N-Methyltyramine

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N-Methyltyramine
Methyltyramine.svg
N-Methyltyramine.png
Names
Preferred IUPAC name
4-[2-(Methylamino)ethyl]phenol
Other names
Methyl-4-tyramine; 4-Hydroxy-N-methylphenethylamine; p-(2-Methylaminoethyl)phenol
Identifiers
3D model (JSmol)
ChEBI
ChemSpider
ECHA InfoCard 100.006.120 OOjs UI icon edit-ltr-progressive.svg
PubChem CID
UNII
  • InChI=1S/C9H13NO/c1-10-7-6-8-2-4-9(11)5-3-8/h2-5,10-11H,6-7H2,1H3 Yes check.svgY
    Key: AXVZFRBSCNEKPQ-UHFFFAOYSA-N Yes check.svgY
  • InChI=1/C9H13NO/c1-10-7-6-8-2-4-9(11)5-3-8/h2-5,10-11H,6-7H2,1H3
    Key: AXVZFRBSCNEKPQ-UHFFFAOYAV
  • Oc1ccc(cc1)CCNC
Properties
C9H13NO
Molar mass 151.209 g·mol−1
Appearancecolorless crystalline solid
Density 1.03 g/mL
Melting point 130 to 131 °C (266 to 268 °F; 403 to 404 K)
Boiling point 271 °C (520 °F; 544 K) (183-185 °C at 9mm; 135 °C at 0.05 mm)
moderately soluble in water
Hazards
Flash point 120 °C (248 °F; 393 K)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
X mark.svgN  verify  (what is  Yes check.svgYX mark.svgN ?)

N-Methyltyramine (NMT), also known as 4-hydroxy-N-methylphenethylamine, is a human trace amine [1] [2] and natural phenethylamine alkaloid found in a variety of plants. [3] As the name implies, it is the N-methyl analog of tyramine, which is a well-known biogenic trace amine with which NMT shares many pharmacological properties. Biosynthetically, NMT is produced by the N-methylation of tyramine via the action of the enzyme phenylethanolamine N-methyltransferase in humans [1] [2] and tyramine N-methyltransferase in plants. [4]

Contents

Occurrence

N-methyltyramine seems to be quite widely distributed in plants. [3] [5]

NMT was isolated as a natural product for the first time, from germinating barley roots, by Kirkwood and Marion in 1950. These chemists found that 600 g of barley, after germination and 10-day growth, yielded 168 mg of N-methyltyramine. [6] 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 NMT. Citing a 1965 study by McFarlane, [7] Poocharoen reported that beer contained ~ 5–8 mg/L of NMT. [8] The NMT 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 NMT in raw barley [9] of ~ 5 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 ~ 27 μg/g. When only green malt roots were examined, their mean content of NMT was ~ 1530 μg/g, whereas the mean level in kilned malt roots was ~ 1960 μg/g. [8]

Studies of Acacia species have shown the presence of significant levels of NMT in their leaves: ~ 240-1240 ppm (or μg/g) in A. rigidula [10] and ~ 190-750 ppm in A. berlandieri . [11] The seeds of A. schweinfurthii yielded 440 μg/g of NMT. [12]

NMT is found in bitter orange, Citrus aurantium, and a concentration of ~ 180 μg/g has been reported from an extract made from the ripe fruit, although the method by which this extract was prepared is not very clearly described. [13]

Chemistry

Synthesis

NMT has been synthesized in a number of ways. One of the earliest syntheses is that reported by Walpole, who made it by the following sequence of steps: (i) acetylation of 4-methoxyphenethylamine with acetic anhydride; (ii) methylation of the amide using Na/methyl iodide; (iii) cleavage of the methyl ether to the phenol using HI; (iv) hydrolysis of the N-acetyl group with aqueous HCl. Walpole also described an alternative, but similar sequence of reactions leading to NMT, beginning with the conversion of 4-methoxyphenethylamine to its benzenesulfonamide, which was then N-methylated and de-protected. [15]

A different method for making NMT was given by Corti, who prepared it by the thermal decarboxylation of N-methyltyrosine (ratanhin), by heating the amino-acid in fluorene at 250 °C. Although N-methyltyrosine occurs naturally, it was made by the methylation of tyrosine using dimethyl sulfate. [16]

