Phenylethanolamine (sometimes abbreviated PEOH), or β-hydroxyphenethylamine, is a

trace amine Trace amines are an endogenous group of trace amine-associated receptor 1 (TAAR1) agonists – and hence, monoaminergic neuromodulators – that are structurally and metabolically related to classical monoamine neurotransmitters. Compared to th ...

with a structure similar to those of other trace phenethylamines as well as the catecholamine neurotransmitters dopamine,

norepinephrine Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as both a hormone and neurotransmitter. The name "noradrenaline" (from Latin '' ad' ...

, and epinephrine. As an

organic compound In chemistry, organic compounds are generally any chemical compounds that contain carbon-hydrogen or carbon-carbon bonds. Due to carbon's ability to catenate (form chains with other carbon atoms), millions of organic compounds are known. T ...

, phenylethanolamine is a β-hydroxylated phenethylamine that is also structurally related to a number of synthetic drugs in the

substituted phenethylamine Substituted phenethylamines (or simply phenethylamines) are a chemical class of organic compounds that are based upon the phenethylamine structure; the class is composed of all the derivative compounds of phenethylamine which can be formed by ...

class. In common with these compounds, phenylethanolamine has strong

cardiovascular The blood circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the entire body of a human or other vertebrate. It includes the cardiovascular system, or vascular system, tha ...

activity and, under the name ''Apophedrin'', has been used as a drug to produce topical

vasoconstriction Vasoconstriction is the narrowing of the blood vessels resulting from contraction of the muscular wall of the vessels, in particular the large arteries and small arterioles. The process is the opposite of vasodilation, the widening of blood vess ...

.''The Merck Index, 10th Ed.'' (1983), p. 1051, Merck & Co., Rahway. In appearance, phenylethanolamine is a white solid. Phenylethanolamine is perhaps best known in the field of bioscience as part of the

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...

name " phenylethanolamine N-methyl transferase", referring to an enzyme which is responsible for the conversion of

into epinephrine, as well as other related transformations.

Occurrence

Phenylethanolamine has been found to occur naturally in several animal species, including humans.

Chemistry

Synthesis

An early synthesis of phenylethanolamine was by the reduction of 2-nitro-1-phenyl-ethanol.G. A. Alles (1927). "The comparative physiological action of phenylethanolamine." ''J. Pharmacol. Exp. Ther.'' 32 121–133. Other early syntheses are summarized in a paper by Hartung and Munch. A more recent synthesis, providing a better yield, is by the reduction of benzoyl cyanide using LiAlH₄.

Properties

Chemically, phenyethanolamine is an

aromatic In chemistry, aromaticity is a chemical property of cyclic ( ring-shaped), ''typically'' planar (flat) molecular structures with pi bonds in resonance (those containing delocalized electrons) that gives increased stability compared to satur ...

compound, an

amine In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen Hydrogen is the chemical element wi ...

, and an alcohol. The amino-group makes this compound a

weak base A weak base is a base that, upon dissolution in water, does not dissociate completely, so that the resulting aqueous solution contains only a small proportion of hydroxide ions and the concerned basic radical, and a large proportion of undissociat ...

, capable of reacting with acids to form salts. Two common salts of phenylethanolamine are the hydrochloride, C₈H₁₁NO.HCl, m.p. 212 °C, and the sulfate, (C₈H₁₁NO)₂.H₂SO₄, m.p. 239–240 °C.M. L. Tainter (1929). "Pharmacological actions of phenylethanolamine." ''J. Pharmacol. Exp. Ther.'' 36 29–54. The pK_a of phenylethanolamine hydrochloride, at 25 °C and at a concentration of 10mM, has been recorded as 8.90. The presence of the hydroxy-group on the

benzylic In organic chemistry, benzyl is the substituent or molecular fragment possessing the structure . Benzyl features a benzene ring () attached to a methylene group () group. Nomenclature In IUPAC nomenclature, the prefix benzyl refers to a subst ...

carbon of the phenylethanolamine molecule creates a

chiral center In stereochemistry, a stereocenter of a molecule is an atom (center), axis or plane that is the focus of stereoisomerism; that is, when having at least three different groups bound to the stereocenter, interchanging any two different groups ...

, so the compound exists in the form of two enantiomers, d- and l-phenylethanolamine, or as the racemic mixture, d,l-phenylethanolamine. The

dextrorotatory Optical rotation, also known as polarization rotation or circular birefringence, is the rotation of the orientation of the plane of polarization about the optical axis of linearly polarized light as it travels through certain materials. Circul ...

isomer corresponds to the S-configuration, and the levorotatory isomer to the R-configurationM. 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. The data given at right is for the

racemate In chemistry, a racemic mixture, or racemate (), is one that has equal amounts of left- and right-handed enantiomers of a chiral molecule or salt. Racemic mixtures are rare in nature, but many compounds are produced industrially as racemates. ...

. The synthesis of (''S'')-(+)-phenylethanolamine, from (+)-

mandelic acid Mandelic acid is an aromatic alpha hydroxy acid with the molecular formula C6H5CH(OH)CO2H. It is a white crystalline solid that is soluble in water and polar organic solvents. It is a useful precursor to various drugs. The molecule is chiral. T ...

, via (+)- mandelamide, has been described. The physical constants reported in this paper are as follows: m.p. 55–57 °C; �= + 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 The subcutaneous tissue (), also called the hypodermis, hypoderm (), subcutis, superficial fascia, is the lowermost layer of the integumentary system in vertebrates. The types of cells found in the layer are fibroblasts, adipose cells, and macro ...

