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Synephrine, or, more specifically, ''p''-synephrine, is an
alkaloid Alkaloids are a class of basic, naturally occurring organic compounds that contain at least one nitrogen atom. This group also includes some related compounds with neutral and even weakly acidic properties. Some synthetic compounds of similar ...
, occurring naturally in some plants and animals, and also in approved drugs products as its ''m''-substituted analog known as neo-synephrine. ''p''-Synephrine (or formerly Sympatol and oxedrine BAN.html" ;"title="British_Approved_Name.html" ;"title="nowiki/>British Approved Name">BAN">British_Approved_Name.html" ;"title="nowiki/>British Approved Name">BAN and ''m''-synephrine are known for their longer acting adrenergic effects compared to
epinephrine Adrenaline, also known as epinephrine, is a hormone and medication which is involved in regulating visceral functions (e.g., respiration). It appears as a white microcrystalline granule. Adrenaline is normally produced by the adrenal glands and ...
and
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'', ...
. This substance is present at very low concentrations in common foodstuffs such as orange juice and other orange (''
Citrus ''Citrus'' is a genus of flowering plant, flowering trees and shrubs in the rue family, Rutaceae. Plants in the genus produce citrus fruits, including important crops such as Orange (fruit), oranges, Lemon, lemons, grapefruits, pomelos, and lim ...
'' species) products, both of the "sweet" and "bitter" variety. The preparations used in
traditional Chinese medicine Traditional Chinese medicine (TCM) is an alternative medical practice drawn from traditional medicine in China. It has been described as "fraught with pseudoscience", with the majority of its treatments having no logical mechanism of action ...
(TCM), also known as Zhi Shi (枳实), are the immature and dried whole oranges from ''
Citrus aurantium Bitter orange, Seville orange, bigarade orange, or marmalade orange is the citrus tree ''Citrus'' × ''aurantium'' and its fruit. It is native to Southeast Asia and has been spread by humans to many parts of the world. It is probably a cross bet ...
'' (Fructus Aurantii Immaturus). Extracts of the same material or purified synephrine are also marketed in the US, sometimes in combination with
caffeine Caffeine is a central nervous system (CNS) stimulant of the methylxanthine class. It is mainly used recreationally as a cognitive enhancer, increasing alertness and attentional performance. Caffeine acts by blocking binding of adenosine t ...
, as a weight-loss-promoting dietary supplement for oral consumption. While the traditional preparations have been in use for millennia as a component of TCM-formulas, synephrine itself is not an approved OTC drug. As a pharmaceutical, ''m''-synephrine (
phenylephrine Phenylephrine is a medication primarily used as a decongestant, to dilate the pupil, to increase blood pressure, and to relieve hemorrhoids. In the United States, it was previously used orally as an over-the-counter decongestant to relieve nas ...
) is still used as a sympathomimetic (i.e. for its hypertensive and
vasoconstrictor 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 ...
properties), mostly by injection for the treatment of emergencies such as
shock Shock may refer to: Common uses Collective noun *Shock, a historic commercial term for a group of 60, see English numerals#Special names * Stook, or shock of grain, stacked sheaves Healthcare * Shock (circulatory), circulatory medical emergen ...
, and rarely orally for the treatment of bronchial problems associated with
asthma Asthma is a long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wheezing, cou ...
and hay-fever. It is important to distinguish between studies concerning synephrine as a single chemical entity (synephrine can exist in the form of either of two
stereoisomers In stereochemistry, stereoisomerism, or spatial isomerism, is a form of isomerism in which molecules have the same molecular formula and sequence of bonded atoms (constitution), but differ in the three-dimensional orientations of their atoms ...
, d- and l-synephrine, which are chemically and pharmacologically distinct), and synephrine which is mixed with other drugs and/or botanical extracts in a "Supplement", as well as synephrine which is present as only one chemical component in a naturally-occurring mixture of
phytochemicals Phytochemicals are chemical compounds produced by plants, generally to help them resist fungi, bacteria and plant virus infections, and also consumption by insects and other animals. The name comes . Some phytochemicals have been used as poison ...
such as the rind or fruit of a bitter orange. Mixtures containing synephrine as only one of their chemical components (regardless of whether these are of synthetic or natural origin) should not be assumed to produce exactly the same biological effects as synephrine alone. In physical appearance, synephrine is a colorless, crystalline solid and is water-soluble. Its molecular structure is based on a phenethylamine skeleton and is related to those of many other drugs and to the major
neurotransmitters A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell. Neur ...
epinephrine Adrenaline, also known as epinephrine, is a hormone and medication which is involved in regulating visceral functions (e.g., respiration). It appears as a white microcrystalline granule. Adrenaline is normally produced by the adrenal glands and ...
and
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'', ...
.


Natural occurrences

Synephrine, although already known as a synthetic
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. The ...
, was first isolated as a natural product from the leaves of various ''
Citrus ''Citrus'' is a genus of flowering plant, flowering trees and shrubs in the rue family, Rutaceae. Plants in the genus produce citrus fruits, including important crops such as Orange (fruit), oranges, Lemon, lemons, grapefruits, pomelos, and lim ...
'' trees, and its presence noted in different ''Citrus'' juices, by Stewart and co-workers in the early 1960s.
A survey of the distribution of synephrine amongst the higher plants was published in 1970 by Wheaton and Stewart. It has subsequently been detected in ''
Evodia ''Euodia'' is a plant genus in the family Rutaceae. ''Euodia'' is sometimes misspelled as ''Evodia''. The species now included in the genus ''Tetradium'' were previously included in ''Euodia'', and may be commonly referred to as euodia. Fossil ...
'' and ''
Zanthoxylum ''Zanthoxylum'' is a genus of about 250 species of deciduous and evergreen trees, shrubs and climbers in the family Rutaceae that are native to warm temperate and subtropical areas worldwide. It is the type genus of the tribe Zanthoxyleae in ...
'' species, all plants of the family Rutaceae. Trace levels (0.003%) of synephrine have also been detected in the dried leaves of ''
Pogostemon cablin PatchouliAlso spelled ''patchouly'' or ''pachouli''. (; ''Pogostemon cablin'') is a species of flowering plant in the family Lamiaceae, commonly called the mint or deadnettle family. The plant grows as a bushy perennial herb, with erect stems ...
'' (
patchouli PatchouliAlso spelled ''patchouly'' or ''pachouli''. (; ''Pogostemon cablin'') is a species of flowering plant in the family Lamiaceae, commonly called the mint or deadnettle family. The plant grows as a bushy perennial herb, with erect stems r ...
, Lamiaceae). It is also found in certain cactus species of the genera ''
Coryphantha ''Coryphantha'' (from Greek, "flowering on the top"), or beehive cactus, is a genus of small to middle-sized, globose or columnar cacti. The genus is native to arid parts of Central America, Mexico, through Arizona, New Mexico, and western Texas ...
'' and ''
Dolichothele ''Dolichothele'' is a genus of spiders in the family Theraphosidae found in Brazil and Bolivia. It was first described in 1923 by Mello-Leitão. Diagnosis It owns a labium, which has less than 10 cuspules, also owning undivided tarsal scop ...
''. However, this compound is found predominantly in a number of ''Citrus'' species, including "bitter" orange varieties.


