Hordenine

Hordenine (N,N-dimethyltyramine) 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). Currently, 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 (i.e. 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.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 (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 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 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.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).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.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.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, in a synergistic manner.