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".{{cite journal| first= A.| last= Heffter |year= 1894| title= Ueber Pellote| journal= Arch. Exp. Pathol. Pharmakol.| volume= 34| pages= 6586}} Twelve years later, E. Léger independently isolated an alkaloid, which he named hordenine, from germinated barley (Hordeum vulgare) seeds.{{cite journal| first= E.| last= Léger | year= 1906| title= Sur l'hordenine: alcaloide nouveau retiré des germes, dits touraillons, de l'orge| language= fr| journal= Compt. Rend.| volume= 142| pages= 108–10}} 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.{{cite journal| first= E.| last= Späth |year= 1919| title= Über die Anhalonium-Alkaloide. I. Anhalin und Mezcalin| language= German| journal= Monatshefte für Chemie| volume= 40| issue= 2 | pages= 129–54| doi= 10.1007/BF01524590 | s2cid= 104408477 }}

Hordenine is present in a fairly wide range of plants, notably amongst the cacti,{{cite web| url= http://www.erowid.org/plants/cacti/cacti_guide/cacti_guide_trichoce.shtml | website= erowid.org| title= Visionary Cactus Guide| publisher= | date= | access-date= January 14, 2021}} but has also been detected in some algae and fungi.{{cite journal| first1= T. A.| last1= Wheaton |first2= I.| last2= Stewart | date= June 1970| journal= Lloydia| title= The distribution of tyramine, N-methyltyramine, hordenine, octopamine, and synephrine in higher plants |pmid= 5495514| volume= 33| issue= 2 | pages= 244–54}}{{cite journal| first= T. A. | last= Smith | year= 1977| title= Phenethylamine and related compounds in plants| journal= Phytochemistry| volume= 16| pages= 9–18| doi= 10.1016/0031-9422(77)83004-5 }}{{cite book |doi=10.1016/S0099-9598(08)60123-6 |title=Chapter 2 β-Phenethylamines and Ephedrines of Plant Origin |series=The Alkaloids: Chemistry and Pharmacology |year=1989 |last1=Lundström |first1=Jan |volume=35 |pages=77–154 |isbn=9780124695351 }} 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.{{cite book |doi=10.1016/S1876-0813(08)60144-X |title=Chapter 22 β-Phenethylamines |series=The Alkaloids: Chemistry and Physiology |year=1953 |last1=Reti |first1=L. |volume=3 |pages=313–338 |isbn=9780124695030 }}

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,{{cite journal| first= W. D.| last= McFarlane |year= 1965| title= Tyrosine derived amines and phenols in wort and beer| journal= Proc. Europ. Brew. Conv.| page= 387}} 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.{{cite thesis |first=Boonthong |last=Poocharoen |year=1983 |title=Determination of selected secondary and tertiary amine alkaloids in barley malt |hdl=1957/27227 |hdl-access=free }} 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{{efn|The level of hordenine in ungerminated barley is negligible, but rises as germination (the first part of the "malting" process) proceeds.}} 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.{{cite journal |last1=Mann |first1=Jay D. |last2=Mudd |first2=S. Harvey |title=Alkaloids and Plant Metabolism |journal=Journal of Biological Chemistry |date=January 1963 |volume=238 |issue=1 |pages=381–385 |doi=10.1016/S0021-9258(19)84008-5 |doi-access=free }} 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.{{cite journal |last1=Lovett |first1=John V. |last2=Hoult |first2=Anne H. C. |last3=Christen |first3=Olaf |title=Biologically active secondary metabolites of barley. IV. Hordenine production by different barley lines |journal=Journal of Chemical Ecology |date=August 1994 |volume=20 |issue=8 |pages=1945–1954 |doi=10.1007/BF02066235 |pmid=24242721 |s2cid=6435423 }}

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.{{cite encyclopedia | url= http://www.genome.jp/kegg/pathway/map/map00350.html | via= genome.jp | title= Tyrosine metabolism - Reference pathway | encyclopedia= Kyoto Encyclopedia of Genes and Genomes | date= | access-date= | archive-date= 2019-07-26 | archive-url= https://web.archive.org/web/20190726082244/http://www.genome.jp/kegg/pathway/map/map00350.html | url-status= dead }}

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).{{cite journal |last1=Kappe |first1=Thomas |last2=Armstrong |first2=Marvin D. |title=Ultraviolet Absorption Spectra and Apparent Acidic Dissociation Constants of Some Phenolic Amines 1 |journal=Journal of Medicinal Chemistry |date=May 1965 |volume=8 |issue=3 |pages=368–374 |doi=10.1021/jm00327a018 |pmid=14323148 }}

Common salts are hordenine hydrochloride,CAS No. 6027-23-2 R-NH₃⁺Cl⁻, m.p. 178 °C, and hordenine sulfate,CAS No. 622-64-0 (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).See, for example:http://www.alibaba.com/showroom/methyl-hordenine-hcl.html

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.