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 Mydriasis is the dilation of the pupil, usually having a non-physiological cause, or sometimes a physiological pupillary response. Non-physiological causes of mydriasis include disease, trauma, or the use of certain types of drugs. Normally, as ...

effect of phenylethanolamine led Tainter to conclude that this drug acted by direct stimulation of the radial dilator muscle in the eye. 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 Goose bumps, goosebumps or goose-pimples are the bumps on a person's skin at the base of body hairs which may involuntarily develop when a person is tickled, cold or experiencing strong emotions such as fear, euphoria or sexual arousal. The f ...

. 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.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. Research by Carpéné and co-workers showed that phenylethanolamine did not significantly stimulate

lipolysis Lipolysis is the metabolic pathway through which lipid triglycerides are hydrolyzed into a glycerol and free fatty acids. It is used to mobilize stored energy during fasting or exercise, and usually occurs in fat adipocytes. The most important ...

in cultured

adipocytes Adipocytes, also known as lipocytes and fat cells, are the cells that primarily compose adipose tissue, specialized in storing energy as fat. Adipocytes are derived from mesenchymal stem cells which give rise to adipocytes through adipogenesis. I ...

("fat cells") from guinea pig or human. Moderate stimulation ( intrinsic activities about half that of the reference standard,

isoprenaline Isoprenaline, or isoproterenol (brand name: Isoprenaline Macure), is a medication used for the treatment of bradycardia (slow heart rate), heart block, and rarely for asthma. It is a non-selective β adrenoceptor agonist that is the isopropyla ...

) 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 SR 59230A is a selective antagonist of the beta-3 adrenergic receptor, but was subsequently shown to also act at α1 adrenoceptors at high doses. It has been shown to block the hyperthermia produced by MDMA 3,4-Methylenedioxymethamphetamine ...

(considered to be a selective β₃-antagonist). Using a β₂ adrenergic receptor preparation derived from

transfected Transfection is the process of deliberately introducing naked or purified nucleic acids into eukaryotic cells. It may also refer to other methods and cell types, although other terms are often preferred: " transformation" is typically used to desc ...

HEK 293 Human embryonic kidney 293 cells, also often referred to as HEK 293, HEK-293, 293 cells, or less precisely as HEK cells, are a specific immortalised cell line derived from a spontaneously miscarried or aborted fetus or human embryonic kidney cells ...

cells, Liappakis and co-workers found that in

wild-type The wild type (WT) is the phenotype of the typical form of a species as it occurs in nature. Originally, the wild type was conceptualized as a product of the standard "normal" allele at a locus, in contrast to that produced by a non-standard, "m ...

receptors, racemic phenylethanolamine had ~ 1/400 x the affinity of epinephrine, and ~ 1/7 x the affinity of norepinephrine in competition experiments with ³ CGP-12177. The two enantiomers of phenylethanolamine were studied for their interaction with the human trace amine associated receptor (

TAAR1 Trace amine-associated receptor 1 (TAAR1) is a trace amine-associated receptor (TAAR) protein that in humans is encoded by the ''TAAR1'' gene. TAAR1 is an intracellular amine-activated and G protein-coupled receptor (GPCR) that is primarily ex ...

) by a research group at

Eli Lilly Eli Lilly (July 8, 1838 – June 6, 1898) was an American soldier, pharmacist, chemist, and businessman who founded the Eli Lilly and Company pharmaceutical corporation. Lilly enlisted in the Union Army during the American Civil War and ...

. From experiments with human TAAR1 expressed in rGα_sAV12-664 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 E_max of ~ 110%, whereas S-(+)-phenylethanolamine (referred to as "S-(+)-β-hydroxy-β-phenylethylamine") had an ED₅₀ of ~1720 nM, with an E_max of ~ 105%. In comparison,

β-phenethylamine Phenethylamine (PEA) is an organic compound, natural monoamine alkaloid, and trace amine, which acts as a central nervous system stimulant in humans. In the brain, phenethylamine regulates monoamine neurotransmission by binding to trace amin ...

itself had an ED₅₀ of ~106 nM, with an E_max of ~ 100%.
Table 3
In other words, phenylethanolamine is a TAAR1 agonist and

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 T_1/2(α) ≃ 6.8 mins and T_1/2(β) ≃ 34.2 mins; the "plasma half-life" of phenylethanolamine was therefore about 30 minutes.

Biochemistry

Phenylethanolamine was found to be an excellent substrate for the

phenylethanolamine N-methyl transferase (PNMT), first isolated from monkey

adrenal glands The adrenal glands (also known as suprarenal glands) are endocrine glands that produce a variety of hormones including adrenaline and the steroids aldosterone and cortisol. They are found above the kidneys. Each gland has an outer cortex whic ...

Julius Axelrod Julius Axelrod (May 30, 1912 – December 29, 2004) was an American biochemist. He won a share of the Nobel Prize in Physiology or Medicine in 1970 along with Bernard Katz and Ulf von Euler. The Nobel Committee honored him for his work on the re ...

, which transformed it into N-methylphenylethanolamine.J.Axelrod (1962). "Purification and properties of phenylethanolamine-N-methyl transferase." ''J. Biol. Chem.'' 237 1657–1660. 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.

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.; in rats, the m.l.d. after intravenous administration was 140 mg/kg.

References

{{DEFAULTSORT:Hydroxyphenethylamine, 2- Phenylethanolamines Phenylethanolamine Phenylethanolamine Norepinephrine releasing agents