Hordenine

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Hordenine
Hordenin - Hordenine.svg
Hordenine.png
Names
IUPAC name
4-(2-Dimethylaminoethyl)phenol
Other names
N,N-Dimethyltyramine; Peyocactin; Anhaline
Identifiers
539-15-1 N
ChEBI CHEBI:5764 YesY
ChEMBL ChEMBL505789 YesY
ChemSpider 61609 YesY
Jmol 3D model Interactive image
KEGG C06199 YesY
PubChem 68313
  • InChI=1S/C10H15NO/c1-11(2)8-7-9-3-5-10(12)6-4-9/h3-6,12H,7-8H2,1-2H3 YesY
    Key: KUBCEEMXQZUPDQ-UHFFFAOYSA-N YesY
  • InChI=1/C10H15NO/c1-11(2)8-7-9-3-5-10(12)6-4-9/h3-6,12H,7-8H2,1-2H3
    Key: KUBCEEMXQZUPDQ-UHFFFAOYAA
  • Oc1ccc(cc1)CCN(C)C
Properties
C10H15NO
Molar mass 165.24 g·mol−1
Appearance colorless solid
Melting point 116 to 117 °C (241 to 243 °F; 389 to 390 K)
Boiling point 173 °C (343 °F; 446 K) at 11 mm Hg; sublimes at 140–150 °C
high in: ethanol; ether; chloroform
Vapor pressure {{{value}}}
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
N verify (what is YesYN ?)
Infobox references

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,[1] 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 cardio-vascular, respiratory and nervous systems. These effects are generally not reproduced by oral administration of the drug in test animals, and there are virtually no scientific reports of the effects of hordenine in human beings. More detailed discussions of hordenine pharmacology and toxicology are given below.

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".[2] Twelve years later, E. Léger independently isolated an alkaloid which he named hordenine from germinated barley (Hordeum vulgare) seeds.[3] 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.[4]

Hordenine is present in a fairly wide range of plants, notably amongst the cacti,[5] but has also been detected in some algae and fungi.[6][7][8] It occurs in grasses, and is found at significantly high concentrations in the seedlings of cereals such as barley (Hordeum vulgare) (~ 0.2%, or 2000 μg/g), proso millet (Panicum miliaceum) (~ 0.2%), and sorghum (Sorghum vulgare) (~0.1%).[7] 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% of the alkaloid.[9]

Since 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,[10] Poocharoen reported that beer contained ~ 12–24 mg/L, wort contained ~11–13 mg/L, and malt contained ~ 67 μg/g of hordenine.[11] 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[12] of ~ 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 ~ 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 ~ 28 μg/g. When only green malt roots were examined, their mean content of hordenine was ~ 3363 μg/g, whereas the mean level in kilned malt roots was ~ 4066 μg/g.[11]

It has been established that, in barley, hordenine levels reach a maximum within 5–11 days of germination, then slowly decrease until only traces remain after 1 month. Furthermore, hordenine is localized primarily in the roots.[13] 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 ~ 2000 μg/g cited in the review by Smith,[7] for example, is consistent with Poocharoen's [11] 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 ~ 67 μg/g.[10] On the other hand, there is a wide range of variability: a study by Lovett and co-workers of 43 different barley lines found concentrations of hordenine in roots ranging from 1-2625 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.[14]

Biosynthesis

It has been shown that hordenine is biosynthesized by the step-wise 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 it is uncertain if the same enzyme is responsible for the second methylation that actually produces hordenine.[13][15]

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).[16]

Common salts are hordenine hydrochloride,[17] R-NH3+Cl−, m.p. 178 °C, and hordenine sulfate,[18] (R-NH3+)2SO42−, m.p. 211 °C.

It should be noted that 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).[19] There are five regioisomeric compounds that 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 and 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.[20]

A more efficient synthetic route was described by Chang and co-workers, 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.[21]

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.[22]

Hordenine labelled with 14C at the position α- to the N has also been prepared,[23] as has hordenine with a 14C-label in both N-methyl groups.[24]

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 (~ 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.[2]

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.[25] In a subsequent paper, Camus reported that the i.v. 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.[26]

The cardiovascular and other effects of hordenine were reviewed in detail by Reitschel, writing in 1937.[27]

More modern studies were carried out by Frank and co-workers, who reported that i.v. 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.[28]

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).[29]

In a survey of the ability of a wide range of arylalkylamines and their derivatives to release norepinephrine (NE) from mouse heart, Daly and co-workers determined that 10 mg hordenine sulfate did not cause any significant NE release, in contrast to the same doses of the closely related compounds N-methyltyramine hydrochloride (which released 36% over control) and tyramine hydrochloride (which released 50% over control).[30]