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.{{cite journal |last1=Barger |first1=George |title=CCXXXV.—Synthesis of hordenine, the alkaloid from barley |journal=J. Chem. Soc., Trans. |date=1909 |volume=95 |pages=2193–2197 |doi=10.1039/CT9099502193 |url=https://zenodo.org/record/1429729 }}

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.{{cite journal |last1=Cheng |first1=Chao-Shing |last2=Ferber |first2=Claus |last3=Bashford |first3=Raymond I. |last4=Grillot |first4=Gerald F. |title=A New Synthesis of Hordenine and Other p-Dialkylaminoethylphenols and Some of Their Derivatives |journal=Journal of the American Chemical Society |date=September 1951 |volume=73 |issue=9 |pages=4081–4084 |doi=10.1021/ja01153a008 }}

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.{{cite journal |last1=Digenis |first1=George A. |last2=Burkett |first2=J. W. |last3=Mihranian |first3=V. |title=A convenient synthesis of 2 - [¹⁴C] - hordenine |journal=Journal of Labelled Compounds |date=April 1972 |volume=8 |issue=2 |pages=231–235 |doi=10.1002/jlcr.2590080208 }}

Hordenine labelled with ¹⁴C at the position α- to the N has also been prepared,{{cite journal |last1=Russo |first1=C. A. |last2=Gros |first2=E. G. |title=Synthesis of 4-{{!}}2-(dimethylamino) ethyl-2-¹⁴C{{!}} phenol (hordenine-α-¹⁴C) |journal=Journal of Labelled Compounds and Radiopharmaceuticals |date=August 1981 |volume=18 |issue=8 |pages=1185–1187 |doi=10.1002/jlcr.2580180813 }}

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.

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.L. Camus (1906). "L'hordénine, son degré de toxicité, symptômes de l'intoxication." Compt. Rend. 142 110-113. 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.L. Camus (1906), "Action de sulfate d'hordenine sur circulation." Compt. Rend. 142 237-239.

The cardiovascular and other effects of hordenine were reviewed in detail by Reitschel, writing in 1937.{{cite journal |last1=Rietschel |first1=Hans Georg |title=Zur Pharmakologie des Hordenins |trans-title=On the pharmacology of hordenine |language=de |journal=Naunyn-Schmiedebergs Archiv für experimentelle Pathologie und Pharmakologie |date=1 March 1937 |volume=186 |issue=2 |pages=387–408 |doi=10.1007/BF01929674 |s2cid=37359919 }}

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.{{cite journal |last1=Frank |first1=M. |last2=Weckman |first2=T. J. |last3=Wood |first3=T. |last4=Woods |first4=W. E. |last5=Tai |first5=Chen L. |last6=Chang |first6=Shih-Ling |last7=Ewing |first7=A. |last8=Blake |first8=J. W. |last9=Tobin |first9=T. |title=Hordenine: pharmacology, pharmacokinetics and behavioural effects in the horse |journal=Equine Veterinary Journal |date=November 1990 |volume=22 |issue=6 |pages=437–441 |doi=10.1111/j.2042-3306.1990.tb04312.x |pmid=2269269 |url=https://uknowledge.uky.edu/context/gerc_facpub/article/1093/viewcontent/Hordenine_pharmacology_pharmacokinetics_and_behavioural_effects_in_the_horse_Equine_Veterinary_Journal__November_1990___FRANK__002_.pdf }}

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).{{cite journal |last1=Hapke |first1=HJ |last2=Strathmann |first2=W |title=Pharmakologische Wirkungen des Hordenin |trans-title=Pharmacological effects of hordenine |language=de |journal=Deutsche Tierärztliche Wochenschrift |date=June 1995 |volume=102 |issue=6 |pages=228–232 |pmid=8582256 |oclc=121700602 }}

Hordenine was found to be a selective substrate for MAO-B, from rat liver, with K_m = 479 μM, and V_max = 128 nM/mg protein/h. It was not deaminated by MAO-A from rat intestinal epithelium.{{cite journal |last1=Barwell |first1=C J |last2=Basma |first2=A N |last3=Lafi |first3=M A K |last4=Leake |first4=L D |title=Deamination of hordenine by monoamine oxidase and its action on vasa deferentia of the rat |journal=Journal of Pharmacy and Pharmacology |date=12 April 2011 |volume=41 |issue=6 |pages=421–423 |doi=10.1111/j.2042-7158.1989.tb06492.x |pmid=2570842 |s2cid=10301433 }}

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.