NMT was also made by Kirkwood and Marion starting from 4-methoxyphenethylamine, but this was first converted to the imine with benzaldehyde, followed by methylation with dimethyl sulfate; the product was converted to N-methyl-4-methoxyphenethylamine, and finally de-O-methylated with HBr to give N-methyltyramine. [6]

Common Salts

N-methyltyramine hydrochloride, C9H13NO.HCl: m.p. 148.5 °C; highly soluble in water and in ethanol. [15]

N-methyltyramine hydrogen oxalate, C9H13NO.C2H2O4: m.p. 250 °C; very poorly soluble in water. [15]

Basicity

The apparent (see original article for discussion) pKas for protonated N-methyltyramine are 9.76 (phenolic H) and 10.71 (ammonium H). [17]

Pharmacology

NMT is a pressor, with a potency of 1/140 × epinephrine. [18] On the basis of experiments using dogs, Hjort described NMT as a "very good pressor agent": a blood pressure rise of >130 mm and ~ 5 minutes duration was produced by the injection of 1-2.5 μM of solutions of the HCl salt into dogs weighing ~ 10 kg. [19] A pressor response, which was inhibited by pre-treatment with reserpine, to the administration of NMT to goats was reported by Camp. [20]

Subcutaneous administration of 10 mg/kg of the HCl salt of NMT to mice enhanced the release of norepinephrine (NE) from the heart by 36% over control, measured after 2 hours. For comparison, the same dose of tyramine hydrochloride caused a release of NE of 50% over control in this assay. [21] A qualitatively similar decrease in the NE content of rat heart after treatment with NMT was observed by Camp. [20]

Without giving many experimental details, Evans et al. reported that NMT increased blood pressure in rats, inhibited electrically-induced contractions of the guinea-pig ileum, relaxed acetylcholine-stimulated tone of isolated guinea-pig trachealis muscle, and increased the rate and contractile force of isolated guinea-pig atrium. The effect on blood pressure was competitively-antagonized by guanethidine, while the effects on the isolated atrium were inhibited by desipramine. Although doses were not given, NMT was described as being equipotent with tyramine on all tissues. It was also noted that the handling of NMT caused migraine headaches in one of the researchers. [12]

NMT has been found to be a potent stimulant of gastrin release in the rat, with an [[ED50]] of ~ 10 μg/kg. [22] These researchers used a bio-assay-guided isolation procedure to show that NMT was the constituent of beer that was responsible for producing enhanced gastrin release, which in turn raises gastric acid secretion. For comparative purposes, they also tested tyramine and N,N-dimethyltyramine (hordenine) in their assay, finding that 83 nM/kg (corresponding to 12.5 μg/kg of NMT) of each compound enhanced gastrin release by ~ 58% for NMT, ~ 24% for tyramine, and ~ 60% for hordenine.

In order to test the indications from earlier studies that, like tyramine itself, NMT produced most of its pharmacological effects by stimulating norepinephrine (NE) release, Koda and co-workers investigated the action of NMT on α2 adrenoceptors, which are involved in the regulation of NE. These researchers found that NMT competed with the binding of [3H]-p-aminoclonidine to α2 receptors from rat brain with an IC50 of ~5.5 x 10−6M. In common with other α2 antagonists, NMT, at i.p. doses of 20 or 100 mg/kg, was also found to inhibit the hypermotility induced in mice by (−)-scopolamine in a dose-dependent manner. The same doses of NMT in the absence of scopolamine had no significant effects on locomotor activity in mice. [23]

Since NMT is one of the constituents of bitter orange, Citrus aurantium , Mercader and co-workers studied its effects on lipolysis, finding that it inhibited lipolysis in rats. NMT (in common with tyramine) also failed to stimulate lipolysis in human adipocytes at a concentration of 10 μg/mL (i.e. ~ 66 μM/L); even at ≥ 100 μg/mL, NMT and tyramine induced only 20% of the lipolysis produced by the reference standard drug, isoprenaline. [24]

NMT is a competitive substrate for MAO. [25]

It is known to be a stimulator of pancreatic secretions in rats. [26]

NMT has been shown to be an agonist of the TAAR1, similarly to its parent compound tyramine. [27] The EC50 of NMT on the human TAAR1 receptor was ~ 2 μM, compared to ~ 1 μM for tyramine. [28]