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 de-aminated by MAO-A from rat intestinal epithelium.[31]

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 (NE), and inhibited its response to tyramine. However, the response to NE of isolated vas deferens taken from rats chronically pre-treated with guanethidine was not affected by hordenine. The investigators concluded that hordenine acted as an inhibitor of NE re-uptake in rat vas deferens.[31]

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 ~14 mg/kg of the free base) enhancing gastrin release by ~ 60%.[32]

In a study of the effects of a large number of compounds on a rat trace amine receptor (rTAR1) expressed in HEK 293 cells, it was found that 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.[33]

Toxicology

LD50 in mouse, by i.p. administration: 299 mg/kg.[34] Other LD50 values given in the literature are: >100 mg/kg (mouse; i.p.),[35] as HCl salt: 113.5 mg/kg (mouse; route of administration unspecified)[36] Minimum lethal dose (as sulfate salt): 300 mg/kg (dog; i.v.); 2000 mg/kg (dog; p.o.); 250 mg/kg (rabbit; i.v.); 300 mg/kg (guinea pig; iv.); 2000 mg/kg (guinea pig; s.c.); ~ 1000 mg/kg (rat; s.c.).[25]

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 i.v., and 800 mg/kg orally. However, the cardiac symptoms of "sudden death" could not be evinced by hordenine.[37]

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,[11] it was eventually established that the levels of hordenine present in malt were too low to account for the observed levels of NDMA.[38]

Pharmacokinetics

The pharmacokinetics of hordenine have been studied in horses. After i.v. administration of the drug, the α-phase T1/2 was found to be ~3 mins., and the β-phase T1/2 was ~35 mins.[28]

Insect interactions

Hordenine has been found to act as a feeding deterrent to grasshoppers (Melanoplus bivittatus),[39] 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.[40]

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 ~ 7%.; admixture with an equal amount of gramine markedly enhanced this inhibitory effect, in a synergistic manner.[41]

