Phenylethanolamine

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Phenylethanolamine
200px
Identifiers
CAS number 7568-93-6 7pxY
PubChem 1000
ChemSpider 975 7pxY
KEGG C02735 7pxY
ChEBI CHEBI:16343 7pxY
ChEMBL CHEMBL19216 7pxY
Jmol-3D images Image 1
Properties
Molecular formula C8H11NO
Molar mass 137.18 g/mol
Appearance pale yellow solid
Melting point 56–57°C
Boiling point 157–160°C at 17 mm Hg pressure
Solubility in water soluble
Except where noted otherwise, data are given for materials in their standard state (at 25 °C (77 °F), 100 kPa)
 14pxY (verify) (what is: 10pxY/10pxN?)
Infobox references

Phenylethanolamine (sometimes abbreviated PEOH), or β-hydroxyphenethylamine, is a biogenic amine related structurally to the major neurotransmitter norepinephrine, and the biogenic amine octopamine. As an organic compound, phenylethanolamine is a β-hydroxylated phenethylamine that is also structurally related to a number of synthetic drugs such as phenylpropanolamine, and the ephedrine family of alkaloids/drugs. In common with these compounds, phenylethanolamine has strong cardiovascular activity[1] and, under the name Apophedrin, has been used as a drug to produce topical vasoconstriction.[2]

In appearance, phenylethanolamine is a colorless solid.

Phenylethanolamine is perhaps best known in the field of bioscience as part of the enzyme name "phenylethanolamine N-methyl transferase", referring to an enzyme which is responsible for the conversion of norepinephrine into epinephrine, as well as other related transformations.[3]

Occurrence

Phenylethanolamine has been found to occur naturally in several animal species, including humans.[4][5]

Chemistry

Synthesis

An early synthesis of phenylethanolamine was by the reduction of 2-nitro-1-phenyl-ethanol.[6] Other early syntheses are summarized in a paper by Hartung and Munch.[7]

A more recent synthesis, providing a better yield, is by the reduction of benzoyl cyanide using LiAlH4.[8]

Properties

Chemically, phenyethanolamine is an aromatic compound, an amine, and an alcohol. The amino-group makes this compound a weak base, capable of reacting with acids to form salts.

Two common salts of phenylethanolamine are the hydrochloride, C8H11NO.HCl, m.p. 212 °C,[6] and the sulfate, (C8H11NO)2.H2SO4, m.p. 239–240 °C.[2][9]

The pKa of phenylethanolamine hydrochloride, at 25 °C and at a concentration of 10mM, has been recorded as 8.90.[10]

The presence of the hydroxy-group on the benzylic C of the phenylethanolamine molecule creates a chiral center, so the compound exists in the form of two enantiomers, d- and l-phenylethanolamine, or as the racemic mixture, d,l-phenylethanolamine. The dextrorotatory isomer[11] corresponds to the S-configuration, and the levorotatory isomer[12] to the R-configuration[13] The data given in the Chembox, at right, is for the racemate.[14]

The synthesis of S-(+)-phenylethanolamine, from (+)-mandelic acid, via (+)-mandelamide, has been described.[15] The physical constants reported in this paper are as follows: m.p. 55–57 °C; [α] = + 47.9° (c 2.4, in ethanol).

Use as a precursor to methamphetamine

Phenylethanolamine production and trade is highly regulated in most countries due to its potential to be used as a precursor in the clandestine synthesis of dextromethamphetamine ("meth"), a powerful, addictive, and neurotoxic stimulant which is widely abused for its euphoric and entactogenic effects. It has been nearly abandoned in clinic practice (clinical applications include management of A.D.D. and narcolepsy) due the availability of a number of drugs which have far more favourable pharmacological profiles (less acute and long-term toxicity, less abuse potential, less risk of fatal overdose, and fewer side effects) such as dextroamphetamine, modafinil and methylphenidate.

Illicit methamphetamine is extremely dangerous to the users health as clandestine methamphetamine production is usually rushed and no purity testings are performed on the final product resulting in precursor chemicals being present in detectable concentrations in almost all products seized by the U.S. D.E.A., many of these precursor are volatile, flammable, corrosive, and toxic and poisonings are difficult to treat as there is no immediate way to tell which precursors were used in a products production (while testing can be performed it requires advanced laboratory equipment and takes far longer than many victims are able to survive). Additionally, dealers often "cut" (add other ingredients) to their product in order to increase its volume and their profits. It is not uncommon for cutting agents to be toxic and as cutting product is a very common practice among drug dealers at every stage of distribution it may be done several times between when the product is produced and when it reaches the user, resulting in a large variety of potentially dangerous adulterants in each batch and making it difficult or impossible to determine the purity of a dose (a dose of one batch may barely contain enough meth to produce effects while an equal volume of another batch may be pure enough to result in a fatal overdose).