In ''Citrus''

Extracts of unripe fruit from Asian cultivars of ''
Citrus aurantium Bitter orange, Seville orange, bigarade orange, or marmalade orange is the citrus tree ''Citrus'' × ''aurantium'' and its fruit. It is native to Southeast Asia and has been spread by humans to many parts of the world. It is probably a cross bet ...
'' (commonly known as "bitter" orange), collected in China, were reported to contain synephrine levels of about 0.1–0.3%, or ~1–3 mg/g; Analysis of dried fruit of ''C. aurantium'' grown in Italy showed a concentration of synephrine of ~1 mg/g, with peel containing over three times more than the pulp. Sweet oranges of the Tarocco, Naveline and Navel varieties, bought on the Italian market, were found to contain ~13–34 μg/g (corresponding to 13–34 mg/kg) synephrine (with roughly equal concentrations in juice and separated pulp); from these results, it was calculated that eating one "average" Tarocco orange would result in the consumption of ~6 mg of synephrine. An analysis of 32 different orange "jams", originating mostly in the US and UK, but including samples from France, Italy, Spain, or Lebanon, showed synephrine levels ranging from 0.05 mg/g–0.0009 mg/g in those jams made from bitter oranges, and levels of 0.05 mg/g–0.006 mg/g of synephrine in jams made from sweet oranges. Synephrine has been found in
marmalade Marmalade is a fruit preserve made from the juice and peel of citrus fruits boiled with sugar and water. The well-known version is made from bitter orange. It is also made from lemons, limes, grapefruits, mandarins, sweet oranges, bergamo ...
made from ''
Citrus unshiu ''Citrus unshiu'' is a semi-seedless and easy-peeling citrus species, also known as miyagawa mandarin, unshu mikan, cold hardy mandarin, satsuma mandarin, satsuma orange, naartjie, and tangerine. ''Citrus unshiu'' was named after Unshu (Wenzho ...
'' (Satsuma mandarin) obtained in Japan, at a concentration of ~0.12 mg/g (or about 2.4 mg/20g serving). Most of the orange marmalades made in the US are produced using "sweet" oranges ('' C. sinensis''), whereas "bitter" or Seville oranges (''C. aurantium'') are used for making the more traditional, bitterer marmalades in the United Kingdom. A sample of commercial Japanese ''C. unshiu'' juice was found to contain ~0.36 mg/g synephrine (or roughly 360 mg/L), while in juice products obtained from a Satsuma mandarin variety grown in California, levels of synephrine ranged from 55 to 160 mg/L . Juices from "sweet" oranges purchased in Brazilian markets were found to contain ~10–22 mg/L synephrine; commercial orange soft drinks obtained on the Brazilian market had an average synephrine content of ~1 mg/L. Commercial Italian orange juices contained ~13–32 mg/L of synephrine In a survey of over 50 citrus fruit juices, either commercially-prepared or hand-squeezed from fresh fruit, obtained on the US market, Avula and co-workers found synephrine levels ranging from ~4–60 mg/L; no synephrine was detected in juices from grapefruit, lime, or lemon. An analysis of the synephrine levels in a range of different citrus fruits, carried out on juices that had been extracted from fresh, peeled fruit, was reported by Uckoo and co-workers, with the following results: Marrs sweet orange (''C. sinensis'' Tan.): ~85 mg/L; Nova tangerine ('' C. reticulata'' Tan.): ~78 mg/L; clementine (''C. clementina'' Tan.): ~115 mg/L; Meyer lemon (''C. limon'' Tan.) ~3 mg/kg; Ugli tangelo (''C. reticulata'' × ''C. paradisi'') ~47 mg/kg. No synephrine was detected in: Rio Red grapefruit (''C. paradisi'' Macf.); Red-fleshed pummelo (''C. grandis'' Tan.); or Wekiwa tangelo (''C. reticulata'' × ''C. paradisi''). Numerous additional comparable analyses of the synephrine content of ''Citrus'' fruits and products derived from them may be found in the research literature.


In humans and other animals

Low levels of synephrine have been found in normal human urine, as well as in other mammalian tissue. To reduce the likelihood that the synephrine detected in urine had a dietary origin, the subjects tested by Ibrahim and co-workers abstained from the consumption of any citrus products for 48 hours prior to providing urine samples. A 2006 study of synephrine in human
blood platelets Platelets, also called thrombocytes (from Greek language, Greek θρόμβος, "clot" and κύτος, "cell"), are a component of blood whose function (along with the Coagulation#Coagulation factors, coagulation factors) is to react to bleeding ...
by D'Andrea and co-workers showed increased levels in platelets from patients suffering from aura-associated migraine (0.72 ng/108 platelets, compared to 0.33 ng/108 platelets in control subjects). Earlier, the same research group had reported a normal human
blood plasma Blood plasma is a light amber-colored liquid component of blood in which blood cells are absent, but contains proteins and other constituents of whole blood in suspension. It makes up about 55% of the body's total blood volume. It is the intr ...
level of synephrine of 0.90–13.69 ng/mL.


Stereoisomers

Since synephrine exists as either of two enantiomers (see Chemistry section below for further discussion), which do not produce identical biological effects (see Pharmacology section below) some researchers have examined the
stereoisomer In stereochemistry, stereoisomerism, or spatial isomerism, is a form of isomerism in which molecules have the same molecular formula and sequence of bonded atoms (constitution), but differ in the three-dimensional orientations of their atoms in ...
ic composition of synephrine extracted from natural sources. Although it seems clear that synephrine is found in those ''Citrus'' species which have been studied predominantly as the l-isomer, low levels of d-synephrine have been detected in juice and marmalade made from ''C. unshiu'', and low levels (0.002%) have been reported in fresh fruit from ''C. aurantium''. There are indications that some d-synephrine may be formed by the
racemization In chemistry, racemization is a conversion, by heat or by chemical reaction, of an optically active compound into a racemic (optically inactive) form. This creates a 1:1 molar ratio of enantiomers and is referred too as a racemic mixture (i.e. conta ...
of l-synephrine as a result of the processing of fresh fruit, although this matter has not been completely clarified. However, regardless of the situation in ''Citrus'' species, Ranieri and McLaughlin reported the ''isolation'' of
racemic 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. ...
(i.e. a mixture of equal amounts of d- and l- stereoisomers) synephrine from a cactus of the genus ''Dolichothele'', under conditions that would be unlikely to cause a significant amount of racemization.


