N-Methyltyramine

Last updated

N-Methyltyramine
Methyltyramine.svg
N-Methyltyramine.png
Clinical data
Other namesMethyl-4-tyramine; 4-Hydroxy-N-methylphenethylamine; p-(2-Methylaminoethyl)phenol
Identifiers
  • 4-[2-(methylamino)ethyl]phenol
CAS Number
PubChem CID
ChemSpider
UNII
ChEBI
CompTox Dashboard (EPA)
ECHA InfoCard 100.006.120 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C9H13NO
Molar mass 151.209 g·mol−1
3D model (JSmol)
Density 1.03 g/cm3
Melting point 130 to 131 °C (266 to 268 °F)
Boiling point 271 °C (520 °F) (183-185 °C at 9mm; 135 °C at 0.05 mm)
Solubility in water Moderate mg/mL (20 °C)
  • Oc1ccc(cc1)CCNC
  • 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
 X mark.svgNYes check.svgY  (what is this?)    (verify)

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]

Biosynthetic pathways for catecholamines and trace amines in the human brain [1] [2] [14]
Catecholamine and trace amine biosynthesis.svg
Interactive icon.svg
N-Methyltyramine is produced from para-tyramine by phenylethanolamine N-methyltransferase (PNMT) in the human brain. [1] [2]