Despite international efforts, illicit trafficking of dextromethamphetamine remains at epidemic levels with the drug being available in nearly every town in America, as such phenylethanolamine continues to be in high demand and is therefor very valuable on the black market (as are other precursors such as methylamine and the more commonly known pseudoephedrine).

Pharmacology

Early, classical pharmacological studies of phenylethanolamine were carried out by Tainter, who observed its effects after administering it to rabbits, cats and dogs. The drug produced a rapid rise in blood pressure when administered intravenously, but had little or no effect when given by any other route: doses as high as 200 mg given subcutaneously to rabbits did not alter blood pressure, nor were there any effects when the drug was intubated into the stomach.

In man, a total oral dose of 1 g also produced no effects.

Doses of 1–5 mg/kg, intravenously, caused no definite changes in respiration in cats or rabbits, and additional experiments showed that phenylethanolamine had no broncho-dilatory properties in animals. There was a similar lack of effect when the drug was given subcutaneously to man.

In vivo and in vitro experiments involving cat and rabbit intestinal smooth muscle showed that the drug produced relaxation and inhibition.

A detailed examination of the mydriatic effect of phenylethanolamine led Tainter to conclude that this drug acted by direct stimulation of the radial dilator muscle in the eye.[9]

Shannon and co-workers confirmed and extended some of Tainter's studies. After administering phenylethanolamine to dogs intravenously, these investigators observed that 10–30 mg/kg of the drug increased pupil diameter, and decreased body temperature; a dose of 10 or 17.5 mg/kg decreased heart rate, but a 30 mg/kg dose caused it to increase. Other effects that were noted included profuse salivation and piloerection. Phenylethanolamine also produced behavioral effects such as stereotyped head movement, rapid eye movement, and repetitive tongue extrusion. These and other observations were suggested to be consistent with an action on α- and β-adrenergic receptors.[16]

Research by Carpéné and co-workers showed that phenylethanolamine[17] did not significantly stimulate lipolysis in cultured adipocytes ("fat cells") from guinea pig or human. Moderate stimulation (intrinsic activities about half that of the reference standard, isoprenaline) was observed in adipocytes from rat or hamster. This lipolysis was inhibited completely by bupranolol (considered to be a non-selective β-blocker), CGP 20712A (considered to be a selective β1-antagonist), and ICI 118,551 (considered to be a selective β2-antagonist), but not by SR 59230A (considered to be a selective β3-antagonist).[18]

Using a β2 adrenergic receptor preparation derived from transfected HEK 293 cells, Liappakis and co-workers[19] found that in wild-type receptors, racemic phenylethanolamine[20] had ~ 1/400 x the affinity of epinephrine, and ~ 1/7 x the affinity of norepinephrine in competition experiments with 3[H]-CGP-12177.[21]

The two enantiomers of phenylethanolamine were studied for their interaction with the human trace amine associated receptor (TAAR1) by a research group at Eli Lilly. From experiments with human TAAR1 expressed in rGαsAV12-664 cells, Wainscott and co-workers observed that R-(-)-phenylethanolamine (referred to as "R-(-)-β-hydroxy-β-phenylethylamine") had an ED50 of ~1800 nM, with an Emax of ~ 110%, whereas S-(+)-phenylethanolamine (referred to as "S-(+)-β-hydroxy-β-phenylethylamine") had an ED50 of ~1720 nM, with an Emax of ~ 105%. In comparison, β-phenethylamine itself had an ED50 of ~106 nM, with an Emax of ~ 100%.[22] In other words, phenylethanolamine is a trace amine and TAAR1 agonist and trace amine.[22]

Pharmacokinetics

The pharmacokinetics of phenylethanolamine, after intravenous administration to dogs, were studied by Shannon and co-workers, who found that the drug followed the "two-compartment model", with T1/2(α) ≃ 6.8 mins and T1/2(β) ≃ 34.2 mins; the "plasma half-life" of phenylethanolamine was therefore about 30 minutes.[16]

Biochemistry

Phenylethanolamine was found to be an excellent substrate for the enzyme phenylethanolamine N-methyl transferase (PNMT), first isolated from monkey adrenal glands by Julius Axelrod, which transformed it into N-methylphenylethanolamine.[23]

Subsequent studies by Rafferty and co-workers showed that substrate specificity of PNMT from bovine adrenal glands for the different enantiomers of phenylethanolamine was in the order R-(-)-PEOH > R,S-(racemic)-PEOH > S-(+)-PEOH.[13]