Pharmacokinetics

The pharmacokinetics of NMT have been studied in rabbits and mice using drug that had been radiolabeled with tritium at C-3 and C-5 on the benzene ring. Plasma concentrations were measured in the rabbits, whereas distribution, metabolism and excretion were determined in the mice. After i.v. administration to rabbits, the α-phase T1/2 was found to be 0.3 minutes, and the β-phase T1/2 was 5.6 minutes. These figures were indicative of a rapid distribution from blood to tissue and a very short plasma half-life. Within 2 minutes of injection, significant levels of radioactivity were detected in all tissues examined, with the highest amounts being in kidney and liver. No detectable radioactivity was left in the plasma after 30 minutes. Some NMT was found in the brains of mice treated with the drug, indicating that a small amount did cross the blood–brain barrier. ~ 80% of the administered dose was recovered from the urine of mice within 1 hour. [29]

Toxicology

LD50 of HCl salt of NMT (mouse; i.p.) = 227 mg/kg. [18] Another acute toxicity study of NMT (under the Sterling-Winthrop company code "WIN 5582") found it to have an LD50 = 275 mg/kg, after intravenous administration to mice. [30]

See also

Related Research Articles

<span class="mw-page-title-main">Monoamine neurotransmitter</span> Monoamine that acts as a neurotransmitter or neuromodulator

Monoamine neurotransmitters are neurotransmitters and neuromodulators that contain one amino group connected to an aromatic ring by a two-carbon chain (such as -CH2-CH2-). Examples are dopamine, norepinephrine and serotonin.

<span class="mw-page-title-main">Phenethylamine</span> Organic compound, a stimulant in humans

Phenethylamine (PEA) is an organic compound, natural monoamine alkaloid, and trace amine, which acts as a central nervous system stimulant in humans. In the brain, phenethylamine regulates monoamine neurotransmission by binding to trace amine-associated receptor 1 (TAAR1) and inhibiting vesicular monoamine transporter 2 (VMAT2) in monoamine neurons. To a lesser extent, it also acts as a neurotransmitter in the human central nervous system. In mammals, phenethylamine is produced from the amino acid L-phenylalanine by the enzyme aromatic L-amino acid decarboxylase via enzymatic decarboxylation. In addition to its presence in mammals, phenethylamine is found in many other organisms and foods, such as chocolate, especially after microbial fermentation.

A biogenic amine is a biogenic substance with one or more amine groups. They are basic nitrogenous compounds formed mainly by decarboxylation of amino acids or by amination and transamination of aldehydes and ketones. Biogenic amines are organic bases with low molecular weight and are synthesized by microbial, vegetable and animal metabolisms. In food and beverages they are formed by the enzymes of raw material or are generated by microbial decarboxylation of amino acids.

<span class="mw-page-title-main">Tyramine</span> Chemical compound

Tyramine, also known under several other names, is a naturally occurring trace amine derived from the amino acid tyrosine. Tyramine acts as a catecholamine releasing agent. Notably, it is unable to cross the blood-brain barrier, resulting in only non-psychoactive peripheral sympathomimetic effects following ingestion. A hypertensive crisis can result, however, from ingestion of tyramine-rich foods in conjunction with the use of monoamine oxidase inhibitors (MAOIs).

<span class="mw-page-title-main">Synephrine</span> Chemical compound

Synephrine, or, more specifically, p-synephrine, is an alkaloid, occurring naturally in some plants and animals, and also in approved drugs products as its m-substituted analog known as neo-synephrine. p-Synephrine and m-synephrine are known for their longer acting adrenergic effects compared to epinephrine and norepinephrine. This substance is present at very low concentrations in common foodstuffs such as orange juice and other orange products, both of the "sweet" and "bitter" variety. The preparations used in traditional Chinese medicine (TCM), also known as Zhi Shi (枳实), are the immature and dried whole oranges from Citrus aurantium. Extracts of the same material or purified synephrine are also marketed in the US, sometimes in combination with caffeine, as a weight-loss-promoting dietary supplement for oral consumption. While the traditional preparations have been in use for millennia as a component of TCM-formulas, synephrine itself is not an approved over the counter drug. As a pharmaceutical, m-synephrine (phenylephrine) is still used as a sympathomimetic, mostly by injection for the treatment of emergencies such as shock, and rarely orally for the treatment of bronchial problems associated with asthma and hay-fever.