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

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 Smith TA (January 1977). "Phenethylamine and related compounds in plants". Phytochemistry. 16 (1): 9–18. Bibcode:1977PChem..16....9S. doi:10.1016/0031-9422(77)83004-5.
  4. ↑ Tyrosine metabolism - Reference pathway Archived 2019-07-26 at the Wayback Machine , Kyoto Encyclopedia of Genes and Genomes (KEGG)
  5. ↑ Wheaton TA, Stewart I (June 1970). "The distribution of tyramine, N-methyltyramine, hordenine, octopamine, and synephrine in higher plants". Lloydia. 33 (2): 244–254. PMID   5495514.
  6. 1 2 Kirkwood S, Marion L (June 1950). "The Biogenesis of Alkaloids. I. The Isolation of N-Methyltyramine from Barley". Journal of the American Chemical Society. 72 (6): 2522–2524. Bibcode:1950JAChS..72.2522K. doi:10.1021/ja01162a050.
  7. ↑ McFarlane WD (1965). "Tyrosine derived amines and phenols in wort and beer". Proceedings, European Brewery Convention. Tenth Congress: 387–395.
  8. 1 2 Poocharoen B (1983). Determination of selected secondary and tertiary amine alkaloids in barley malt (Ph.D. thesis). Oregon State University.
  9. ↑ The level of NMT in ungerminated barley is generally negligible, but rises as germination (the first part of the "malting" process) proceeds.
  10. ↑ Clement BA, Goff CM, Forbes TD (November 1998). "Toxic amines and alkaloids from Acacia rigidula". Phytochemistry. 49 (5): 1377–1380. Bibcode:1998PChem..49.1377C. doi:10.1016/S0031-9422(97)01022-4.
  11. ↑ Clement BA, Goff CM, Forbes TD (September 1997). "Toxic amines and alkaloids from Acacia berlandieri". Phytochemistry. 46 (2): 249–254. Bibcode:1997PChem..46..249C. doi:10.1016/S0031-9422(97)00240-9.
  12. 1 2 Evans CS, Bell EA, Johnson ES (January 1979). "N-methyltyramine, a biologically active amine in Acacia seeds". Phytochemistry. 18 (12): 2022–2023. Bibcode:1979PChem..18.2022E. doi:10.1016/S0031-9422(00)82727-2.
  13. ↑ Nelson BC, Putzbach K, Sharpless KE, Sander LC (November 2007). "Mass spectrometric determination of the predominant adrenergic protoalkaloids in bitter orange (Citrus aurantium)". Journal of Agricultural and Food Chemistry. 55 (24): 9769–9775. Bibcode:2007JAFC...55.9769N. doi:10.1021/jf072030s. PMID   17966980.
  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 Walpole GS (1910). "Syntheses of p-hydroxyphenethylalkylamines". Journal of the Chemical Society, Transactions. 97: 941–999. doi:10.1039/CT9109700941.
  16. ↑ Corti UA (1949). "Über Ergebnisse der Methylierung von Tyrosin mit Dimethylsulfat und einige Derivate des N-Methyltyramins". Helvetica Chimica Acta. 32 (3): 681–686. Bibcode:1949HChAc..32..681C. doi:10.1002/hlca.19490320309.
  17. ↑ Kappe T, Armstrong MD (May 1965). "Ultraviolet Absorption Spectra and Apparent Acidic Dissociation Constants of Some Phenolic Amines". Journal of Medicinal Chemistry. 8 (3): 368–374. doi:10.1021/jm00327a018. PMID   14323148.
  18. 1 2 Hartung WH (February 1945). "Beta-Phenethylamine Derivatives". Industrial & Engineering Chemistry. 37 (2): 126–137. doi:10.1021/ie50422a007.
  19. ↑ Hjort AM (September 1934). "Some Physiological Properties of Certain N-Methylated-Β-Phenylethylamines". The Journal of Pharmacology and Experimental Therapeutics. 52 (1): 101–112. doi:10.1016/S0022-3565(25)03391-9.
  20. 1 2 Camp BJ (April 1970). "Action of N-methyltyramine and N-methyl beta-phenylethylamine on certain biological systems" . American Journal of Veterinary Research. 31 (4): 755–62. doi:10.2460/ajvr.1970.31.04.755. PMID   5437111.
  21. ↑ Daly JW, Creveling CR, Witkop B (May 1966). "The chemorelease of norepinephrine from mouse hearts. Structure-activity relationships. I. Sympathomimetic and related amines". Journal of Medicinal Chemistry. 9 (3): 273–80. doi:10.1021/jm00321a001. PMID   5960887.
  22. ↑ Yokoo Y, Kohda H, Kusumoto A, Naoki H, Matsumoto N, Amachi T, et al. (1999). "Isolation from beer and structural determination of a potent stimulant of gastrin release". Alcohol and Alcoholism. 34 (2). Oxford, Oxfordshire: 161–8. doi:10.1093/alcalc/34.2.161. PMID   10344776.
  23. ↑ Koda H, Yokoo Y, Matsumoto N, Suwa Y, Fukazawa H, Ishida H, et al. (November 1999). "Antagonistic effect of N-methyltyramine on alpha2-adrenoceptor in mice". Japanese Journal of Pharmacology. 81 (3): 313–5. doi: 10.1254/jjp.81.313 . PMID   10622222.
  24. ↑ Mercader J, Wanecq E, Chen J, Carpéné C (September 2011). "Isopropylnorsynephrine is a stronger lipolytic agent in human adipocytes than synephrine and other amines present in Citrus aurantium". Journal of Physiology and Biochemistry. 67 (3): 443–452. doi:10.1007/s13105-011-0078-2. PMID   21336650.
  25. ↑ Kemmerling W (1996). "Toxicity of Palicourea marcgravii: combined effects of fluoroacetate, N-methyltyramine and 2-methyltetrahydro-beta-carboline". Zeitschrift für Naturforschung C. 51 (1–2): 59–64. doi: 10.1515/znc-1996-1-211 . PMID   8721213.
  26. ↑ Tsutsumi E, Kanai S, Ohta M, Suwa Y, Miyasaka K (February 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.
  27. ↑ 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.
  28. ↑ Lindemann L, Ebeling M, Kratochwil NA, Bunzow JR, Grandy DK, Hoener MC (March 2005). "Trace amine-associated receptors form structurally and functionally distinct subfamilies of novel G protein-coupled receptors". Genomics. 85 (3): 372–385. doi:10.1016/j.ygeno.2004.11.010. PMID   15718104.
  29. ↑ Hai H, Guo ZG, Wang JM (1989). "Disposition of N-methyl-tyramine in rabbits and mice" (PDF). Zhougguo Yao Li Xue Bao[Acta Pharmacologica Sinica]. 10: 41–45.
  30. ↑ Lands AM, Grant JI (November 1952). "The vasopressor action and toxicity of cyclohexylethylamine derivatives" . The Journal of Pharmacology and Experimental Therapeutics. 106 (3): 341–345. doi:10.1016/S0022-3565(25)05104-3. PMID   13000630.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.