Phenylethanolamine

Phenylethanolamine (sometimes abbreviated PEOH), 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[1] and, under the name Apophedrin, has been used as a drug to produce topical vasoconstriction.[2]

Phenylethanolamine
Names
IUPAC name
2-Amino-1-phenylethanol
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.028.609
KEGG
UNII
Properties
C8H11NO
Molar mass 137.18 g/mol
Appearance pale yellow solid
Melting point 56 to 57 °C (133 to 135 °F; 329 to 330 K)
Boiling point 157 to 160 °C (315 to 320 °F; 430 to 433 K) at 17 mmHg
soluble
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
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Infobox references

In appearance, phenylethanolamine is a white 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 carbon 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 at right is for the racemate.

The synthesis of (S)-(+)-phenylethanolamine, from (+)-mandelic acid, via (+)-mandelamide, has been described.[14] The physical constants reported in this paper are as follows: m.p. 55–57 °C; [α] = + 47.9° (c 2.4, in ethanol).

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.[15]

Research by Carpéné and co-workers showed that phenylethanolamine[16] 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).[17]

Using a β2 adrenergic receptor preparation derived from transfected HEK 293 cells, Liappakis and co-workers[18] found that in wild-type receptors, racemic phenylethanolamine[19] had ~ 1/400 x the affinity of epinephrine, and ~ 1/7 x the affinity of norepinephrine in competition experiments with 3[H]-CGP-12177.[20]

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%.[21] In other words, phenylethanolamine is a TAAR1 agonist and trace amine.[21]

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.[15]

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.[22]

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. 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. 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. 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. 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. 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.
  15. 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.
  16. The drug was tested in the form of a racemic mixture.
  17. 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.
  18. 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.
  19. Named imprecisely as "hydroxyphenethylamine"
  20. Considered to be an antagonist of β1 and β2 receptors, and an agonist of β3 receptors.
  21. 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" (PDF). The Journal of Pharmacology and Experimental Therapeutics. 320 (1): 475–485. doi:10.1124/jpet.106.112532. PMID 17038507. Substitution on the ethylamine side chain produced a variety of effects on potency at the human TAAR1, depending on the nature of the substituent. For example, a β-methyl substituent was well tolerated, being as potent as β-PEA itself (Table 3). However, changing that substitution to a β-hydroxy resulted in a 10-fold reduction in potency ...
    "Table 3"
  22. J.Axelrod (1962). "Purification and properties of phenylethanolamine-N-methyl transferase." J. Biol. Chem. 237 1657–1660.
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