Biosynthesis

The biosynthesis of synephrine in ''Citrus'' species is believed to follow the pathway:
tyrosine -Tyrosine or tyrosine (symbol Tyr or Y) or 4-hydroxyphenylalanine is one of the 20 standard amino acids that are used by cells to synthesize proteins. It is a non-essential amino acid with a polar side group. The word "tyrosine" is from the Gr ...
tyramine Tyramine ( ) (also spelled tyramin), also known under several other names, is a naturally occurring trace amine derived from the amino acid tyrosine. Tyramine acts as a catecholamine releasing agent. Notably, it is unable to cross the blood-b ...
''N''-methyltyramine → synephrine, involving the enzymes
tyrosine decarboxylase The enzyme tyrosine decarboxylase () catalyzes the chemical reaction :L-tyrosine \rightleftharpoons tyramine + CO2 Hence, this enzyme has one substrate, L-tyrosine, and two products, tyramine and carbon dioxide. This enzyme belongs to the fam ...
in the first step, tyramine ''N''-methyltransferase in the second, and ''N''-methyl-tyramine-β-hydroxylase in the third. This pathway differs from that thought to occur in animals, involving
octopamine Octopamine (molecular formula C8H11NO2; also known as OA, and also norsynephrine, ''para''-octopamine and others) is an organic chemical closely related to norepinephrine, and synthesized biologically by a homologous pathway. Octopamine is ofte ...
: tyramine → octopamine → synephrine, where the conversion of tyramine to octopamine is mediated by dopamine-β-hydroxylase, and the conversion of octopamine to synephrine by phenylethanolamine ''N''-methyltransferase.


Presence in nutritional/dietary supplements

Some dietary supplements, sold for the purposes of promoting weight-loss or providing energy, contain synephrine as one of several constituents. Usually, the synephrine is present as a natural component of ''Citrus aurantium'' ("bitter orange"), bound up in the plant matrix, but could also be of synthetic origin, or a purified phytochemical (i.e. extracted from a plant source and purified to chemical homogeneity). The concentration range found by Santana and co-workers in five different supplements purchased in the US was about 5–14 mg/g.


Pharmaceutical use

As a synthetic drug, synephrine first appeared in Europe in the late 1920s, under the name of ''Sympatol''. One of the earliest papers describing its pharmacological and toxicological properties was written by Lasch, who obtained it from the Viennese company Syngala. By 1930, ''Sympatol'' was referred to as a Boehringer product, while one of the first US Patents describing its preparation and use was assigned to Frederick Stearns & Co. in 1933. Despite the date of this patent, clinical and pharmacological research on synephrine obtained from Frederick Stearns & Co was being carried out in the US by 1930. Writing in 1931, Hartung reported that in 1930 the Council on Pharmacy and Chemistry of the American Medical Association had accepted synephrine for inclusion in its list of “New and Non-Official Remedies” as an agent for the treatment, by either oral or parenteral administration, "of attacks of hay fever, asthma, coughing, spasms of asthma and pertussis (whooping cough)." However, synephrine was dropped from the Council's list in 1934, and its apparent re-advertising as a new drug by the Stearns company ten years later elicited a scathing comment from the Editors of the Journal of the American Medical Association. The third edition (1965) of ''Drill's Pharmacology in Medicine'' stated, with reservations, that synephrine was "advertised as an antihistaminic to be used in the treatment of the common cold...", under the trade name of "Synephrin Tartrate", and indicated that the dose was 100 mg, given intramuscularly, or subcutaneously. Published in 1966, the ''Textbook of Organic Medicinal and Pharmaceutical Chemistry'' described synephrine (in the form of its racemic tartrate) as a sympathomimetic agent that was "less effective than epinephrine", and which had been used for the treatment of chronic
hypotension Hypotension is low blood pressure. Blood pressure is the force of blood pushing against the walls of the arteries as the heart pumps out blood. Blood pressure is indicated by two numbers, the systolic blood pressure (the top number) and the dia ...
, collapse due to shock, and other conditions leading to
hypotension Hypotension is low blood pressure. Blood pressure is the force of blood pushing against the walls of the arteries as the heart pumps out blood. Blood pressure is indicated by two numbers, the systolic blood pressure (the top number) and the dia ...
.C. O. Wilson, O. Gisvold, and R. F. Doerge (Eds.) (1966). ''Textbook of Organic Medicinal and Pharmaceutical Chemistry, 5th ed.,'' p.438, Lippincott, Philadelphia. In a later (1972) textbook, synephrine was described as a drug, sold in Europe, that was administered in situations involving shock, such as surgical or bacteremic shock, and
spinal anesthesia Spinal anaesthesia (or spinal anesthesia), also called spinal block, subarachnoid block, intradural block and intrathecal block, is a form of neuraxial regional anaesthesia involving the injection of a local anaesthetic or opioid into the subara ...
-related shock. The recommended dose was given here as 25–50 mg, by intravenous, intramuscular or subcutaneous administration. There is no mention of synephrine in editions of ''Drill's Pharmacology in Medicine'' later than the 3rd, nor is there any reference to synephrine in the 2012 '' Physicians' Desk Reference'', nor in the current
FDA The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...
"Orange Book". One current reference source describes synephrine as a vasoconstrictor that has been given to hypotensive patients, orally or by injection, in doses of 20–100 mg. One website from a healthcare media company, accessed in February, 2013, refers to oxedrine as being indicated for
hypotensive Hypotension is low blood pressure. Blood pressure is the force of blood pushing against the walls of the arteries as the heart pumps out blood. Blood pressure is indicated by two numbers, the systolic blood pressure (the top number) and the dia ...
states, in oral doses of 100–150 mg tid, and as a "
conjunctiva The conjunctiva is a thin mucous membrane that lines the inside of the eyelids and covers the sclera (the white of the eye). It is composed of non-keratinized, stratified squamous epithelium with goblet cells, stratified columnar epithelium ...
l decongestant" to be topically applied as a 0.5% solution. However, no supporting references are provided.


Names

There has been some confusion about the biological effects of synephrine because of the similarity of this un-prefixed name to the names ''m-synephrine'', ''Meta-synephrine'' and ''Neosynephrine'', all of which refer to a related drug and naturally-occurring
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 atoms have been replaced by a substituen ...
more commonly known as
phenylephrine Phenylephrine is a medication primarily used as a decongestant, to dilate the pupil, to increase blood pressure, and to relieve hemorrhoids. In the United States, it was previously used orally as an over-the-counter decongestant to relieve nas ...
. Although there are chemical and pharmacological similarities between synephrine and phenylephrine, they are nevertheless different substances. The confusion is compounded by the fact that synephrine has been marketed as a drug under numerous different names, including ''Sympatol'', ''Sympathol'', ''Synthenate'', and ''oxedrine'', while phenylephrine has also been called ''m-Sympatol''. The synephrine with which this article deals is sometimes referred to as ''p-synephrine'' in order to distinguish it from its positional isomers, ''m''-synephrine and ''o''-synephrine. A comprehensive listing of alternative names for synephrine may be found in the ChemSpider entry (see Chembox, at right). Confusion over the distinctions between ''p''- and ''m''-synephrine has even contaminated the primary research literature. Even the name "''p''-synephrine" is not unambiguous, since it does not specify stereochemistry. The only completely unambiguous names for synephrine are: (''R'')-(−)-4- -hydroxy-2-(methylamino)ethylhenol (for the l-enantiomer); (''S'')-(+)-4- -hydroxy-2-(methylamino)ethylhenol (for the d-enantiomer); and (''R'',''S'')-4- -hydroxy-2-(methylamino)ethylhenol (for the racemate, or d,l-synephrine) (see
Chemistry Chemistry is the science, scientific study of the properties and behavior of matter. It is a natural science that covers the Chemical element, elements that make up matter to the chemical compound, compounds made of atoms, molecules and ions ...
section).


