N-methyltyramine seems to be quite widely distributed in plants.[3][5]
NMT was isolated as anatural product for the first time, from germinatingbarley 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 tomalt, is used extensively in the production ofbeer, 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 ofAcacia species have shown the presence of significant levels of NMT in their leaves: ~ 240-1240 ppm (or μg/g) inA. rigidula[10] and ~ 190-750 ppm inA. berlandieri.[11] The seeds ofA. schweinfurthii yielded 440 μg/g of NMT.[12]
NMT is found inbitter 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]
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 of4-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 ofN-methyltyrosine (ratanhin), by heating the amino-acid influorene at 250 °C. Although N-methyltyrosine occurs naturally, it was made by the methylation oftyrosine using dimethyl sulfate.[16]
NMT was also made by Kirkwood and Marion starting from 4-methoxyphenethylamine, but this was first converted to theimine with benzaldehyde, followed by methylation withdimethyl sulfate; the product was converted to N-methyl-4-methoxyphenethylamine, and finally de-O-methylated with HBr to give N-methyltyramine.[6]
NMT is apressor, 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 withreserpine, 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 ofnorepinephrine (NE) from the heart by 36% over control, measured after 2 hours. For comparison, the same dose oftyramine 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, relaxedacetylcholine-stimulated tone of isolated guinea-pigtrachealis muscle, and increased the rate and contractile force of isolated guinea-pig atrium. The effect on blood pressure was competitively-antagonized byguanethidine, while the effects on the isolated atrium were inhibited bydesipramine. 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 causedmigraine headaches in one of the researchers.[12]
NMT has been found to be a potent stimulant ofgastrin 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 raisesgastric 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 stimulatingnorepinephrine (NE) release, Koda and co-workers investigated the action of NMT on α2adrenoceptors, 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 thehypermotility induced in mice by (−)-scopolamine in a dose-dependent manner. The same doses of NMT in the absence of scopolamine had no significant effects onlocomotor activity in mice.[23]
Since NMT is one of the constituents of bitter orange,Citrus aurantium, Mercader and co-workers studied its effects onlipolysis, finding that itinhibited lipolysis in rats. NMT (in common with tyramine) also failed to stimulate lipolysis in humanadipocytes 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 has been shown to be anagonist of theTAAR1, similarly to its parent compoundtyramine.[27] The EC50 of NMT on the human TAAR1 receptor was ~ 2 μM, compared to ~ 1 μM fortyramine.[28]
The pharmacokinetics of NMT have been studied in rabbits and mice using drug that had beenradiolabeled withtritium 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 ofradioactivity 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 theblood–brain barrier. ~ 80% of the administered dose was recovered from the urine of mice within 1 hour.[29]
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]
^abcdLindemann 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.PMID15860375.
^Wheaton TA, Stewart I (June 1970). "The distribution of tyramine, N-methyltyramine, hordenine, octopamine, and synephrine in higher plants".Lloydia.33 (2):244–254.PMID5495514.
^abKirkwood 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.
^McFarlane WD (1965). "Tyrosine derived amines and phenols in wort and beer".Proceedings, European Brewery Convention. Tenth Congress:387–395.
^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.PMID17966980.
^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.PMID24374199.
^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.
^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.PMID14323148.
^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.
^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.PMID5960887.
^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.PMID10344776.
^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.PMID21336650.
^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.PMID19298333.
^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.PMID15860375.
^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.PMID15718104.
Notes: (1) TAAR1 activity of ligands varies significantly between species. Some agents that are TAAR1 ligands in some species are not in other species. This navbox includes all TAAR1 ligands regardless of species. (2) See the individual pages for references, as well as theList of trace amines,TAAR, andTAAR1 pages. See also:Receptor/signaling modulators
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