Hordenine

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%). 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 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, ==Biosynthesis==

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. ==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 °C, and hordenine sulfate, (R-NH3+)2SO42−, m.p. 211 °C. The "methyl hordenine HCl" 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 was reported in 1909 by Barger in which 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 of a mixture of 2-[14C]-tyramine and 40% formaldehyde 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 ==

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. 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 (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, 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 was not affected by hordenine. The investigators concluded that hordenine acted as an inhibitor of NE reuptake in rat vas deferens. In a study of the effects of a large number of compounds on a rat trace amine receptor (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 production through the rTAR1. The potency of tyramine in this receptor preparation was slightly higher than that of hordenine. Toxicology 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. 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. 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). Although hordenine is capable of reacting with nitrosating agents (e.g. nitrite ion, NO2−) to form the carcinogen N-nitrosodimethylamine (NDMA), and was investigated as a possible precursor for the significant amounts of NDMA once found in beer, ==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 markedly enhanced this inhibitory effect. == See also ==