Chemistry


Properties

In terms of molecular structure, synephrine has a phenethylamine skeleton, with a
phenol Phenol (also called carbolic acid) is an aromatic organic compound with the molecular formula . It is a white crystalline solid that is volatile. The molecule consists of a phenyl group () bonded to a hydroxy group (). Mildly acidic, it req ...
ic hydroxy- group, an alcoholic hydroxy- group, and an ''N''-methylated
amino 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 atoms have been replaced by a substituent ...
-group. Alternatively, synephrine might be described as a phenylethanolamine with an ''N''-methyl and ''p''-hydroxy substituent. The amino-group confers basic properties on the molecule, whereas the phenolic –OH group is weakly acidic: the apparent (see original article for discussion) pKas for protonated synephrine are 9.55 (phenolic H) and 9.79 (ammonium H). Common salts of
racemic 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. ...
synephrine are its
hydrochloride In chemistry, a hydrochloride is an acid salt resulting, or regarded as resulting, from the reaction of hydrochloric acid with an organic base (e.g. an amine). An alternative name is chlorhydrate, which comes from French. An archaic alternative n ...
, C9H13NO2.HCl, m.p. 150–152°, the
oxalate Oxalate (IUPAC: ethanedioate) is an anion with the formula C2O42−. This dianion is colorless. It occurs naturally, including in some foods. It forms a variety of salts, for example sodium oxalate (Na2C2O4), and several esters such as dimethyl o ...
(C9H13NO2)2.C2H2O4, m.p. 221–222 °C, and the
tartrate A tartrate is a salt or ester of the organic compound tartaric acid, a dicarboxylic acid. The formula of the tartrate dianion is O−OC-CH(OH)-CH(OH)-COO− or C4H4O62−. The main forms of tartrates used commercially are pure crystalline ta ...
(Sympatol), (C9H13NO2)2.C4H6O6, m.p. 188–190 °C. 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 ...
C of the synephrine 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- synephrine, or as the
racemic mixture 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. ...
, d,l- synephrine. 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 ...
d-isomer corresponds to the (''S'')-configuration, and the
levorotatory 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 ...
l-isomer to the (''R'')-configuration.J. M. Midgley, C. M. Thonoor, A. F. Drake, C. M. Williams, A. E. Koziol and G. J. Palenik (1989). "The resolution and absolute configuration by X-ray crystallography of the isomeric octopamines and synephrines." ''J. Chem. Soc., Perkin Trans. 2'' 963-969. Racemic synephrine has been resolved using ammonium 3-bromo-camphor-8-sulfonate. The enantiomers were not characterized as their free bases, but converted to the hydrochloride salts, with the following properties: (''S'')-(+)-C9H13NO2.HCl: m.p. 178 °C; = +42.0°, c 0.1 (H2O); (''R'')-(−)-C9H13NO2.HCl: m.p. 176 °C; = −39.0°, c 0.2 (H2O) (−)-Synephrine, as the free base isolated from a ''Citrus'' source, has m.p. 162–164 °C (with decomposition). The
X-ray structure X-ray crystallography is the experimental science determining the atomic and molecular structure of a crystal, in which the crystalline structure causes a beam of incident X-rays to diffract into many specific directions. By measuring the angles ...
for synephrine has been determined.


Synthesis

Early and seemingly inefficient syntheses of synephrine were discussed by Priestley and Moness, writing in 1940. These chemists optimized a route beginning with the ''O''-benzoylation of ''p''-hydroxy-phenacyl chloride, followed by reaction of the resulting ''O''-protected chloride with ''N''-methyl-benzylamine to give an amino-ketone. This intermediate was then hydrolyzed with HCl/alcohol to the ''p''-hydroxy-aminoketone, and the product then reduced catalytically to give (racemic) synephrine. A later synthesis, due to Bergmann and Sulzbacher, began with the ''O''-benzylation of ''p''-hydroxy-benzaldehyde, followed by a
Reformatskii reaction The Reformatsky reaction (sometimes misspelled Reformatskii reaction) is an organic reaction which condenses aldehydes or ketones with α-halo esters using metallic zinc to form β-hydroxy-esters: The organozinc reagent, also called a 'Reform ...
of the protected aldehyde with ethyl bromoacetate/Zn to give the expected β-hydroxy ester. This intermediate was converted to the corresponding acylhydrazide with hydrazine, then the acylhydrazide reacted with HNO2, ultimately yielding the ''p''-benzyloxy-phenyloxazolidone. This was ''N''-methylated using dimethyl sulfate, then hydrolyzed and ''O''-debenzylated by heating with HCl, to give racemic synephrine.


Structural relationships

Much reference has been made in the literature (both lay and professional) of the structural kinship of synephrine with
ephedrine Ephedrine is a central nervous system (CNS) stimulant that is often used to prevent low blood pressure during anesthesia. It has also been used for asthma, narcolepsy, and obesity but is not the preferred treatment. It is of unclear benefit in ...
, or with
phenylephrine Phenylephrine is a medication primarily used as a decongestant, to dilate the pupil, to increase blood pressure, and to relieve hemorrhoids. In the United States, it was previously used orally as an over-the-counter decongestant to relieve nas ...
, often with the implication that the perceived similarities in structure should result in similarities in pharmacological properties. However, from a chemical perspective, synephrine is also related to a very large number of other drugs whose structures are based on the phenethylamine skeleton, and although some properties are common, others are not, making unqualified comparisons and generalizations inappropriate. Thus, replacement of the ''N''-
methyl In organic chemistry, a methyl group is an alkyl derived from methane, containing one carbon atom bonded to three hydrogen atoms, having chemical formula . In formulas, the group is often abbreviated as Me. This hydrocarbon group occurs in many ...
group in synephrine with a hydrogen atom gives
octopamine Octopamine (molecular formula C8H11NO2; also known as OA, and also norsynephrine, ''para''-octopamine and others) is an organic chemical closely related to norepinephrine, and synthesized biologically by a homologous pathway. Octopamine is ofte ...
; replacement of the β- hydroxy group in synephrine by a H atom gives ''N''-methyltyramine; replacement of the synephrine
phenol Phenol (also called carbolic acid) is an aromatic organic compound with the molecular formula . It is a white crystalline solid that is volatile. The molecule consists of a phenyl group () bonded to a hydroxy group (). Mildly acidic, it req ...
ic 4-OH group by a –H gives halostachine. If the synephrine phenolic 4-OH group is shifted to the ''meta''-, or 3-position on the benzene ring, the compound known as phenylephrine (or ''m''-synephrine, or "Neo-synephrine") results; if the same group is shifted to the ''ortho''-, or 2-position on the ring, ''o''-synephrine results. Addition of another phenolic –OH group to the 3-position of the benzene ring produces the
neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell. Neuro ...
epinephrine Adrenaline, also known as epinephrine, is a hormone and medication which is involved in regulating visceral functions (e.g., respiration). It appears as a white microcrystalline granule. Adrenaline is normally produced by the adrenal glands and ...
; addition of a
methyl In organic chemistry, a methyl group is an alkyl derived from methane, containing one carbon atom bonded to three hydrogen atoms, having chemical formula . In formulas, the group is often abbreviated as Me. This hydrocarbon group occurs in many ...
group to the α-position in the side-chain of synephrine gives
oxilofrine Oxilofrine (also known as methylsynephrine, hydroxyephrine, oxyephrine, and 4-HMP) is a stimulant drug and is an amphetamine chemically related to ephedrine and to synephrine. Oxilofrine is currently a World Anti-Doping Agency (WADA) prohibited ...
(methylsynephrine). Four stereoisomers (two pairs of enantiomers) are possible for this substance. Extension of the synephrine ''N''-methyl substituent by one methylene unit to an ''N''-
ethyl Ethyl may refer to: Arts and entertainment * Cold Ethyl, a Swedish rock band *Ethyl Sinclair, a character in the ''Dinosaurs'' television show Science and technology * Ethyl group, an organic chemistry moiety * Ethyl alcohol (or ethanol) * E ...
gives the
hypotensive Hypotension is low blood pressure. Blood pressure is the force of blood pushing against the walls of the arteries as the heart pumps out blood. Blood pressure is indicated by two numbers, the systolic blood pressure (the top number) and the dia ...
experimental drug "Sterling #573"/"Aethyl-Sympatol". The above structural relationships all involve a change at ''one'' position in the synephrine molecule, and numerous other similar changes, many of which have been explored, are possible. However, the structure of ephedrine differs from that of synephrine at ''two'' different positions: ephedrine has no substituent on the phenyl ring where synephrine has a 4-OH group, and ephedrine has a methyl group on the position α- to the N in the side-chain, where syneprine has only a H atom. Furthermore, "synephrine" exists as either of two enantiomers, while "ephedrine" exists as one of four different enantiomers; there are, in addition, racemic mixtures of these enantiomers. The main differences of the synephrine isomers compared for example to the
ephedrine Ephedrine is a central nervous system (CNS) stimulant that is often used to prevent low blood pressure during anesthesia. It has also been used for asthma, narcolepsy, and obesity but is not the preferred treatment. It is of unclear benefit in ...
s are the hydroxy-substitutions on the benzene ring. Synephrines are direct sympathomimetic drugs while the ephedrines are both direct and indirect sympathomimetics. One of the main reasons for these differential effects is the obviously increased polarity of the hydroxy-substituted phenyl ethyl amines which renders them less able to penetrate the blood-brain barrier as illustrated in the examples for tyramine and the amphetamine analogs.