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%.{{cite journal |last1=Yokoo |first1=Y. |last2=Kohda |first2=H. |last3=Kusumoto |first3=A. |last4=Naoki |first4=H. |last5=Matsumoto |first5=N. |last6=Amachi |first6=T. |last7=Suwa |first7=Y. |last8=Fukazawa |first8=H. |last9=Ishida |first9=H. |last10=Tsuji |first10=K. |last11=Nukaya |first11=H. |title=Isolation from beer and structural determination of a potent stimulant of gastrin release. |journal=Alcohol and Alcoholism |date=1 March 1999 |volume=34 |issue=2 |pages=161–168 |doi=10.1093/alcalc/34.2.161 |pmid=10344776 |doi-access=free }}

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.{{cite journal |last1=Bunzow |first1=James R. |last2=Sonders |first2=Mark S. |last3=Arttamangkul |first3=Seksiri |last4=Harrison |first4=Laura M. |last5=Zhang |first5=Ge |last6=Quigley |first6=Denise I. |last7=Darland |first7=Tristan |last8=Suchland |first8=Katherine L. |last9=Pasumamula |first9=Shailaja |last10=Kennedy |first10=James L. |last11=Olson |first11=Susan B. |last12=Magenis |first12=R. Ellen |last13=Amara |first13=Susan G. |last14=Grandy |first14=David K. |title=Amphetamine, 3,4-Methylenedioxymethamphetamine, Lysergic Acid Diethylamide, and Metabolites of the Catecholamine Neurotransmitters Are Agonists of a Rat Trace Amine Receptor |journal=Molecular Pharmacology |date=1 December 2001 |volume=60 |issue=6 |pages=1181–1188 |doi=10.1124/mol.60.6.1181 |pmid=11723224 |s2cid=14140873 }}

LD₅₀ in mice, by intraperitoneal (IP) administration: 299 mg/kg.{{cite journal |last1=Shinoda |first1=Masato |last2=Ohta |first2=Setsuko |last3=Takagi |first3=Yoshinari |title=放射線障害防護薬剤に関する研究(第17報)フェネチラミン系化合物の放射線障害防護効力について |trans-title=Studies on Chemical Protectors against Radiation. XVII. Radioprotective Activities of Phenethylamine Compounds |language=ja |journal=Yakugaku Zasshi |date=1977 |volume=97 |issue=10 |pages=1117–1124 |doi=10.1248/yakushi1947.97.10_1117 |pmid=592104 |doi-access=free }} Other LD₅₀ values given in the literature are: >100 mg/kg (mouse; IP),{{cite journal |last1=Batista |first1=Leonia Maria |last2=Almeida |first2=R. Nobrega de |title=Central effects of the constituents of Mimosa opthalmocentra Mart. ex Benth |journal=Acta Farmaceutica Bonaerense |volume=16 |issue=2 |year=1997 |pages=83–86 |url=http://www.acuedi.org/ddata/7053.pdf}} as HCl salt: 113.5 mg/kg (mouse; route of administration unspecified){{cite book| title= Merck Index| edition= 10th | year= 1983| page= 687| place= Rahway, New Jersey| publisher= Merck & Co.}} 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 evinced by hordenine.{{cite journal |last1=Bourke |first1=Ca |last2=Carrigan |first2=Mj |last3=Dixon |first3=Rj |title=Experimental evidence that tryptamine alkaloids do not cause Phalaris aquatica sudden death syndrome in sheep |journal=Australian Veterinary Journal |date=July 1988 |volume=65 |issue=7 |pages=218–220 |doi=10.1111/j.1751-0813.1988.tb14462.x |pmid=3421887 }}

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.{{cite journal |last1=Poocharoen |first1=Boonthong. |last2=Barbour |first2=James F. |last3=Libbey |first3=Leonard M. |last4=Scanlan |first4=Richard A. |title=Precursors of N-nitrosodimethylamine in malted barley. 1. Determination of hordenine and gramine |journal=Journal of Agricultural and Food Chemistry |date=November 1992 |volume=40 |issue=11 |pages=2216–2221 |doi=10.1021/jf00023a033 }}

The pharmacokinetics of hordenine have been studied in horses. After IV administration of the drug, the α-phase T_1/2 was found to be about 3 mins., and the β-phase T_1/2 was about 35 mins.

Hordenine has been found to act as a feeding deterrent to grasshoppers (Melanoplus bivittatus),{{cite journal |last1=Harley |first1=K. L. S. |last2=Thorsteinson |first2=A. J. |title=The influence of plant chemicals on the feeding behavior, development, and survival of the two-striped grasshopper, Melanoplus bivittatus (Say), Acrididae: Orthoptera |journal=Canadian Journal of Zoology |date=1 May 1967 |volume=45 |issue=3 |pages=305–319 |doi=10.1139/z67-043 }} 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.{{cite journal |last1=Bernays |first1=E. A. |last2=Oppenheim |first2=S. |last3=Chapman |first3=R. F. |last4=Kwon |first4=H. |last5=Gould |first5=F. |title=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 |journal=Journal of Chemical Ecology |date=1 February 2000 |volume=26 |issue=2 |pages=547–563 |doi=10.1023/A:1005430010314 |s2cid=5695174 }}

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.{{cite journal |last1=Liu |first1=D. L. |last2=Lovett |first2=J. V. |title=Biologically active secondary metabolites of barley. II. Phytotoxicity of barley allelochemicals |journal=Journal of Chemical Ecology |date=October 1993 |volume=19 |issue=10 |pages=2231–2244 |doi=10.1007/BF00979660 |pmid=24248572 |s2cid=8193525 }}

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