<span class="mw-page-title-main">Hordenine</span> Chemical compound

Hordenine 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. 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. As of September 2012, 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, 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.

<span class="mw-page-title-main">Trace amine</span> Amine receptors in the mammalian brain

Trace amines are an endogenous group of trace amine-associated receptor 1 (TAAR1) agonists – and hence, monoaminergic neuromodulators – that are structurally and metabolically related to classical monoamine neurotransmitters. Compared to the classical monoamines, they are present in trace concentrations. They are distributed heterogeneously throughout the mammalian brain and peripheral nervous tissues and exhibit high rates of metabolism. Although they can be synthesized within parent monoamine neurotransmitter systems, there is evidence that suggests that some of them may comprise their own independent neurotransmitter systems.

<span class="mw-page-title-main">Methyllycaconitine</span> Chemical compound

Methyllycaconitine (MLA) is a diterpenoid alkaloid found in many species of Delphinium (larkspurs). In common with many other diterpenoid alkaloids, it is toxic to animals, although the acute toxicity varies with species. Early research was focused on identifying, and characterizing the properties of methyllycaconitine as one of the principal toxins in larkspurs responsible for livestock poisoning in the mountain rangelands of North America. Methyllycaconitine has been explored as a possible therapeutic agent for the treatment of spastic paralysis, and it has been shown to have insecticidal properties. Most recently, it has become an important molecular probe for studying the pharmacology of the nicotinic acetylcholine receptor.

β-Methylphenethylamine Chemical compound

β-Methylphenethylamine is an organic compound of the phenethylamine class, and a positional isomer of the drug amphetamine, with which it shares some properties. In particular, both amphetamine and β-methylphenethylamine are human TAAR1 agonists. In appearance, it is a colorless or yellowish liquid.

<i>Senegalia berlandieri</i> Species of plant

Senegalia berlandieri is a shrub native to the Southwestern United States and northeast Mexico that belongs to the Mimosoid clade of Fabaceae. It grows 1 to 5 metres tall, with blossoms that are spherical and white, occurring from February through April. The berlandieri epithet comes from the name of Jean-Louis Berlandier, a French naturalist who studied wildlife native to Texas and Mexico. S. berlandieri contains a wide variety of alkaloids and has been known to cause toxic reactions in domestic animals such as goats.

<i>N</i>-Methylphenethylamine Chemical compound

N-Methylphenethylamine (NMPEA) is a naturally occurring trace amine neuromodulator in humans that is derived from the trace amine, phenethylamine (PEA). It has been detected in human urine and is produced by phenylethanolamine N-methyltransferase with phenethylamine as a substrate, which significantly increases PEA's effects. PEA breaks down into phenylacetaldehyde which is further broken down into phenylacetic acid by monoamine oxidase. When this is inhibited by monoamine oxidase inhibitors, it allows more of the PEA to be metabolized into nymphetamine (NMPEA) and not wasted on the weaker inactive metabolites.

<span class="mw-page-title-main">Methedrone</span> Chemical compound of the cathinone class

Methedrone is a recreational drug of the cathinone chemical class. Chemically, methedrone is closely related to para-methoxymethamphetamine (PMMA), methylone and mephedrone. Methedrone received media attention in 2009 after the death of two young Swedish men. In both cases toxicology analysis showed methedrone was the only drug present in both men during the time of their overdose and subsequent deaths.

<span class="mw-page-title-main">Monoamine oxidase B</span> Protein-coding gene in the species Homo sapiens

Monoamine oxidase B, also known as MAO-B, is an enzyme that in humans is encoded by the MAOB gene.