Pharmacology


Synopsis

Classical pharmacological studies on animals and isolated animal tissues showed that the principal actions of parenterally-administered synephrine included raising blood-pressure, dilating the pupil, and constricting peripheral blood vessels. There is now ample evidence(what evidence?) that synephrine produces most of its biological effects by acting as an
agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...
(i.e. stimulating) at adrenergic receptors, with a distinct preference for the α1 over the α2 sub-type. However, the potency of synephrine at these receptors is relatively low (i.e. relatively large concentrations of the drug are required to activate them). The potency of synephrine at adrenergic receptors of the β-class (regardless of sub-type) is much lower than at α-receptors. There is some evidence that synephrine also has weak activity at 5-HT receptors, and that it interacts with
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 ...
(trace amine-associated receptor 1). In common with virtually all other simple phenylethanolamines (β-hydroxy-phenethylamines), the (''R'')-(−)-, or l-, enantiomer of synephrine is more potent than the (''S'')-(+)-, or d-, enantiomer in most, but not all preparations studied. However, the majority of studies have been conducted with a racemic mixture of the two enantiomers. Since the details regarding such variables as test species, receptor source, route of administration, drug concentration, and stereochemical composition are important but often incomplete in other Reviews and Abstracts of research publications, many are provided in the more technical review below, in order to support as fully as possible the broad statements made in this Synopsis.


