Hordenine

Hordenine is an alkaloid of the phenethylamine class that occurs naturally in a variety of plants, taking its name from one of the most common, barley (Hordeum species). Chemically, hordenine is the N-methyl derivative of N-methyltyramine, and the N,N-dimethyl derivative of the well-known biogenic amine tyramine, from which it is biosynthetically derived and with which it shares some pharmacological properties (see below). As of September 2012^[update], hordenine is widely sold as an ingredient of nutritional supplements, with sellers claiming that it stimulates the central nervous system and promotes weight loss by enhancing metabolism. In experiments in which animals are given sufficiently large doses parenterally (by injection), hordenine produces 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.

The first report of the isolation from a natural source of the compound 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 (Hordeum vulgare) seeds. Ernst Späth subsequently showed that these alkaloids were identical and proposed the correct molecular structure for the 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 (Hordeum vulgare) (about 0.2%, or 2000 μg/g), proso millet (Panicum miliaceum) (about 0.2%), and sorghum (Sorghum vulgare) (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.

Because barley, via its conversion to malt, is used extensively in the production of beer, 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.

Hordenine is biosynthesized by the stepwise N-methylation of tyramine, 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.

Since the hordenine molecule contains both a basic (amine) and acidic (phenol) functional group, it is amphoteric.

The apparent (see original article for discussion) pK_as for protonated hordenine are 9.78 (phenolic H) and 10.02 (ammonium H).