<span class="mw-page-title-main">TAAR1</span> Protein-coding gene in the species Homo sapiens

Trace amine-associated receptor 1 (TAAR1) is a trace amine-associated receptor (TAAR) protein that in humans is encoded by the TAAR1 gene. TAAR1 is an intracellular amine-activated Gs-coupled and Gq-coupled G protein-coupled receptor (GPCR) that is primarily expressed in several peripheral organs and cells, astrocytes, and in the intracellular milieu within the presynaptic plasma membrane of monoamine neurons in the central nervous system (CNS). TAAR1 was discovered in 2001 by two independent groups of investigators, Borowski et al. and Bunzow et al. TAAR1 is one of six functional human trace amine-associated receptors, which are so named for their ability to bind endogenous amines that occur in tissues at trace concentrations. TAAR1 plays a significant role in regulating neurotransmission in dopamine, norepinephrine, and serotonin neurons in the CNS; it also affects immune system and neuroimmune system function through different mechanisms.

<span class="mw-page-title-main">Deoxyepinephrine</span> Chemical compound

Deoxyepinephrine, also known by the common names N-methyldopamine and epinine, is an organic compound and natural product that is structurally related to the important neurotransmitters dopamine and epinephrine. All three of these compounds also belong to the catecholamine family. The pharmacology of epinine largely resembles that of its "parent", dopamine. Epinine has been found in plants, insects and animals. It is also of significance as the active metabolic breakdown product of the prodrug ibopamine, which has been used to treat congestive heart failure.

<span class="mw-page-title-main">Pempidine</span> Chemical compound

Pempidine is a ganglion-blocking drug, first reported in 1958 by two research groups working independently, and introduced as an oral treatment for hypertension.

<span class="mw-page-title-main">Phenylethanolamine</span> Chemical compound

Phenylethanolamine, or β-hydroxyphenethylamine, is a trace amine with a structure similar to those of other trace phenethylamines as well as the catecholamine neurotransmitters dopamine, norepinephrine, and epinephrine. As an organic compound, phenylethanolamine is a β-hydroxylated phenethylamine that is also structurally related to a number of synthetic drugs in the substituted phenethylamine class. In common with these compounds, phenylethanolamine has strong cardiovascular activity and, under the name Apophedrin, has been used as a drug to produce topical vasoconstriction.

<span class="mw-page-title-main">Candicine</span> Chemical compound

Candicine is a naturally occurring organic compound that is a quaternary ammonium salt with a phenethylamine skeleton. It is the N,N,N-trimethyl derivative of the well-known biogenic amine tyramine, and, being a natural product with a positively charged nitrogen atom in its molecular structure, it is classed as an alkaloid. Although it is found in a variety of plants, including barley, its properties have not been extensively studied with modern techniques. Candicine is toxic after parenteral administration, producing symptoms of neuromuscular blockade; further details are given in the "Pharmacology" section below.

<i>N</i>,<i>N</i>-Dimethyldopamine Chemical compound

N,N-Dimethyldopamine (DMDA) is an organic compound belonging to the phenethylamine family. It is related structurally to the alkaloid epinine (N-methyldopamine) and to the major neurotransmitter dopamine (of which it is the N,N-dimethylated analog). Because of its structural relationship to dopamine, DMDA has been the subject of a number of pharmacological investigations. DMDA has been detected in Acacia rigidula.

<span class="mw-page-title-main">Halostachine</span> Alkaloid

Halostachine is a natural product, an alkaloid first isolated from the Asian shrub Halostachys caspica, and structurally a β-hydroxy-phenethylamine related to its better-known "parent" biogenic amine, phenylethanolamine, to the adrenergic drug synephrine, and to the alkaloid ephedrine. The pharmacological properties of halostachine have some similarity to those of these structurally-related compounds, and Halostachys caspica extracts have been included as a constituent of certain OTC dietary supplements, but halostachine has never been developed as a prescription drug. Although it is found in nature as a single stereoisomer, halostachine is more commonly available as a synthetic product in the form of its racemate. In appearance it is a colorless solid.