Pharmacology research

Pharmacological studies on synephrine date back to the late 1920s, when it was observed that injected synephrine raised blood pressure, constricted peripheral blood vessels, dilated pupils, stimulated the uterus, and relaxed the intestines in experimental animals. Representative of this early work is the paper by Tainter and Seidenfeld, who were the first researchers to systematically compare the different effects of the two synephrine enantiomers, d- and l- synephrine, as well as of the racemate, d,l-synephrine, in various animal assays. In experiments on anesthetized cats, Tainter and Seidenfeld confirmed earlier reports of the increase in blood pressure produced by intravenous doses of synephrine, showing that the median
pressor An antihypotensive agent, also known as a vasopressor agent or simply vasopressor, or pressor, is any substance, whether endogenous or a medication, that tends to raise low blood pressure. Some antihypotensive drugs act as vasoconstrictors to in ...
doses for the isomers were: l-synephrine: 0.5 mg/kg; d,l-synephrine: 1.0 mg/kg; and d-synephrine: 2–20 mg/kg. These effects lasted 2–3 minutes, peaking at ~30 seconds after administration. l-Synephrine was thus the more potent enantiomer, with about 1/60x the potency of the standard pressor l-epinephrine in the same assay. A later study, by Lands and Grant, showed that a dose of ~0.6 mg/kg of racemic synephrine, given intravenously to anesthetized dogs, produced a rise in blood pressure of 34 mmHg lasting 5–10 minutes, and estimated that this pressor activity was about 1/300x that of epinephrine. Using cats and dogs, Tainter and Seidenfeld observed that neither d- nor l-synephrine caused any changes in the tone of normal
bronchi A bronchus is a passage or airway in the lower respiratory tract that conducts air into the lungs. The first or primary bronchi pronounced (BRAN-KAI) to branch from the trachea at the carina are the right main bronchus and the left main bronchus. ...
, ''in situ'', even at "maximum" doses. Furthermore, the marked brocho-constriction produced by injections of
histamine Histamine is an organic nitrogenous compound involved in local immune responses, as well as regulating physiological functions in the gut and acting as a neurotransmitter for the brain, spinal cord, and uterus. Since histamine was discovered ...
was not reversed by either l-synephrine or d,l-synephrine. In experiments with isolated sheep
carotid In anatomy, the left and right common carotid arteries (carotids) (Entry "carotid"
in
vasoconstrictor 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 ...
activity: l-synephrine was the most potent, producing strong contractions at a concentration of 1:10000. d-Synephrine was about 1/2 as potent as the l-isomer, but d,l-synephrine (which would have been expected to have a potency of 1/2 that of l-synephrine even if the d-isomer were completely inactive) did not produce significant and irregular contractions until a concentration of 1:2500had been reached, implying an inhibitory interaction between the two enantiomers. Qualitatively similar results were obtained in a rabbit ear preparation: 25 mg l-synephrine produced significant (50%) vasoconstriction, while the same concentration of d-synephrine elicited essentially no response. In contrast, d,l-synephrine did not produce any constriction up to 25 mg, but 25 – 50 mg caused a relaxation of the blood vessels, which again suggested that the d-isomer might be inhibiting the action of the l-isomer. Experiments on strips of rabbit duodenum showed that l-synephrine caused a modest reduction in contractions at a concentration of 1:17000, but that the effects of the d- and d,l- forms were much weaker. Racemic synephrine, given intramuscularly, or by instillation, was found to significantly reduce the inflammation caused by instillation of
mustard oil Mustard oil can mean either the pressed oil used for cooking, or a pungent essential oil also known as volatile oil of mustard. The essential oil results from grinding mustard seed, mixing the grounds with water, and extracting the resulting vol ...
into the eyes of rabbits. Subcutaneous injection of racemic synephrine into rabbits was reported to cause a large rise in
blood sugar Glycaemia, also known as blood sugar level, blood sugar concentration, or blood glucose level is the measure of glucose concentrated in the blood of humans or other animals. Approximately 4 grams of glucose, a simple sugar, is present in the blo ...
. In experiments on anesthetized cats, Papp and Szekeres found that synephrine (stereochemistry unspecified) raised the thresholds for auricular and ventricular
fibrillation Fibrillation is the rapid, irregular, and unsynchronized contraction of muscle fibers. An important occurrence is with regard to the heart. Cardiology There are two major classes of cardiac fibrillation: atrial fibrillation and ventricular fib ...
, an indication of anti-arrhythmic properties. Evidence that synephrine might have some
central Central is an adjective usually referring to being in the center of some place or (mathematical) object. Central may also refer to: Directions and generalised locations * Central Africa, a region in the centre of Africa continent, also known as ...
effects comes from the research of Song and co-workers, who studied the effects of synephrine in mouse models of anti-depressant activity. These researchers observed that oral doses of 0.3 – 10 mg/kg of racemic synephrine were effective in shortening the duration of immobility produced in the assays, but did not cause any changes in spontaneous motor activity in separate tests. This characteristic immobility could be counteracted by the pre-administration of
prazosin Prazosin is an α1 blocker medication primarily used to treat high blood pressure, symptoms of an enlarged prostate, and nightmares related to post-traumatic stress disorder (PTSD). It is a less preferred treatment of high blood pressure. Oth ...
. Subsequent experiments using the individual enanatiomers of synephrine revealed that although the d-isomer significantly reduced the duration of immobility in the tail suspension test, at an oral dose of 3 mg/kg, the l-isomer had no effect at the same dose. In mice pre-treated with
reserpine Reserpine is a drug that is used for the treatment of high blood pressure, usually in combination with a thiazide diuretic or vasodilator. Large clinical trials have shown that combined treatment with reserpine plus a thiazide diuretic reduces m ...
, an oral dose of 0.3 mg/kg d-synephrine significantly reversed the
hypothermia Hypothermia is defined as a body core temperature below in humans. Symptoms depend on the temperature. In mild hypothermia, there is shivering and mental confusion. In moderate hypothermia, shivering stops and confusion increases. In severe ...
, while l-synephrine required a dose of 1 mg/kg to be effective. Experiments with slices of
cerebral cortex The cerebral cortex, also known as the cerebral mantle, is the outer layer of neural tissue of the cerebrum of the brain in humans and other mammals. The cerebral cortex mostly consists of the six-layered neocortex, with just 10% consisting of ...
taken from rat brain showed that d-synephrine inhibited the uptake of sup>3Hnorepinephrine with an IC50 = 5.8 μM; l-synephrine was less potent (IC50 = 13.5 μM). d-Synephrine also competitively inhibited the binding of
nisoxetine Nisoxetine, originally synthesized in the Lilly research laboratories during the early 1970s, is a potent and selective inhibitor for the reuptake of norepinephrine (noradrenaline) into synapses. It currently has no clinical applications in hum ...
to rat brain cortical slices, with a Ki = 4.5 μM; l-synephrine was less potent (Ki = 8.2 μM). In experiments on the release of sup>3Hnorepinephrine from rat brain cortical slices, however, the l-isomer of synephrine was a more potent enhancer of the release (EC50 = 8.2 μM) than the d-isomer (EC50 = 12.3 μM). This enhanced release by l-synephrine was blocked by nisoxetine. Burgen and Iversen, examining the effect of a broad range of phenethylamine-based drugs on sup>14Cnorepinephrine-uptake in the isolated rat heart, observed that racemic synephrine was a relatively weak inhibitor (IC50 = 0.12 μM) of the uptake. Another receptor-oriented study by Wikberg revealed that synephrine (
stereochemistry Stereochemistry, a subdiscipline of chemistry, involves the study of the relative spatial arrangement of atoms that form the structure of molecules and their manipulation. The study of stereochemistry focuses on the relationships between stereois ...
unspecified) was a more potent agonist at guinea pig
aorta The aorta ( ) is the main and largest artery in the human body, originating from the left ventricle of the heart and extending down to the abdomen, where it splits into two smaller arteries (the common iliac arteries). The aorta distributes o ...
α1 receptors (pD2 = 4.81) than at
ileum The ileum () is the final section of the small intestine in most higher vertebrates, including mammals, reptiles, and birds. In fish, the divisions of the small intestine are not as clear and the terms posterior intestine or distal intestine m ...
α2 receptors (pD2 = 4.48), with a relative affinity ratio of α21 = 0.10. Although clearly indicating a selectivity of synephrine for α1 receptors, its potency at this receptor sub-class is still relatively low, in comparison with that of phenylephrine (pD2 at α1 = 6.32). Brown and co-workers examined the effects of the individual enantiomers of synephrine on α1 receptors in rat
aorta The aorta ( ) is the main and largest artery in the human body, originating from the left ventricle of the heart and extending down to the abdomen, where it splits into two smaller arteries (the common iliac arteries). The aorta distributes o ...
, and on α2 receptors in rabbit saphenous vein. In the aorta preparation, l-synephrine gave a pD2 = 5.38 (potency relative to norepinephrine = 1/1000), while d-synephrine had a pD2 = 3.50 (potency relative to norepinephrine = 1/50000); in comparison, l-phenylephrine had pD2 = 7.50 (potency relative to norepinephrine ≃ 1/6). No antagonism of norepinephrine was produced by concentrations of l-synephrine up to 10−6 M. In the rabbit saphenous assay, the pD2 of l-synephrine was 4.36 (potency relative to norepinephrine ≃ 1/1700), and that of d-synephrine was < 3.00; in comparison, l-phenylephrine had pD2 = 5.45 (potency relative to norepinephrine ≃ 1/140). No antagonism of norepinephrine was produced by concentrations of l-synephrine up to 10−5 M. A study of the effects of synephrine (stereochemistry unspecified) on strips of guinea pig aorta and on the field-stimulated guinea pig
ileum The ileum () is the final section of the small intestine in most higher vertebrates, including mammals, reptiles, and birds. In fish, the divisions of the small intestine are not as clear and the terms posterior intestine or distal intestine m ...
showed that synephrine had an agonist potency of −logKa = 3.75 in the aorta assay. In comparison, epinephrine had a potency of −logKa = 5.70. There was no significant effect on the ileum at synephrine concentrations up to about 2 × 10−4 M, indicating selectivity for the α1 receptor, but relatively low potency. In binding experiments with central adrenergic receptors, using a preparation from rat cerebral cortex, l-synephrine had pIC50 = 3.35, and d-synephrine had pIC50 = 2.42 in competition against sup>3H
prazosin Prazosin is an α1 blocker medication primarily used to treat high blood pressure, symptoms of an enlarged prostate, and nightmares related to post-traumatic stress disorder (PTSD). It is a less preferred treatment of high blood pressure. Oth ...
(standard α1 ligand); against sup>3H
yohimbine Yohimbine (), also known as quebrachine, is an indole alkaloid derived from the bark of the African tree '' Pausinystalia johimbe''; also from the bark of the unrelated South American tree ''Aspidosperma quebracho-blanco''. Yohimbine is an α2 ...
(standard α2 ligand), l-synephrine showed a pIC50 = 5.01, and d-synephrine showed a pIC50 = 4.17. Experiments conducted by Hibino and co-workers also showed that synephrine (stereochemistry unspecified) produced a dose-dependent constriction of isolated rat aorta strips, in the concentration range 10−5–3 × 10−6 M. This constriction was found to be competitively antagonized by prazosin (a standard α1 antagonist) and
ketanserin Ketanserin ( INN, USAN, BAN) (brand name Sufrexal; former developmental code name R41468) is a drug used clinically as an antihypertensive agent and in scientific research to study the serotonin system; specifically, the 5-HT2 receptor family. I ...
, with prazosin being the more potent antagonist (pA2 = 9.38, vs pA2 = 8.23 for ketanserin). Synephrine constrictions were also antagonized by BRL-15,572, but not by
SB-216,641 SB-216641 is a drug which is a selective antagonist for the serotonin receptor 5-HT1B, with around 25x selectivity over the closely related 5-HT1D receptor. It is used in scientific research, and has demonstrated anxiolytic An anxiolyti ...
(used here as a selective 5-HT1B antagonist), or by
propranolol Propranolol, sold under the brand name Inderal among others, is a medication of the beta blocker class. It is used to treat high blood pressure, a number of types of irregular heart rate, thyrotoxicosis, capillary hemangiomas, performance an ...
(a common β antagonist). In studies on guinea pig atria and
trachea The trachea, also known as the windpipe, is a Cartilage, cartilaginous tube that connects the larynx to the bronchi of the lungs, allowing the passage of air, and so is present in almost all air-breathing animals with lungs. The trachea extends ...
, Jordan and co-workers also found that synephrine had negligible activity on β1 and β2 receptors, being about 40000x less potent than norepinephrine. Experiments with cultured white fat cells from several animal species, including human, by Carpéné and co-workers showed that racemic synephrine produced
lipolytic 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 ...
effects, but only at high concentrations (0.1-1 mM). The potency, expressed in terms of pD2 of synephrine in these species was as follows: rat: 4.38; hamster: 5.32; guinea pig: 4.31; human: 4.94. In comparison,
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 ...
had a pD2 = 8.29 and norepinephrine had pD2 = 6.80 in human white fat cells. The lipolytic effect of 1 mM/L of synephrine on rat white fat cells was antagonized by various β-antagonists with the following inhibitory concentrations (IC50): bupranolol: 0.11 μM; CGP-20,712A (β1 antagonist): 6.09 μM; ICI-118,551 (β2 antagonist): 3.58 μM; SR-5923A (β3 antagonist): 17 μM. The binding of racemic synephrine to cloned human adrenergic receptors has been examined: Ma and co-workers found that synephrine bound to α1A, α2A and α2C with low affinity (pKi = 4.11 for α1A; 4.44 for α2A; 4.61 for α2C). Synephrine behaved as a
partial agonist In pharmacology, partial agonists are drugs that bind to and activate a given receptor, but have only partial efficacy at the receptor relative to a full agonist. They may also be considered ligands which display both agonistic and antagonis ...
at α1A receptors, but as an antagonist at α2A and α2C sub-types. Racemic synephrine has been shown to be an
agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the ago ...
of the
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 ...
, although its potency at the human TAAR1 is relatively low (EC50 = 23700 nM; Emax = 81.2%).


