researcher found a mean concentration of hordenine in raw barley around 0.7 μg/g; in green malts (i.e. barley that had been soaked in water for 2 days then germinated for 4 days), the mean concentration was about 21 μg/g, and in kilned malts (i.e. green malts that had been heated in a kiln for 1–2 days), the mean concentration was about 28 μg/g. When only green malt roots were examined, their mean content of hordenine was roughly 3363 μg/g, whereas the mean level in kilned malt roots was around 4066 μg/g. In barley, hordenine levels reach a maximum within 5–11 days of germination, then slowly decrease until only traces remain after one month. Furthermore, hordenine is localized primarily in the roots. In comparing literature values for hordenine concentrations in "barley" or barley "malt", therefore, consideration should be made of the age and parts of the plant being analyzed: the figure of about 2,000 μg/g cited in the review by Smith, for example, is consistent with Poocharoen's figures for the hordenine levels in the ''roots'' of malted barley, but not in "whole" malt, where his figures of 21-28 μg/g are more consistent with McFarlane's figure of about 67 μg/g. However, a wide range of variability is seen; a study by Lovett and co-workers of 43 different barley lines found concentrations of hordenine in roots ranging from 1 to 2625 μg/g fresh weight. These workers concluded that hordenine production was not under significant genetic control, but much more susceptible to environmental factors such as light duration.


Biosynthesis

Hordenine is biosynthesized by the stepwise ''N''-methylation of
tyramine Tyramine ( ) (also spelled tyramin), 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-b ...
, which is first converted to ''N''-methyltyramine, and which, in turn is methylated to hordenine. The first step in this sequence is accomplished by the enzyme tyramine N-methyltransferase (tyramine methylpherase), but if the same enzyme is responsible for the second methylation that actually produces hordenine is uncertain.


Chemistry


Basicity

Since the hordenine molecule contains both a basic (amine) and acidic (phenol) functional group, it is amphoteric. The apparent (see original article for discussion) pKas for protonated hordenine are 9.78 (phenolic H) and 10.02 (ammonium H). Common salts are hordenine hydrochloride, R-NH3+Cl−, m.p. 178 Â°C, and hordenine sulfate, (R-NH3+)2SO42−, m.p. 211 Â°C. The "
methyl hordenine HCl In organic chemistry, a methyl group is an alkyl derived from methane, containing one carbon atom bonded to three hydrogen atoms, having chemical formula . In formulas, the group is often abbreviated as Me. This hydrocarbon group occurs in many ...
" which is listed as an ingredient on the labels of some nutritional supplements is in all likelihood simply hordenine hydrochloride, since the "description" of "methyl hordenine HCl" given by virtually all bulk suppliers of this substance corresponds to that for hordenine hydrochloride (or possibly just hordenine). Five regioisomeric compounds would correspond to the name "methyl hordenine HCl", if it were interpreted according to the rules of chemical nomenclature: α-methyl hordenine, β-methyl hordenine, 2-methyl hordenine, 3-methyl hordenine, and 4-O-methyl hordenine - each in the form of its HCl salt; ''N''-methyl hordenine is better known as the natural product candicine, but is excluded from the possibilities because it is a quaternary ammonium salt that cannot be protonated, hence cannot form a hydrochloride salt.


Synthesis

The first synthesis of hordenine is due to Barger: 2-phenylethyl alcohol was first converted to 2-phenylethyl chloride using PCl5; this chloride was reacted with dimethylamine to form N,N-dimethyl-phenylethylamine, which was then nitrated using HNO3; the N,N-dimethyl-4-nitro-phenethylamine was reduced to N,N-dimethyl-4-amino-phenethylamine with Sn/HCl; this amine was finally converted to hordenine by diazotization/hydrolysis using NaNO2/H2SO4/H2O. A more efficient synthetic route was described by Chang and coworkers, who also provided references to earlier syntheses. This synthesis began with ''p''-methoxy-phenylethyl alcohol, which was simultaneously ''O''-demethylated and converted to the iodide by heating with HI; the resulting p-hydroxy-phenylethyl iodide was then heated with dimethylamine to give hordenine. Radio-labelled hordenine has been prepared by the
hydrogenation Hydrogenation is a chemical reaction between molecular hydrogen (H2) and another compound or element, usually in the presence of a Catalysis, catalyst such as nickel, palladium or platinum. The process is commonly employed to redox, reduce or S ...
of a mixture of 2- sup>14Ctyramine and 40%
formaldehyde Formaldehyde ( , ) (systematic name methanal) is a naturally occurring organic compound with the formula and structure . The pure compound is a pungent, colourless gas that polymerises spontaneously into paraformaldehyde (refer to section F ...
in the presence of 10% Pd-on-charcoal catalyst. The labelled C in the hordenine is thus the C which is β- to the N. Hordenine labelled with 14C at the position α- to the N has also been prepared,


