Hordenine, also known as anhaline, peyocactin, N,N-dimethyltyramine or 4-hydroxy-N,N-dimethylphenethylamine, is an alkaloid of the phenethylamine family 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. Like tyramine, hordenine acts as a norepinephrine releasing agent. As of September 2012, hordenine is widely sold as an ingredient of 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.
Use and effects Arthur Heffter tried hordenine at a dose of 100 mg and observed no detectable effects. Subsequent studies found that in doses of 200 to 500 mg, hordenine produces robust sympathomimetic effects, including vasoconstriction, bronchodilation, and pressor effects. Other sources have also stated hordenine to be a "stimulant".
Toxicology Working with Léger's hordenine sulfate, Camus determined minimum lethal doses for the dog, rabbit, guinea pig, and rat. 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). 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, 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 replicated by hordenine. 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, it was eventually established that the levels of hordenine present in malt were too low to account for the observed levels of NDMA.
Pharmacology
Pharmacodynamics The first pharmacological study of hordenine to be recorded is that of Arthur Heffter, who was also the first to isolate it. Using the sulfate salt, 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 minutes. The alkaloid was also observed to produce a paralysis of the nervous system in frogs. The cardiovascular and other effects of hordenine were reviewed in detail by H. G. Reitschel, writing in 1937. More modern studies were carried out by M. Frank and coworkers, who reported that intravenous 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 minutes. The same dose of hordenine given orally did not produce any of the effects seen after parenteral administration. In a 1995 study, H. J. Hapke and W. 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 norepinephrine, and inhibited its response to tyramine. However, the response to norepinephrine 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 norepinephrine reuptake in rat vas deferens. Hordenine has been found to be a potent stimulant of gastrin release in the rat, being essentially equipotent with N-methyltyramine: 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 (rTAR1) expressed in HEK 293 cells, hordenine, at a concentration of 1 μM, had almost identical potency to that of the same concentration of phenethylamine in stimulating cAMP production through the rTAR1. The potency of tyramine in this receptor preparation was slightly higher than that of hordenine.
… excerpt ends here. Continue reading the full article.