See also

References

  1. ↑ September, 2012.
  2. ↑ 2.0 2.1 A. Heffter (1894). "Ueber Pellote." Arch. exp. Path. Pharmakol. 34 65-86.
  3. ↑ E. Léger (1906). "Sur l'hordenine: alcaloide nouveau retiré des germes, dits touraillons, de l'orge." Compt. Rend. 142 108-110.
  4. ↑ E. Späth (1919). "Über die Anhalonium-Alkaloide. I. Anhalin und Mezcalin." Monatschefte für Chemie 40 129-154.
  5. ↑ www.erowid.org
  6. ↑ T. A. Wheaton and I. Stewart (1970) Lloydia 33 244-254.
  7. ↑ 7.0 7.1 7.2 T. A. Smith (1977). "Phenethylamine and related compounds in plants." Phytochem. 16 9-18.
  8. ↑ J. Lundstrom (1989). "β-Phenethylamines and ephedrines of plant origin." In The Alkaloids, Vol. 35" (A. Brossi, Ed.) pp. 77-154.
  9. ↑ L. Reti (1953). In The Alkaloids, Vol. III, (R. H. F. Manske and H. L. Holmes, Eds.), pp. 313-338, New York: Academic Press.
  10. ↑ 10.0 10.1 W. D. McFarlane (1965) Proc. Europ. Brew. Conv. 387.
  11. ↑ 11.0 11.1 11.2 11.3 B. Poocharoen (1983), Ph. D. Thesis, Oregon State University. http://ir.library.oregonstate.edu/xmlui/handle/1957/27227
  12. ↑ The level of hordenine in ungerminated barley is negligible, but rises as germination (the first part of the "malting" process) proceeds.
  13. ↑ 13.0 13.1 J. D. Mann and S. H. Mudd (1963) J. Biol. Chem. 238 381-385.
  14. ↑ J. V. Lovett, A. H. C. Hoult and O. Christen (1994)."Biologically active secondary metabolites of barley. IV. Hordenine production by different barley lines." J. Chem. Ecol. 20 1945-1954.
  15. ↑ Tyrosine metabolism - Reference pathway, Kyoto Encyclopedia of Genes and Genomes (KEGG)
  16. ↑ T. Kappe and M. D. Armstrong (1965). "Ultraviolet absorption spectra and apparent acidic dissociation constants of some phenolic amines." J. Med. Chem. 8 368-374.
  17. ↑ CAS No. 6027-23-2
  18. ↑ CAS No. 622-64-0
  19. ↑ See, for example:http://www.alibaba.com/showroom/methyl-hordenine-hcl.html
  20. ↑ G. Barger (1909). "Synthesis of hordenine, the alkaloid from barley." J. Chem. Soc., Trans. 95 2193-2197.
  21. ↑ C.-S. Chang et al. (1951). "A new synthesis of hordenine and other p-dialkylaminoethylphenols and some of their derivatives." J. Am Chem. Soc." 73 4081-4084.
  22. ↑ G. A. Digenis, J. W. Burkett and V. Mihranian (1972). "A convenient synthesis of 2-[14C]-hordenine." J. Labelled Cmpds. 8 231-235.
  23. ↑ C. A. Russo and E. G. Gross (1981). "Synthesis of 4-(2-(dimethylamino)ethyl-2-14C)phenol (hordenine-α-14C)." J. Labelled Cmpds. and Radiopharm. 18 1185.
  24. ↑ C. A. Russo and E. G. Gross (1983). "Metabolism of [methyl-14C2] hordenine in Hordeum vulgare plants." Phytochem. 22 1839-1840.
  25. ↑ 25.0 25.1 L. Camus (1906). "L'hordénine, son degré de toxicité, symptômes de l'intoxication." Compt. Rend. 142 110-113.
  26. ↑ L. Camus (1906), "Action de sulfate d'hordenine sur circulation." Compt. Rend. 142 237-239.
  27. ↑ H. G. Reitschel (1937). "Zur Pharmakologie des Hordenins." Arch. exp. Path. Pharmakol. 186 387-408.
  28. ↑ 28.0 28.1 M. Frank et al. (1990). "Hordenine: pharmacology, pharmacokinetics and behavioral effects in the horse." Equine Vet. J. 22 437-441.
  29. ↑ H. J. Hapke and W. Strathmann (1995). "Pharmacological effects of hordenine." Dtsch. Tierarztl. Wochenschr. 102 228-232.
  30. ↑ J. W. Daly, C. R. Creveling and B. Witkop (1966). "The chemorelease of norepinephrine from mouse hearts. Structure-activity relationships. I. Sympathomimetic and related amines." J. Med. Chem. 9 273-280.
  31. ↑ 31.0 31.1 C. J. Barwell et al. (1989). "Deamination of hordenine by monoamine oxidase and its action on vasa deferentia of the rat." J. Pharm. Pharmacol. 41 421-423.
  32. ↑ Y. Yokoo et al. (1999) Alcohol & Alcoholism 34 161-168. http://alcalc.oxfordjournals.org/content/34/2/161.full.pdf+html
  33. ↑ J. R. Bunzow, M. S. Sonders, S. Arttamangkul, L. M. Harrison, G. Zhang, D. I. Quigley, T. Darland, K. L. Suchland, S. Pasumamula, J. L. Kennedy, S. B. Olson, R. E. Magenis, S. G. Amara, and D. K. Grandy (2001)."Amphetamine, 3,4-methylenedioxymethamphetamine, lysergic acid diethylamide, and metabolites of the catecholamine neurotransmitters are agonists of a rat trace amine receptor." Mol. Pharmacol. 60 1181-1188.
  34. ↑ M. Shinoda et al. (1977) Yakugaku Zasshi 97 1117-1124
  35. ↑ L. M. Batista and R. N. de Almeida (1997) Acta Farm. Bonaerense 16 83-86.
  36. ↑ Merck Index, 10th Ed. (1983), p.687, Rahway: Merck & Co.
  37. ↑ C. A. Bourke, M. J.Carrigan, and R. J. Dixon (1988) Aust. Vet. J. 65 218-220.
  38. ↑ B. Poocharoen et al. (1992). "Precursors of N-nitrosodimethylamine in malted barley. 1. Determination of hordenine and gramine." J. Agric. Food. Chem. 40 2216-2221.
  39. ↑ K. L. S. Harley (1967). "The influence of plant chemicals on the feeding behavior, development, and survival of the two-striped grasshopper, Melanoplus bivittatus (Sap), Aeridae: Orthoptera." Can J. Zool. 45 305-319.
  40. ↑ E. A. Bernays et al. (2000). "Taste sensitivity of insect herbivores to deterrents is greater in specialists than in generalists: a behavioral test of the hypothesis with two closely related caterpillars." J. Chem. Ecol. 26 547-563.
  41. ↑ D. L. Liu and J. V. Lovett (1993)."Biologically active secondary metabolites of barley. II. Phytotoxicity of barley allelochemicals" J. Chem. Ecol. 19 2231-2244.
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