Pharmacology

The first pharmacological study of hordenine to be recorded is that of Heffter, who was also the first to isolate it. Using the sulfate salt (see "Chemistry"), Heffter gave a subcutaneous dose of 0.3 g to a 2.8-kg cat (about 107 mg/kg), and observed no effects besides violent vomiting; the cat behaved normally within 45 mins. He also took a dose of 100 mg orally himself, without experiencing any observable effect. However, the alkaloid was observed to produce a paralysis of the nervous system in frogs. Working with Léger's (see "Occurrence") hordenine sulfate, Camus determined minimum lethal doses for the dog, rabbit, guinea pig, and rat (see "Toxicology"). The associated symptoms of toxicity following parenteral doses were: excitation, vomiting, respiratory difficulties, convulsions, and paralysis, with death occurring as a result of respiratory arrest.L. Camus (1906). "L'hordénine, son degré de toxicité, symptômes de l'intoxication." ''Compt. Rend.'' 142 110-113. In a subsequent paper, Camus reported that the intravenous (IV) administration of some hundreds of mg of hordenine sulfate to dogs or rabbits caused an increase in blood pressure and changes in the rhythm and force of contraction of the heart, noting also that the drug was not orally active. The cardiovascular and other effects of hordenine were reviewed in detail by Reitschel, writing in 1937. More modern studies were carried out by Frank and coworkers, who reported that IV administration of 2 mg/kg of hordenine to horses produced substantial respiratory distress, increased the rate of respiration by 250%, doubled the heart rate, and caused sweating without changes in basal body temperature or behavior. All effects disappeared within 30 mins. The same dose of hordenine given orally did not produce any of the effects seen after parenteral administration. In a 1995 study, Hapke and Strathmann reported that in dogs and rats, hordenine produced a positive inotropic effect on the heart (i.e. increased the strength of contraction), increased systolic and diastolic blood pressure, and increased the volume of peripheral blood flow. Movements of the gut were inhibited. Additional experiments on isolated tissue lead these investigators to conclude that hordenine was an indirectly acting adrenergic agent that produced its pharmacological effects by releasing stored
norepinephrine Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as both a hormone and neurotransmitter. The name "noradrenaline" (from Latin '' ad'', ...
(NE). Hordenine was found to be a selective substrate for MAO-B, from rat liver, with Km = 479 μM, and Vmax = 128 nM/mg protein/h. It was not deaminated by MAO-A from rat intestinal epithelium. In contrast to
tyramine Tyramine ( ) (also spelled tyramin), 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-b ...
, hordenine did not produce contraction of isolated rat vas deferens, but a 25 μM concentration of the drug did potentiate its response to submaximal doses of NE, and inhibited its response to tyramine. However, the response to NE of isolated vas deferens taken from rats chronically treated with
guanethidine Guanethidine is an antihypertensive drug that reduces the release of catecholamines, such as norepinephrine. Guanethidine is transported across the sympathetic nerve membrane by the same mechanism that transports norepinephrine itself (NET, upta ...
was not affected by hordenine. The investigators concluded that hordenine acted as an inhibitor of NE reuptake in rat vas deferens. Hordenine has been found to be a potent stimulant of
gastrin Gastrin is a peptide hormone that stimulates secretion of gastric acid (HCl) by the parietal cells of the stomach and aids in gastric motility. It is released by G cells in the pyloric antrum of the stomach, duodenum, and the pancreas. Gastrin ...
release in the rat, being essentially equipotent with
N-methyltyramine ''N''-Methyltyramine (NMT), also known as 4-hydroxy-''N''-methylphenethylamine, is a human trace amine and natural substituted phenethylamine, phenethylamine alkaloid found in a variety of plants.T. A. Smith (1977). "Phenethylamine and related c ...
: 83 nM/kg of hordenine (corresponding to about 14 mg/kg of the free base) enhancing gastrin release by roughly 60%. In a study of the effects of a large number of compounds on a rat
trace amine receptor Trace amine-associated receptors (TAARs), sometimes referred to as trace amine receptors (TAs or TARs), are a class of G protein-coupled receptors that were discovered in 2001. TAAR1, the first of six functional human TAARs, has gained considerab ...
(rTAR1) expressed in HEK 293 cells, hordenine, at a concentration of 1 μM, had almost identical potency to that of the same concentration of β-phenethylamine in stimulating
cAMP Camp may refer to: Outdoor accommodation and recreation * Campsite or campground, a recreational outdoor sleeping and eating site * a temporary settlement for nomads * Camp, a term used in New England, Northern Ontario and New Brunswick to descri ...
production through the rTAR1. The potency of tyramine in this receptor preparation was slightly higher than that of hordenine.