Pharmacokinetics

The pharmacokinetics of synephrine were studied by Hengstmann and Aulepp, who reported a peak plasma concentration at 1–2 hours, with an elimination half-life (T1/2) of ~ 2 hours.


Metabolism

Studies of the metabolism of synephrine by monoamine oxidases derived from rat brain
mitochondria A mitochondrion (; ) is an organelle found in the Cell (biology), cells of most Eukaryotes, such as animals, plants and Fungus, fungi. Mitochondria have a double lipid bilayer, membrane structure and use aerobic respiration to generate adenosi ...
showed that synephrine was a substrate for
deamination Deamination is the removal of an amino group from a molecule. Enzymes that catalyse this reaction are called deaminases. In the human body, deamination takes place primarily in the liver, however it can also occur in the kidney. In situations of ...
by both
MAO-A Monoamine oxidase A, also known as MAO-A, is an enzyme that in humans is encoded by the ''MAOA'' gene. This gene is one of two neighboring gene family members that encode mitochondrial enzymes which catalyze the oxidative deamination of amines, s ...
and
MAO-B Monoamine oxidase B, also known as MAOB, is an enzyme that in humans is encoded by the ''MAOB'' gene. The protein encoded by this gene belongs to the flavin monoamine oxidase family. It is an enzyme located in the outer mitochondrial membrane. I ...
, with Km = 250 μM and Vmax = 32.6 nM/mg protein/30 minutes; there was some evidence for preferential deamination by MAO-A.


Effects in humans

A number of studies of the effects of synephrine in humans, most of them focusing on its cardiovascular properties, have been performed since its introduction as a synthetic drug around 1930. The paper by Stockton and co-workers is representative, describing the effects of racemic synephrine in humans with particular attention to differences resulting from different routes of administration. Thus, it was shown by these investigators that ''intramuscular'' injections (average effective dose = 200 mg) of the drug produced an increase in systolic blood pressure and pulse rate, without affecting the
diastolic Diastole ( ) is the relaxed phase of the cardiac cycle when the chambers of the heart are re-filling with blood. The contrasting phase is systole when the heart chambers are contracting. Atrial diastole is the relaxing of the atria, and ventricu ...
pressure. The blood pressure increase reached a maximum (~25 mmHg) in 5 minutes following the injection, then gradually returned to normal over the course of 1 hour. Doses of drug greater than 200 mg caused side-effects such as heart palpitations, headache, sweating, and feelings of apprehension. When given ''intravenously'', doses of 25–50 mg sufficed to produce a mean maximum increase in the blood pressure of 29 mmHg in 2 minutes, and a return to baseline within 30 minutes. Respiration was generally not affected during these experiments. ''Subcutaneous'' administration of synephrine in doses ≤ 200 mg had no effects on blood pressure or pulse rate. ''Oral'' doses of 500–1500 mg of the drug did not affect blood pressure or respiration, but pulse rate was increased by ~12%, and the highest doses caused nausea and vomiting. The i.m. administration of 75–500 mg of synephrine did not relieve acute
asthma Asthma is a long-term inflammatory disease of the airways of the lungs. It is characterized by variable and recurring symptoms, reversible airflow obstruction, and easily triggered bronchospasms. Symptoms include episodes of wheezing, cou ...
attacks, contradicting an earlier claim. However, the topical application of 1–3% solutions of the drug to the
nasal mucosa The nasal mucosa lines the nasal cavity. It is part of the respiratory mucosa, the mucous membrane lining the respiratory tract. The nasal mucosa is intimately adherent to the periosteum or perichondrium of the nasal conchae. It is continuous w ...
of patients with
sinusitis Sinusitis, also known as rhinosinusitis, is inflammation of the mucous membranes that line the sinuses resulting in symptoms that may include thick nasal mucus, a plugged nose, and facial pain. Other signs and symptoms may include fever, head ...
did produce a beneficial constriction without local irritation. A more recent study showed that the administration of synephrine by continuous intravenous infusion, at the rate of 4 mg/minute, significantly increased mean arterial and systolic pressure, but
diastolic Diastole ( ) is the relaxed phase of the cardiac cycle when the chambers of the heart are re-filling with blood. The contrasting phase is systole when the heart chambers are contracting. Atrial diastole is the relaxing of the atria, and ventricu ...
pressure and heart rate were unaltered.; further details of this investigation are summarized in a review by Fugh-Berman and Myers. There are a number of studies, references to many of which may be found in the review by Stohs and co-workers dealing with the effects produced by dietary supplements and herbal medications that contain synephrine as only one of many different chemical ingredients. These are outside the scope of the present article (see also the " Safety/Efficacy/Controversy" sub-section).