References

  1. 1 2 3 4 Broadley KJ (March 2010). "The vascular effects of trace amines and amphetamines". Pharmacology & Therapeutics. 125 (3): 363–375. doi:10.1016/j.pharmthera.2009.11.005. PMID   19948186.
  2. 1 2 3 4 Lindemann L, Hoener MC (May 2005). "A renaissance in trace amines inspired by a novel GPCR family". Trends in Pharmacological Sciences. 26 (5): 274–281. doi:10.1016/j.tips.2005.03.007. PMID   15860375.
  3. 1 2 T. A. Smith (1977). "Phenethylamine and related compounds in plants." Phytochemistry16 9 – 18.
  4. ↑ Tyrosine metabolism - Reference pathway Archived 2019-07-26 at the Wayback Machine , Kyoto Encyclopedia of Genes and Genomes (KEGG)
  5. ↑ T. A. Stewart and I. Stewart (1970) Lloydia33 244-254.
  6. 1 2 S. Kirkwood and L. Marion (1950) J. Am. Chem. Soc.72 2522-2524.
  7. ↑ W. D. McFarlane (1965). "Tyrosine derived amines and phenols in wort and beer." Proc. Europ. Brew. Conv. 387.
  8. 1 2 B. Poocharoen (1983), Ph. D. Thesis, Oregon State University. http://ir.library.oregonstate.edu/xmlui/handle/1957/27227
  9. ↑ The level of NMT in ungerminated barley is generally negligible, but rises as germination (the first part of the "malting" process) proceeds.
  10. ↑ B. A. Clement, C. M. Goff and T. D. A. Forbes (1998). "Toxic amines and alkaloids from Acacia rigidula." Phytochemistry49 1377-1380.
  11. ↑ B. A. Clement, C. M. Goff and T. D. A. Forbes (1997) Phytochemistry46 249-254.
  12. 1 2 C. S. Evans, E. A. Bell and E. S. Johnson (1979) Phytochemistry18 2022-2023.
  13. ↑ B. C. Nelson et al. (2007) J. Agric. Fd. Chem.55 9769-9775.
  14. ↑ Wang X, Li J, Dong G, Yue J (February 2014). "The endogenous substrates of brain CYP2D". European Journal of Pharmacology. 724: 211–218. doi:10.1016/j.ejphar.2013.12.025. PMID   24374199.
  15. 1 2 3 G. S. Walpole (1910) J. Chem. Soc., Trans.97 941-999.
  16. ↑ U. A. Corti (1949) Helv. Chim. Acta32 681-686.
  17. ↑ T. Kappe and M. D. Armstrong (1965) J. Med. Chem.8 368-374.
  18. 1 2 W. H. Hartung (1945) Ind. Eng. Chem.37 126-137.
  19. ↑ A. J. Hjort (1934) J. Pharmacol. Exp. Ther.101-112.
  20. 1 2 B. J. Camp (1970) Am. J. Vet. Res.31 755-762.
  21. ↑ J. W. Daly, C. R. Creveling and B. Witkop (1966) J. Med. Chem.9 273-280.
  22. ↑ Y. Yokoo et al. (1999) Alcohol & Alcoholism34 161-168. http://alcalc.oxfordjournals.org/content/34/2/161.full.pdf+html
  23. ↑ H. Koda et al. (1999) Jpn. J. Pharmacol.81 313-315.
  24. ↑ J. Mercader, E. Wanecq, J. Chen and C. Carpene (2011) J. Physiol. Biochem.67 443-452.
  25. ↑ W. Kemmerling (1996) Z. Naturforsch. C51 59-64.
  26. ↑ Tsutsumi, E.; Kanai, S.; Ohta, M.; Suwa, Y.; Miyasaka, K., Eri; Kanai, Setsuko; Ohta, Minoru; Suwa, Yoshihide; Miyasaka, Kyoko (2010). "Stimulatory effect of N-methyltyramine, a congener of beer, on pancreatic secretion in conscious rats". Alcoholism: Clinical and Experimental Research. 34 (Suppl 1): S14–S17. doi:10.1111/j.1530-0277.2009.00893.x. PMID   19298333.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  27. ↑ Lindemann, L.; Hoener, M. C. (2005). "A renaissance in trace amines inspired by a novel GPCR family". Trends in Pharmacological Sciences. 26 (5): 274–281. doi:10.1016/j.tips.2005.03.007. PMID   15860375.
  28. ↑ L. Lindemann et al. (2005) Genomics85 372-385.
  29. ↑ H. Hai, Z.-G. Guo and J.-M. Wang (1989) Zhougguo Yao Li Xue Bao (Acta Pharmacologica Sinica)10 41-45. http://www.chinaphar.com/1671-4083/10/41.pdf
  30. ↑ A. M. Lands and J. I. Grant (1952). "The vasopressor action and toxicity of cyclohexylethylamine derivatives." J. Pharmacol. Exp. Ther.106 341-345.
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