Toxicology

LD50 in mice, by intraperitoneal (IP) administration: 299 mg/kg. Other LD50 values given in the literature are: >100 mg/kg (mouse; IP), as HCl salt: 113.5 mg/kg (mouse; route of administration unspecified) Minimum lethal dose (as sulfate salt): 300 mg/kg (dog; IV); 2000 mg/kg (dog; oral); 250 mg/kg (rabbit; IV); 300 mg/kg (guinea pig; IV); 2000 mg/kg (guinea pig; subcutaneous); about 1000 mg/kg (rat; subcutaneous). From experiments aimed at identifying the toxin responsible for producing the locomotor disorder ("staggers") and rapidly lethal cardiac toxicosis ("sudden death") periodically observed in livestock feeding on the grass ''
Phalaris aquatica ''Phalaris aquatica'', known by the common names bulbous canary-grass and Harding grass, is a species of grass in the genus ''Phalaris'' of the family Poaceae. Description It is an erect, waist-high, stout perennial bunch grass, with grayish to ...
'', Australian researchers determined that the lowest doses of hordenine that would induce symptoms of "staggers" in sheep were 20 mg/kg IV, and 800 mg/kg orally. However, the cardiac symptoms of "sudden death" could not be evinced by hordenine. Although hordenine is capable of reacting with nitrosating agents (e.g. nitrite ion, NO2−) to form the
carcinogen A carcinogen is any substance, radionuclide, or radiation that promotes carcinogenesis (the formation of cancer). This may be due to the ability to damage the genome or to the disruption of cellular metabolic processes. Several radioactive substan ...
N-nitrosodimethylamine (NDMA), and was investigated as a possible precursor for the significant amounts of NDMA once found in beer, it was eventually established that the levels of hordenine present in malt were too low to account for the observed levels of NDMA.


Pharmacokinetics

The pharmacokinetics of hordenine have been studied in horses. After IV administration of the drug, the α-phase T1/2 was found to be about 3 mins., and the β-phase T1/2 was about 35 mins.


Insect interactions

Hordenine has been found to act as a feeding deterrent to grasshoppers (''Melanoplus bivittatus''), and to caterpillars of ''Heliothis virescens'' and ''Heliothis subflexa''; the estimated concentration of hordenine that reduced feeding duration to 50% of control was 0.4M for ''H. virescens'' and 0.08M for ''H. subflexa''.


Plant interactions

Hordenine has some plant growth-inhibiting properties: Liu and Lovett reported that, at a concentration of 50 ppm, it reduced the radicle length in seedlings of white mustard (''Sinapis alba'') by around 7%; admixture with an equal amount of
gramine Gramine (also called donaxine) is a naturally occurring indole alkaloid present in several plant species. Gramine may play a defensive role in these plants, since it is toxic to many organisms. Occurrence Gramine has been found in the giant reed, ...
markedly enhanced this inhibitory effect.


See also

*
Tyramine Tyramine ( ) (also spelled tyramin), 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-b ...
*
N-Methyltyramine ''N''-Methyltyramine (NMT), also known as 4-hydroxy-''N''-methylphenethylamine, is a human trace amine and natural substituted phenethylamine, phenethylamine alkaloid found in a variety of plants.T. A. Smith (1977). "Phenethylamine and related c ...
* Candicine * N,N-Dimethyldopamine *
4-Hydroxyamphetamine 4-Hydroxyamphetamine (4HA), also known as hydroxyamfetamine, hydroxyamphetamine, oxamphetamine, norpholedrine, ''para''-hydroxyamphetamine, and α-methyltyramine, is a drug that stimulates the sympathetic nervous system. It is used medically ...
*
Pholedrine Pholedrine (Paredrinol, Pulsotyl, Veritol), also known as 4-hydroxy-''N''-methylamphetamine (4-HMA), 4-hydroxymethamphetamine, and ''para''-hydroxymethamphetamine, is a drug that stimulates the sympathetic nervous system. It is administered as a ...
* O-desmethylvenlafaxine * Venlafaxine


Notes


References

{{Phenethylamines Phenethylamine alkaloids Phenols Plant toxins