Toxicology

The acute toxicities of racemic synephrine in different animals, reported in terms of "maximum tolerated dose" after s.c administration, were as follows: mouse: 300 mg/kg; rat: 400 mg/kg; guinea pig: 400 mg/kg. "Lethal doses", given s.c., were found to be: mouse: 400 mg/kg; rat: 500 mg/kg; guinea pig: 500 mg/kg. Another study of this compound, administered i.v. in mice, gave an LD50 = 270 mg/kg. The "subchronic toxicity" of synephrine was judged to be low in mice, after administration of oral doses of 30 and 300 mg/kg over a period of 28 days, in a recent study employing modern methodology carried out by Arbo and co-workers. Generally, this treatment did not result in significant alterations in biochemical or hematological parameters, nor in relative organ weights, but some changes were noted in
glutathione Glutathione (GSH, ) is an antioxidant in plants, animals, fungi, and some bacteria and archaea. Glutathione is capable of preventing damage to important cellular components caused by sources such as reactive oxygen species, free radicals, pe ...
(GSH) concentration, and in the activity of
glutathione peroxidase Glutathione peroxidase (GPx) () is the general name of an enzyme family with peroxidase activity whose main biological role is to protect the organism from oxidative damage. The biochemical function of glutathione peroxidase is to reduce lipid h ...
(GPx).


Safety/efficacy/controversy

There exists considerable controversy about the safety and/or efficacy of ''synephrine-containing preparations'', which are often confused with synephrine alone, sometimes with ''m''-synephrine. Furthermore, this body of literature deals with mixtures containing synephrine as only one of several biologically-active components, even, in some cases, without explicit confirmation of the presence of synephrine.


Invertebrates

In insects, synephrine has been found to be a very potent agonist at many invertebrate
octopamine Octopamine (molecular formula C8H11NO2; also known as OA, and also norsynephrine, ''para''-octopamine and others) is an organic chemical closely related to norepinephrine, and synthesized biologically by a homologous pathway. Octopamine is ofte ...
receptor preparations, and is even more potent than octopamine at a
locust Locusts (derived from the Vulgar Latin ''locusta'', meaning grasshopper) are various species of short-horned grasshoppers in the family Acrididae that have a swarming phase. These insects are usually solitary, but under certain circumstanc ...
(''
Schistocerca ''Schistocerca'' is a genus of grasshoppers, commonly called bird grasshoppers, many of which swarm as locusts. The best known species is probably the desert locust (''S. gregaria'') and trans-Atlantic flight may explain the biogeography of some ...
americana gregaria'') nerve-muscle preparation. Synephrine (racemic) is also more potent than octopamine (racemic) at inducing light-emission in the firefly (''
Photinus Photinus (Greek Φωτεινός; died 376), was a Christian bishop of Sirmium in Pannonia Secunda (today the town Sremska Mitrovica in Serbia), best known for denying the incarnation of Christ, thus being considered a heresiarch by the Catholic C ...
'' species) light organ. Synephrine exhibits similarly high potency in stimulating
adenylate cyclase Adenylate cyclase (EC 4.6.1.1, also commonly known as adenyl cyclase and adenylyl cyclase, abbreviated AC) is an enzyme with systematic name ATP diphosphate-lyase (cyclizing; 3′,5′-cyclic-AMP-forming). It catalyzes the following reaction: :A ...
activity and in decreasing clotting time in
lobster Lobsters are a family (biology), family (Nephropidae, Synonym (taxonomy), synonym Homaridae) of marine crustaceans. They have long bodies with muscular tails and live in crevices or burrows on the sea floor. Three of their five pairs of legs ...
(''
Homarus americanus The American lobster (''Homarus americanus'') is a species of lobster found on the Atlantic coast of North America, chiefly from Labrador to New Jersey. It is also known as Atlantic lobster, Canadian lobster, true lobster, northern lobster, Cana ...
'') hematocytes. Racemic synephrine was found to increase
cAMP Camp may refer to: Outdoor accommodation and recreation * Campsite or campground, a recreational outdoor sleeping and eating site * a temporary settlement for nomads * Camp, a term used in New England, Northern Ontario and New Brunswick to descri ...
in the abdominal epidermis of the blood-sucking bug, ''
Rhodnius prolixus ''Rhodnius prolixus'' is the principal triatomine vector of the Chagas parasite due to both its sylvatic and domestic populations in northern South America as well as to its exclusively domestic populations in Central America. It has a wide ran ...
''. Rachinsky reported that synephrine was equipotent with octopamine in stimulating JH (
juvenile hormone Juvenile hormones (JHs) are a group of acyclic sesquiterpenoids that regulate many aspects of insect physiology. The first discovery of a JH was by Vincent Wigglesworth. JHs regulate development, reproduction, diapause, and polyphenisms.The chem ...
) release in the
corpora allata In insect physiology and anatomy, the corpus allatum (plural: corpora allata) is an endocrine gland that generates juvenile hormone; as such, it plays a crucial role in metamorphosis. Surgical removal of the corpora allata (an allatectomy) can cau ...
of
honey bee A honey bee (also spelled honeybee) is a eusocial flying insect within the genus ''Apis'' of the bee clade, all native to Afro-Eurasia. After bees spread naturally throughout Africa and Eurasia, humans became responsible for the current co ...
(''
Apis mellifera The western honey bee or European honey bee (''Apis mellifera'') is the most common of the 7–12 species of honey bees worldwide. The genus name ''Apis'' is Latin for "bee", and ''mellifera'' is the Latin for "honey-bearing" or "honey carrying", ...
''), but Woodring and Hoffmann found that synephrine had no effect on the synthesis of JH III, in ''in vitro'' preparations from the cricket, ''
Gryllus bimaculatus ''Gryllus bimaculatus'' is a species of cricket in the subfamily Gryllinae. Most commonly known as the two-spotted cricket, it has also been called the "African" or "Mediterranean field cricket", although its recorded distribution also includes ...
''.


Footnotes


See also

* Halostachine * Deterenol *
Octopamine Octopamine (molecular formula C8H11NO2; also known as OA, and also norsynephrine, ''para''-octopamine and others) is an organic chemical closely related to norepinephrine, and synthesized biologically by a homologous pathway. Octopamine is ofte ...


References

{{Phenethylamines Phenethylamines Alpha-1 adrenergic receptor agonists Alkaloids found in Rutaceae Human metabolites Phenols Phenylethanolamines TAAR1 agonists Trace amines