Toxicology

The minimum lethal dose (m.l.d.) upon subcutaneous administration to guinea pigs was ~ 1000 mg/kg; the m.l.d. upon intravenous administration to rabbits was 25–30 mg/kg.;[6] in rats, the m.l.d. after intravenous administration was 140 mg/kg.[9]

See also

References

  1. W. H. Hartung (1945). "Beta-phenethylamine derivatives." Ind. Eng. Chem. 37 126–136.
  2. 2.0 2.1 The Merck Index, 10th Ed. (1983), p. 1051, Merck & Co., Rahway.
  3. J. Axelrod (1966). "Methylation reactions in the formation and metabolism of catecholamines and other biogenic amines. Pharmacol. Rev. 18 95–113.
  4. E. E. Inwang, A. D. Mosnaim and H. C. Sabelli (1973). "Isolation and characterization of phenethylamine and phenylethanolamine from human brain." J. Neurochem. 20 1469–1473.
  5. H. E. Shannon and C. M. Degregorio (1982). "Self-administration of the endogenous trace amines beta-phenylethylamine, N-methyl phenylethylamine and phenylethanolamine in dogs." J. Pharmacol. Exp. Ther. 222 52–60.
  6. 6.0 6.1 6.2 G. A. Alles (1927). "The comparative physiological action of phenylethanolamine." J. Pharmacol. Exp. Ther. 32 121–133.
  7. W. H. Hartung and J. C. Munch (1929). "Amino alcohols. I. Phenylpropanolamine and para-tolylpropanolamine." J. Am. Chem. Soc. 51 2262–2266.
  8. A. Burger and E. D. Hornbacker (1952). "Reduction of acyl cyanides with lithium aluminum hydride." J. Am. Chem. Soc. 74 5514.
  9. 9.0 9.1 9.2 M. L. Tainter (1929). "Pharmacological actions of phenylethanolamine." J. Pharmacol. Exp. Ther. 36 29–54.
  10. J. Armstrong and R. B. Barlow (1976). "The ionization of phenolic amines, including apomorphine, dopamine and catecholamines and an assessment of zwitterion constants." Br. J. Pharmacol. 57 501–516.
  11. CAS # 56613-81-1
  12. CAS # 2549-14-6
  13. 13.0 13.1 M. F. Rafferty , D. S. Wilson , J. A. Monn , P. Krass , R. T. Borchardt , and G. L. Grunewald (1982). "Importance of the aromatic ring in adrenergic amines. 7. Comparison of the stereoselectivity of norepinephrine N-methyltransferase for aromatics. Nonaromatic substrates and inhibitors." J. Med. Chem. 25 1198–1204.
  14. CAS # 7568-93-6
  15. A. I. Meyers and J. Slade (1980). "Asymmetric addition of organometallics to chiral ketooxazolines. Preparation of enantiomerically enriched α-hydroxy acids." J. Org. Chem. 45 2785–2791.
  16. 16.0 16.1 H. E. Shannon, E. J. Cone and D. Yousefnejad (1981). "Physiologic effects and plasma kinetics of phenylethanolamine and its N-methyl homolog in the dog." J. Pharmacol. Exp. Ther. 217 379–385.
  17. The drug was tested in the form of a racemic mixture.
  18. C. Carpéné, J. Galitzky, E. Fontana, C. Atgié, M. Lafontan and M. Berlan(1999). "Selective activation of β3- adrenoceptors by octopamine: comparative studies in mammalian fat cells." Naunyn-Schmiedebergs Arch. Pharmacol. 359 310–321.
  19. G. Liapakis, W. C. Chan, M. Papadokostaki and J. A. Javitch (2004). "Synergistic contributions of the functional groups of epinephrine to its affinity and efficacy at the β2 adrenergic receptor." Mol. Pharmacol. 65 1181–1190.
  20. Named imprecisely as "hydroxyphenethylamine"
  21. Considered to be an antagonist of β1 and β2 receptors, and an agonist of β3 receptors.
  22. 22.0 22.1 Wainscott DB, Little SP, Yin T, Tu Y, Rocco VP, He JX, Nelson DL (January 2007). "Pharmacologic characterization of the cloned human trace amine-associated receptor1 (TAAR1) and evidence for species differences with the rat TAAR1". The Journal of Pharmacology and Experimental Therapeutics 320 (1): 475–85. PMID 17038507. doi:10.1124/jpet.106.112532. 
  23. J.Axelrod (1962). "Purification and properties of phenylethanolamine-N-methyl transferase." J. Biol. Chem. 237 1657–1660.
      
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