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 ofbenzoyl cyanide usingLiAlH4.[8]
Chemically, phenyethanolamine is anaromatic compound, anamine, and an alcohol. The amino-group makes this compound aweak 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]
ThepKa of phenylethanolamine hydrochloride, at 25 °C and at a concentration of 10mM, has been recorded as 8.90.[10]
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).
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 givensubcutaneously 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 nobroncho-dilatory properties in animals. There was a similar lack of effect when the drug was given subcutaneously to man.
In vivo andin vitro experiments involving cat and rabbit intestinal smooth muscle showed that the drug produced relaxation and inhibition.
A detailed examination of themydriatic 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 andpiloerection. 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 stimulatelipolysis in culturedadipocytes ("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 bybupranolol (considered to be a non-selectiveβ-blocker),CGP 20712A (considered to be a selective β1-antagonist), andICI 118,551 (considered to be a selective β2-antagonist), but not bySR 59230A (considered to be a selective β3-antagonist).[17]
Using a β2adrenergic receptor preparation derived fromtransfectedHEK 293 cells, Liappakis and co-workers[18] found that inwild-type receptors, racemic phenylethanolamine[19] had ~ 1/400 x the affinity of epinephrine, and ~ 1/7 x the affinity of norepinephrine in competition experiments with3[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 atEli 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 aTAAR1 agonist andtrace amine.[21]
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]
Subsequent studies by Rafferty and co-workers showed that substrate specificity of PNMT from bovine adrenal glands for the differentenantiomers of phenylethanolamine was in the order R-(−)-PEOH > R,S-(racemic)-PEOH > S-(+)-PEOH.[13]
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]
^J. Axelrod (1966). "Methylation reactions in the formation and metabolism of catecholamines and other biogenic amines.Pharmacol. Rev.18 95–113.
^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.
^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.
^abcG. A. Alles (1927). "The comparative physiological action of phenylethanolamine."J. Pharmacol. Exp. Ther.32 121–133.
^W. H. Hartung and J. C. Munch (1929). "Amino alcohols. I. Phenylpropanolamine and para-tolylpropanolamine."J. Am. Chem. Soc.51 2262–2266.
^A. Burger and E. D. Hornbacker (1952). "Reduction of acyl cyanides with lithium aluminum hydride."J. Am. Chem. Soc.74 5514.
^abcM. L. Tainter (1929). "Pharmacological actions of phenylethanolamine."J. Pharmacol. Exp. Ther.36 29–54.
^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.
^abM. 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.
^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.
^abH. 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.
^The drug was tested in the form of aracemic mixture.
^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.
^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.
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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